Objective To screen the antimalarial compounds of daphnetin derivatives against Plasmodium falciparum in vitro. Method Plasmodium faciparum （FCC1） was cultured in vitro by a modified method of Trager and Jensen. Ant...Objective To screen the antimalarial compounds of daphnetin derivatives against Plasmodium falciparum in vitro. Method Plasmodium faciparum （FCC1） was cultured in vitro by a modified method of Trager and Jensen. Antimalarial compounds were screened by microscopy-based assay and microfluorimetric method. Results DA79 and DA78 showed potent antimalarial activity against Plasmodiumfalciparum cultured in vitro. Conclusion Though the relationship between the structures of daphnetin derivatives and their antimalarial activities has not been clarified yet, this study may provide a new direction for discovery of more potential antimalarial compounds.展开更多
Present research on the antimalarial mechanisms of artemisinin(ART)is mainly focused on covalent drug binding targets alkylated by free radicals,while non-covalent binding targets have rarely been reported.Here,we dev...Present research on the antimalarial mechanisms of artemisinin(ART)is mainly focused on covalent drug binding targets alkylated by free radicals,while non-covalent binding targets have rarely been reported.Here,we developed a novel photoaffinity probe of ART to globally capture and identify the antimalarial target proteins of ART through chemical proteomics.The results demonstrated that ART can bind to par-asite proteins by both covalent and non-covalent modification,and these may jointly contribute to the antimalarial effects.Our work enriches the research on the antimalarial targets of ART,and provides a new perspective for further exploring the antimalarial mechanism of ART.展开更多
Objective:To investigate the antimalarial activity and toxicity of the crude ethanolic extract of its pericarp both in vitro and in vim.Methods:The antimalarial activity of Gareinja mangostana(G.mangostana)Linn.extrac...Objective:To investigate the antimalarial activity and toxicity of the crude ethanolic extract of its pericarp both in vitro and in vim.Methods:The antimalarial activity of Gareinja mangostana(G.mangostana)Linn.extract against 3D7 and Kl Plasmodium falciparum(P.falciparum)clone were assessed using SYBR green I-based assay.A 4-day suppressive test of Plasmodium berghei{P.berghei)infected mouse was performed to investigate in vivo antimalarial activity.Results:The in vitro antimalarial activity was seleclive(SI>5?and classified as weak and good lo moderate activity against both 3D7 and K1 P.falciparum,clones with median IC_(50)(range)values of 11.12(10.94-11.29)and 7.54(6.80-7.68)μg/mL,respectively.The extract was considered nontoxic to mice.The maximum tolerated doses for acute and subacute toxicity in mice were 5 000and 2 000 mg/kg,respectively.Median(range)parasite density on day 4 of the negative control group(25%Tween-80),mice treated with 250,500,1000,and 2 000 mg/kg body weight of the extract,and 10 mg/kg body weight of chloroquine for 14 d were 12.8(12.2-13.7),11.4(9.49-13.8),11.6(9.9-12.5),11.7(10.6-12.8),10.9(9.4-11.6)and 0(0-0)%respectively.Parasite density on day 4in the control group treated with Tween-80 was higher than the groups treated with chloroquine and all dose levels of the extract.Conclusions:G.mangostana linn,showed weak antimalarial activity of the extract both in vitro and in vivo could be due to limitation of absorption of the active compounds.展开更多
A series of 5-substituted-3-[{5-（6-methyl-2-oxo/thioxo-4-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl）-1,3,4-oxadiazol-2-yl}-imino] -1,3-dihydro-2H-indol-2-one were synthesized,characterized and screened for their anti-t...A series of 5-substituted-3-[{5-（6-methyl-2-oxo/thioxo-4-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl）-1,3,4-oxadiazol-2-yl}-imino] -1,3-dihydro-2H-indol-2-one were synthesized,characterized and screened for their anti-tubercular and antimalarial activity.展开更多
Objective:To investigate the antileishinanial,antimicrobial and antimalarial activities of the pure metabolites from Jatropha multifida used in African ethnomedicine.Methods:The methanolic stem bark extract of Jatroph...Objective:To investigate the antileishinanial,antimicrobial and antimalarial activities of the pure metabolites from Jatropha multifida used in African ethnomedicine.Methods:The methanolic stem bark extract of Jatropha multifida used in Nigerian folk medicine as remedy against bacterial infections was subjected to column chromatography and HPLC analyses lo obtain three known metabolites,microcyclic lathyrane dilerpenoids(1-3).Structures were confirmed by comparison of 1D and 2D spectral data with literature.Results:The three compounds exhibited inhibition of antileishmanial,antimalarial and antimicrobial actions against the tested organisms with compouds 2 and 3 active against Cryptococcus neoformans at IC_(50)of 82 and 8.7 μg/ml,respectively.Conclusions:The research lends support to the ethnomedicinal use of the plant in combating microbial infections,leishmaniasis and malarial infections.展开更多
Objective: To document plants used in traditional treatment of malaria in the Awash-Fentale District, the Afar Region of Ethiopia, and to evaluate antimalarial activity of selected ones against Plasmodium berghei in m...Objective: To document plants used in traditional treatment of malaria in the Awash-Fentale District, the Afar Region of Ethiopia, and to evaluate antimalarial activity of selected ones against Plasmodium berghei in mice. Methods: Semi-structured interviews were carried out with purposively selected informants in the District to gather information on plants used in the traditional treatment of malaria. Standard procedures were used to investigate acute toxicity and a four-day suppressive effect of crude aqueous and ethanol extracts of the leaves of the two most frequently cited plants [Aloe trichosantha(A. trichosantha) and Cadaba rotundifolia(C. rotundifolia)] against Plasmodium berghei in Swiss albino mice. Results: The informants cited a total of 17 plants used in the traditional treatment of malaria in Awash-Fentale District. Plant parts were prepared as infusions or decoctions. Leaf was the most commonly cited(44%) plant part, followed by stem(22%). Shrubs were the most frequently cited(63%) medicine source followed by trees(21%). Of the 17 plants, C. rotundifolia and A. trichosantha were the most frequently mentioned plants in the district. Ethanol extracts of the leaves of C. rotundifolia and A. trichosantha suppressed P. berghei parasitaemia significantly accounting for 53.73% and 49.07%, respectively at 900 mg/kg. The plants were found to be non-toxic up to a dose of 1 500 mg/kg. Conclusions: Seventeen plant species were reported to be used for treatment of malaria in the Awash Fentale Distinct, among which A. trichosantha and C. rotundifolia were the most preferred ones. P. berghei suppressive activity of these plants may partly explain their common use in the community.展开更多
Objective:To evaluate the antimalarial activity of the aqueous extract of Euphorbia(E.)cordifolia Elliot against Plasmodium(P.)berghei-infected mice.Methods:Thirty healthy Swiss mice were intraperitoneally inoculated ...Objective:To evaluate the antimalarial activity of the aqueous extract of Euphorbia(E.)cordifolia Elliot against Plasmodium(P.)berghei-infected mice.Methods:Thirty healthy Swiss mice were intraperitoneally inoculated with 200μL of P.berghei parasitized-erythrocytes and divided into five groups,and then daily treated for 5 d with single dose of 10 mL/kg of distilled water for malaria control,10 mg/kg of chloroquine for the chloroquine control and 100,200 and 400 mg/kg of the aqueous extract of E.cordifolia for the three test groups.Parasitaemia was monitored by Giemsa-staining.At the end of the treatment,animals were sacrificed,and blood was collected for haematological and biochemical analyses.Organs were collected for biochemical and histopathological analyses.Statistical significance(P<0.05)was evaluated by analysis of variance followed by the Tukey post-test using Graphpad prism 7.0.Results:E.cordifolia extract decreased the parasite load to 2.46%,with an effective dose(ED50)of 113.07 mg/kg compared to the malaria group where the parasite load increased to(46.46±10.28)%.E.cordifolia extract prevented hypoglycaemia,anaemia,leucocytosis and thrombocytopenia,attenuated the increase of transaminases activities,bilirubin and creatinine rate,and improved catalase and superoxide dismutase activities,while reducing malondialdehyde contents in the liver and kidney.E.cordifolia extract significantly prevented histological damages observed in the malaria control group.No acute toxicity sign was observed in mice with plant extract at the dose up to 5000 mg/kg.Conclusions:E.cordifolia extract at 200 and 400 mg/kg showed significant antimalarial effects.This results support its traditional use in the treatment of malaria.展开更多
Malaria is one of the most devastating infectious diseases that caused millions of clinical cases annually despite decades of prevention efforts. Recent cases of Plasmodium falciparum resistance against the only remai...Malaria is one of the most devastating infectious diseases that caused millions of clinical cases annually despite decades of prevention efforts. Recent cases of Plasmodium falciparum resistance against the only remaining class of effective antimalarial(artemisinin) in South East Asia may soon pose a significant threat. Hence, the identification of new antimalarial compounds with a novel mode of action is necessary to curb this problem. Protein kinase has been implicated as a valid target for drug development in diseases such as cancer and diabetes in humans. A similar approach is now recognized for the treatment of protozoan-related disease including malaria. Few Plasmodium protein kinases that are not only crucial for their survival but also have unique structural features have been identified as a potential target for drug development. In this review, studies on antimalarial drug development exploiting the size of Plasmodium protein kinase ATP gatekeeper over the past 15 years are mainly discussed. The ATP-binding site of Plasmodium protein kinases such as Pf CDPK1, Pf CDPK4, Pf PKG, Pf PK7, and Pf PI4K showed great potential for selective and multi-target inhibitions owing to their smaller or unique ATP-gatekeeper amino acid subunits compared to that of human protein kinase. Hence it is a feasible solution to identify a new class of active antimalarial agents with a novel mode of action and longer clinical life-span.展开更多
One previously undescribed angeloylated noreudesmane sesquiterpenoid,dobinin O(1),along with four known eudesmane sesquiterpenoids(2-5)were isolated from the peeled roots of Dobinea delavayi.Their structures were eluc...One previously undescribed angeloylated noreudesmane sesquiterpenoid,dobinin O(1),along with four known eudesmane sesquiterpenoids(2-5)were isolated from the peeled roots of Dobinea delavayi.Their structures were elucidated by extensive spectroscopic data analyses.In addition,compound 1 exhibited moderate antimalarial activity against Plasmodium yoelii BY265RFP with the inhibition ratio of 17.8±13.3%at the dose of 30 mg/kg/day.展开更多
Objective Sulfanilamide,sulfadiazine,and dapsone were the first sulfonamides to be used to treat malaria by disrupting the folate biosynthesis process,which is essential for parasite survival.Therefore,we aimed to syn...Objective Sulfanilamide,sulfadiazine,and dapsone were the first sulfonamides to be used to treat malaria by disrupting the folate biosynthesis process,which is essential for parasite survival.Therefore,we aimed to synthesize novel N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives through a rational drug design approach.Methods All compounds were synthesized by the conventional method,and the products were characterized by spectral analysis(1 H NMR and mass spectrometry).The progression of the reaction was monitored using thin-layer chromatography(TLC).All the derivatives were analyzed for their effective binding mode in the allosteric site of the plasmodium cysteine protease falcipain-2.Antibacterial and antifungal activities were determined using the broth dilution method.Results S6(N-(2-thiazol-4 yl)-acetyl-aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide and S9(N-(1 H-benzo[d]imidazol-2-yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide formed five hydrogen bonds;S8(N-(2-1 H-imidazol-2 yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide and S10(N-(1 H-benzo[d]imidazol-5-yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide formed four hydrogen bonds with the allosteric site of the enzyme.Considering the docking scores and formation of hydrogen bonds with the target enzyme,the novel derivatives were processed for wet lab synthesis.All the newly synthesized derivatives were subjected to in vitro antimalarial,antifungal,and antibacterial activities.All the derivatives exhibited sufficient sensitivity to the Plasmodium falciparum strain compared to the standards.Moreover,compounds S9 and S10 showed the most potent dual antimicrobial and antimalarial activities.They also exhibited powerful molecular interactions in molecular docking studies.Conclusion Based on the above results,it was concluded that N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives have excellent biological potential to act as antimalarial,antifungal,and antibacterial agents.展开更多
Following highly prevalent Plasmodium resistant strains to antimalarial monotherapies in malaria endemic countries, uncomplicated malaria treatment policy changed to artemisinine-based combination therapies (ACTs). Af...Following highly prevalent Plasmodium resistant strains to antimalarial monotherapies in malaria endemic countries, uncomplicated malaria treatment policy changed to artemisinine-based combination therapies (ACTs). After adoption of this new treatment policy in a country, sufficient care is needed to be taken to prevent occurrence of resistance to the latest drugs. As Cameroon shifted to ACT in 2004, this study aimed to assess knowledge and practices of health workers in government health facilities of the Littoral region regarding mild malaria management in health facilities as well as according to prescription qualities of ACTs in leaflets received in pharmacies. A total of 66 physicians and 16 nurses were questioned in 10 health facilities and 503 medical leaflets with ACTs prescriptions were viewed in 17 pharmacies. All medical workers questioned correctly were defined mild malaria and were aware of the antimalarial policy change in Cameroon. Overall ACTs prescription for mild malaria management in children and adult patients was 72.2% and 87.8% respectively. An important proportion of health workers prescribed antimalarial monotherapies and non recommended antimalarial for uncomplicated malaria treatment. 31.7% of participants did not systematically recommend laboratory diagnostic test before antimalarial prescription. Of leaflets viewed in pharmacies, ACTs were prescribed by physicians, nurses and laboratory technicians. Age was the only criteria for ACTs prescription. Appropriate ACTs quality prescription ranged between 81.2% and 94.4%. Of the ACTs prescribed, blisters had the highest (92.9%) appropriate quality prescription and solutions the lowest (83.3%). According to qualification of prescribers, physicians had the highest score (93.1%) of appropriate quality prescription and laboratory technicians the lowest score (28.1%). For all ACTs containing medical leaflets, concomitant medications were recorded namely antipyretic (73.9%), antibiotic (21.9%), non steroid anti-inflammatory (19.9%) or vitamins (18.1%). Data gathered indicated that although health workers were aware of uncomplicated malaria treatment policy change in Cameroon, mild malaria mismanagement was prevailing in health facilities of the Littoral region and ACTs quality prescription in medical leaflets was not optimal. Therefore, awareness is still needed among prescribers in order to prevent or at least slow the occurrence of Plasmodium resistant strains to ACTs in Cameroon.展开更多
Malaria is a real public health problem. It’s one of the pathologies that mobilize the scientific community. Resistance to existing treatments is the basis for the search for new treatments. Some molecules such as Ma...Malaria is a real public health problem. It’s one of the pathologies that mobilize the scientific community. Resistance to existing treatments is the basis for the search for new treatments. Some molecules such as Manzamenones have shown important antimalarial properties. These molecules belong to the family of atypical fatty acid derivatives. This work presents the relative stabilities, some reactivity properties and the privileged sites of interaction by hydrogen bond of fourteen Manzamenones and two antimalarial drugs: quinine and Artemisinin. These analyses were performed using quantum chemical calculations. We employed the two-layer ONIOM calculation method;namely ONIOM (B3LYP/6-311++G (d, p): AM1) for the fourteen Manzamenones. The geometries of the two antimalarials are calculated at B3LYP/6-311++G (d, p). The electrostatic potential (ESP) calculation of all molecules is done at the B3LYP/6-31++G (d, p) level. The formation processes of the molecules are discussed from the thermodynamic quantities we have calculated. The relative stabilities, the energies of the frontier orbitals, the energy gaps, the dipole moment, etc., are evaluated and discussed. The electrostatic potential at the molecular surface has been used to identify the sites favorable to the formation of hydrogen bonds.展开更多
Objective: To evaluate the antimalarial activity of the ethylacetate and butanol fractions of Combretum nigricans(C. nigricans) leaf extract in mice. Methods: C. nigricans solvent(butanol and ethylacetate) fractions w...Objective: To evaluate the antimalarial activity of the ethylacetate and butanol fractions of Combretum nigricans(C. nigricans) leaf extract in mice. Methods: C. nigricans solvent(butanol and ethylacetate) fractions were screened for their phytochemical constituents using standard procedures illustrated by Harborne and Evans. The Peters' 4-day suppressive test against early malaria infection, Rane's curative test against established malaria and prophylactic test for residual activity were employed for evaluating the antimalarial potential in mice. Results: The phytochemical screening revealed the presence of alkaloids, terpenoids, saponins, and flavonoids in both fractions at different intensity. Both fractions exhibited significant antimalarial activity in all test models(P<0.05). The ethylacetate fraction of C. nigricans had better chemosuppressive and curative effects compared to the butanol fraction, which however, elicited a better chemoprophylactic effect. The chemosuppressive effect of C. nigricans ethylacetate fraction(200-800 mg/kg) was 77.6%, 69.1% and 86.1%; curative effect was 62.3%, 71.3% and 72.4%; while the chemoprophylactic activity was 32.1%, 48.6% and 61.2% respectively. C. nigricans butanol fraction(200-800 mg/kg) had 40.3%, 54.1% and 69.1% chemosuppression; 26.2%, 36.9% and 34.5% curative effect; and 48.4%, 70.0% and 87.4% chemoprophylaxis. Conclusions: Both solvent fractions of C. nigricans possess antimalarial activity, and may be useful at different stages of malaria therapy.展开更多
Cancer is a leading cause of death globally, while malaria is the leading cause of death from parasitic diseases in Nigeria. Historically, plant remedies have been used to manage both cancer and malaria.Interestingly,...Cancer is a leading cause of death globally, while malaria is the leading cause of death from parasitic diseases in Nigeria. Historically, plant remedies have been used to manage both cancer and malaria.Interestingly, the possibility of treating cancer with antimalarial remedies has long been reported, even though the two diseases appear to have little in common. However, a body of research has indicated the potential anticancer activity of both synthetic and nature-derived antimalarials. In Nigeria, over 100 plants are used for the management of malaria, but little is known for their potential role in combatting cancer. Therefore, this review is to highlight the documented anticancer activities of plants used to treat malaria in Nigeria, with the goal of supporting anticancer drug discovery. Scientific databases were used to search for antimalarial plants using selected keywords. Of over 100 plants used to treat malaria in Nigeria, 56 have documented anticancer properties, containing alkaloids, flavonoids, tannins, terpenes,terpenoids, quinones, anthraquinones, saponins, steroids, sterols, organosulfur compounds and other polyphenols as the major bioactive components. The major mechanisms of anticancer activity include induction of apoptosis and autophagy, arrest of cell growth, generation of reactive oxygen species and inhibition of angiogenesis. However, mechanistic and clinical investigations of the anticancer properties of most of these plants are still lacking. Notwithstanding, the huge anticancer potential uncovered by the in vitro or in vivo studies and a few clinical studies, Nigerian antimalarial plants may provide a valuable resource, ready to be harnessed for anticancer drug development.展开更多
Objective:To determine the suppressive and curative activity of aqueous leaf extract of Ageratum conyzoides(A.conyzoides) in combination with chloroquine and artesunate, respectively against Plasmodium berghei infecti...Objective:To determine the suppressive and curative activity of aqueous leaf extract of Ageratum conyzoides(A.conyzoides) in combination with chloroquine and artesunate, respectively against Plasmodium berghei infection in mice.Methods:Using malaria(Plasmodium berghei) infected albino mice of both sexes,aqueous extracts of A.conyzoides in combination with chloroquine and artesunate were tested for antimalarial activity,respectively.Four-day suppressive test and Rane’s curative test were carried out.Results:Suppressive tests showed significant dose dependent reduction in parasitemia level produced by the extract-chloroquine and extract-artesunate combinations.Suppressive activities of both extract-drug combinations were greater than the individual drugs alone.Extract-chloroquine(100:5) produced the highest suppressive effect(98%suppression).Curative tests showed absolute survival in two extract-drug combinations.Two extract-drug combinations produced higher curative effects than the individual drugs alone.The highest dose combinations of extract-chloroquine(100:5) and extract-artesunate(100:5) produced absolute parasitemia clearance(cure) in the infected mice. Conclusions:The study indicated that aqueous extract of A.conyzoides had the ability to potentiate the antimalarial activity of chloroquine and artesunate against induced plasmodiasis in mice.It contributes a lot in the malaria endemic and poverty stricken tropics.展开更多
Resistance to malaria parasites has quickly developed to almost all used antimalarial drugs. Cysteine protease falcipain-2(FP-2) and Plasmodium falciparum dihydrofolate reductase(PfDHFR) have crucial roles, which are ...Resistance to malaria parasites has quickly developed to almost all used antimalarial drugs. Cysteine protease falcipain-2(FP-2) and Plasmodium falciparum dihydrofolate reductase(PfDHFR) have crucial roles, which are absolutely necessary, in the parasite life cycle. In this study, based on the uniform pharmacophores of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the identification of 14, which showed potent inhibition against FP-2 and PfDHFR enzyme(IC_(50)= 6.8 + 1.8 mmol/L and IC_(50)= 8.8 + 0.3 mmol/L) and P. falciparum 3D7 strain(IC50= 2.9mmol/L).Additionally, 14 exhibited more potent inhibition to the proliferation of chloroquine-resistant P.falciparum Dd2 strain(IC_(50)= 1.1 mmol/L) than pyrimethamine(IC_(50)>10 mmol/L), and 14 displayed micromolar inhibitory activities against two clinical isolated strains Fab9(IC_(50)= 2.6 mmol/L) and GB4(IC_(50)= 1.0 mmol/L). Collectively, these data demonstrated that 14 might be a good lead compound for the treatment of malaria.展开更多
Objective: To determine ex vivo antimalarial activity and cytotoxicity of endophytic Streptomyces SUK 08 as well as the main core structure fractionated from its crude extract.Methods: The activities of SUK 08 crude e...Objective: To determine ex vivo antimalarial activity and cytotoxicity of endophytic Streptomyces SUK 08 as well as the main core structure fractionated from its crude extract.Methods: The activities of SUK 08 crude extract were evaluated by using the Plasmodium lactate dehydrogenase assay and synchronization test against rodent malaria parasite Plasmodium berghei, instead of human malarial parasite Plasmodium falciparum. The cytotoxicity of the crude extract was determined by MTT assay. The crude extract was analyzed by thin-layer chromatography and gas chromatography–mass spectrophotometry.Results: The ethyl acetate crude extract showed very promising antimalarial activity with IC50 of 1.25 mg/m L. The synchronization tests showed that ethyl acetate extraction could inhibit all stages of the Plasmodium life cycle, but it was most effective at the Plasmodium ring stage. On the basis of a MTT assay on Chang Liver cells, ethyl acetate and ethanol demonstrated IC50 values of >1.0 mg/m L. The IC50 of parasitemia at 5% and30% for this extract was lower than chloroquine. Thin-layer chromatography, with 1: 9 ratio of ethyl acetate: hexane, was used to isolate several distinct compounds. Based on gas chromatography–mass spectrophotometry analysis, three core structures were identified as cyclohexane, butyl propyl ester, and 2,3-heptanedione. Structurally, these compounds were similar to currently available antimalarial drugs.Conclusions: The results suggest that compounds isolated from Streptomyces SUK 08 are viable antimalarial drug candidates that require further investigations.展开更多
Malaria is a parasitic disease which has as etiological agents protozoa of the genus Plasmodium prevalent in tropical countries. The appearance of Plasmodium strains resistant to artemisinin has become necessary the d...Malaria is a parasitic disease which has as etiological agents protozoa of the genus Plasmodium prevalent in tropical countries. The appearance of Plasmodium strains resistant to artemisinin has become necessary the development of new drugs using computational tools to combat this epidemic. Diverse transporter proteins can act as antimalarials targets, thereby being the enzyme deoxyhypusine synthase a promising antimalarial target. The present study aimed to investigate 15 most active inhibitors of deoxyhypusine synthase target, deposited in databases Binding DB, in order to trace a pattern of physicochemical, pharmacokinetic and toxicological properties of the inhibitors for this enzyme and propose new inhibitors of deoxyhypusine synthase target. The physicochemical properties were obtained according to the Lipinski parameters to evaluate oral absorption. Based on the certain properties were proposed three new inhibitors (A, B and C). The ADME/Tox properties were calculated for new inhibitors compared with results of the selected compounds. The fifteen inhibitors for oral administration showed satisfactory results, because they have adapted to the Lipinski parameters. In relation to the penetration of the blood-brain barrier the inhibitors analyzed showed penetration values less than 1, and ranged from 0.0411815 to 0.481764, being that the compound 1 showed value of CBrain/CBlood = 0.135467. Compound B showed a higher strength in plasma protein binding in relation to the compound 1, having a variation be-tween them of ±1.489344. Therefore, the compound B would present a longer halflife compared with compound 1. The proposed compounds showed positive and satisfactory results, being able to reach less adverse effects related to the central nervous system depending of administered dose.展开更多
Objective:To obtain suitable artimisinin-based drug candidates with high antimalarial activity.Methods:Three different reaction schemes were used to synthesize a total of 15 artemisininbased compounds.The first synthe...Objective:To obtain suitable artimisinin-based drug candidates with high antimalarial activity.Methods:Three different reaction schemes were used to synthesize a total of 15 artemisininbased compounds.The first synthetic scheme involved the synthesis of diazido aliphatic and aromatic compounds from commercially available dihalides and azido derivatives of artemisinin.The second scheme consisted of the reaction of dibromoaliphatic compounds with sodium azide in dimethylformamide which yielded the desired compounds.Artemisinin-based compounds on treatment with sodium azide and bromotrimethylsilane in dichloromethane produced the most potent compound GB-2.Another potent compound GB-1 was synthesized from artemisinin by treatment with alcohols in the presence of Aberlyst-15 in anhydrous dichloromethane.The third scheme involved the Huisgen 1,3-dipolar cycloaddition between the synthesized aliphatic and aromatic diazides and two alkyne derivatives of artemisinin to obtain the desired artemisinin dimers with average yields.Results:The best in vitro antiplasmodial activity was shown by the compound GB-2 registering IC_(50)value 0.066μg/mL against chloroquine-sensitive and 0.865μg/mL against chloroquineresistant strains of Plasmodium falciparum.It suppressed 59.0%parasitaemia in vivo of rodent malaria parasite Plasmodium berghei in Swiss albino model at 50μg/kg body weight dosage.Molecular docking interactions of Plasmodium falciparum ATP6(PfATP6)protein revealed strong bonding of GB-2 with Thr255 residue which is likely to be the reason for excellent antimalarial activity of this compound.Conclusion:Two compounds GB-1 and GB-2 exhibited excellent in vitro antiplasmodial activity and fair in vivo antimalarial activity.Of the two,GB-2 showed better activity which could be attributed to its strong bonding interactions with Thr255 as evidenced from the molecular docking study.Study helped in identifying artemisinin analogues possessing good antimalarial properties and further research in structural alterations of the selected molecules should be carried out which may result in obtaining potent drug candidates against the malarial parasite.展开更多
Six new ent-abietane diterpenoids,abientaphlogatones A−F(1−6),along with two undescribed ent-abietane diterpenoid glucosides,abientaphlogasides A−B(7−8)and four known analogs were isolated from the aerial parts of Phl...Six new ent-abietane diterpenoids,abientaphlogatones A−F(1−6),along with two undescribed ent-abietane diterpenoid glucosides,abientaphlogasides A−B(7−8)and four known analogs were isolated from the aerial parts of Phlogacanthus curviflorus(P.curviflorus).The structures of these compounds were determined using high-resolution electrospray ionization mass spectrometry(HR-ESI-MS),one-dimensional and two-dimensional nuclear magnetic resonance(NMR)spectroscopy,electronic circular dichroism(ECD)spectra,and quantum chemical calculations.Notably,compounds 5 and 6 represented the first reported instances of entnorabietane diterpenoids from the genus Phlogacanthus.In theβ-hematin formation inhibition assay,compounds 2,4,7−10,and 12 displayed antimalarial activity,with IC_(50) values of 12.97−65.01μmol·L−1.Furthermore,compounds 4,5,8,and 10 demonstrated neuroprotective activity in PC12 cell injury models induced by H_(2)O_(2) and MPP+.展开更多
文摘Objective To screen the antimalarial compounds of daphnetin derivatives against Plasmodium falciparum in vitro. Method Plasmodium faciparum （FCC1） was cultured in vitro by a modified method of Trager and Jensen. Antimalarial compounds were screened by microscopy-based assay and microfluorimetric method. Results DA79 and DA78 showed potent antimalarial activity against Plasmodiumfalciparum cultured in vitro. Conclusion Though the relationship between the structures of daphnetin derivatives and their antimalarial activities has not been clarified yet, this study may provide a new direction for discovery of more potential antimalarial compounds.
基金supported by grants from the National Key Research and Development Program of China(Nos.2020YFA0908000 and 2022YFC2303600)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTD-C-202002)+10 种基金the National Natural Science Foundation of China(Nos.82141001,82274182,82074098 and 82173914)the CACMS Innovation Fund(Nos.CI2021A05101 and CI2021A05104):the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences(No.CI2021B014)the Science and Technology Foundation of Shenzhen(No.JCYj20210324115800001)the Science and Technology Foundation of Shenzhen(Shenzhen Clinical Medical Research Center for Geriatric Diseases)Establishment of Sino-Austria"Belt and Road"Joint Laboratory on Traditional Chinese Medicine for Severe Infectious Diseases and Joint Research(No.2020YFE0205100)the Fundamental Research Funds for the Central Public Welfare Research Institutes(Nos.ZZ14-YQ-050,ZZ14-YQ-051,ZZ14-YQ-052,ZZ14-FL-002,ZZ14-ND-010 and ZZ15-ND-10)Introduce innovative team projects of Jinan(No.202228029)Shenzhen Governmental Sustainable Development Fund(No.KCXFZ20201221173612034)Shenzhen Key Laboratory of Kidney Diseases(No.ZDSYS201504301616234)Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties(No.SZGSPO01).
文摘Present research on the antimalarial mechanisms of artemisinin(ART)is mainly focused on covalent drug binding targets alkylated by free radicals,while non-covalent binding targets have rarely been reported.Here,we developed a novel photoaffinity probe of ART to globally capture and identify the antimalarial target proteins of ART through chemical proteomics.The results demonstrated that ART can bind to par-asite proteins by both covalent and non-covalent modification,and these may jointly contribute to the antimalarial effects.Our work enriches the research on the antimalarial targets of ART,and provides a new perspective for further exploring the antimalarial mechanism of ART.
基金supported by The National Research Couneil of Thailand.(Grant No.034/2556)Thammasat University and the Cammission on Higher Education,Ministry of Education of Thailand(NRI Project)
文摘Objective:To investigate the antimalarial activity and toxicity of the crude ethanolic extract of its pericarp both in vitro and in vim.Methods:The antimalarial activity of Gareinja mangostana(G.mangostana)Linn.extract against 3D7 and Kl Plasmodium falciparum(P.falciparum)clone were assessed using SYBR green I-based assay.A 4-day suppressive test of Plasmodium berghei{P.berghei)infected mouse was performed to investigate in vivo antimalarial activity.Results:The in vitro antimalarial activity was seleclive(SI>5?and classified as weak and good lo moderate activity against both 3D7 and K1 P.falciparum,clones with median IC_(50)(range)values of 11.12(10.94-11.29)and 7.54(6.80-7.68)μg/mL,respectively.The extract was considered nontoxic to mice.The maximum tolerated doses for acute and subacute toxicity in mice were 5 000and 2 000 mg/kg,respectively.Median(range)parasite density on day 4 of the negative control group(25%Tween-80),mice treated with 250,500,1000,and 2 000 mg/kg body weight of the extract,and 10 mg/kg body weight of chloroquine for 14 d were 12.8(12.2-13.7),11.4(9.49-13.8),11.6(9.9-12.5),11.7(10.6-12.8),10.9(9.4-11.6)and 0(0-0)%respectively.Parasite density on day 4in the control group treated with Tween-80 was higher than the groups treated with chloroquine and all dose levels of the extract.Conclusions:G.mangostana linn,showed weak antimalarial activity of the extract both in vitro and in vivo could be due to limitation of absorption of the active compounds.
文摘A series of 5-substituted-3-[{5-（6-methyl-2-oxo/thioxo-4-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl）-1,3,4-oxadiazol-2-yl}-imino] -1,3-dihydro-2H-indol-2-one were synthesized,characterized and screened for their anti-tubercular and antimalarial activity.
基金supported by the Fulbright Senior Scholar program granted to Dr A.Falodun to study at the School of Pharmacy,University of Mississippisupported by NIH,NIAID,Division of AIDS.Grant No.Al 27094(antifungal)+1 种基金the USDA Agricultural Research Service Specific Cooperative Agreement No.58-6408-1-603(antibacterial)TETFUND/DESS/RP/UNIV/BENIN/VOL.111 2013 and URPC VC.23
文摘Objective:To investigate the antileishinanial,antimicrobial and antimalarial activities of the pure metabolites from Jatropha multifida used in African ethnomedicine.Methods:The methanolic stem bark extract of Jatropha multifida used in Nigerian folk medicine as remedy against bacterial infections was subjected to column chromatography and HPLC analyses lo obtain three known metabolites,microcyclic lathyrane dilerpenoids(1-3).Structures were confirmed by comparison of 1D and 2D spectral data with literature.Results:The three compounds exhibited inhibition of antileishmanial,antimalarial and antimicrobial actions against the tested organisms with compouds 2 and 3 active against Cryptococcus neoformans at IC_(50)of 82 and 8.7 μg/ml,respectively.Conclusions:The research lends support to the ethnomedicinal use of the plant in combating microbial infections,leishmaniasis and malarial infections.
基金supported by the School of Graduate Studies,Addis Ababa University,for financially supporting the research work(grant number GSR/1702/99)
文摘Objective: To document plants used in traditional treatment of malaria in the Awash-Fentale District, the Afar Region of Ethiopia, and to evaluate antimalarial activity of selected ones against Plasmodium berghei in mice. Methods: Semi-structured interviews were carried out with purposively selected informants in the District to gather information on plants used in the traditional treatment of malaria. Standard procedures were used to investigate acute toxicity and a four-day suppressive effect of crude aqueous and ethanol extracts of the leaves of the two most frequently cited plants [Aloe trichosantha(A. trichosantha) and Cadaba rotundifolia(C. rotundifolia)] against Plasmodium berghei in Swiss albino mice. Results: The informants cited a total of 17 plants used in the traditional treatment of malaria in Awash-Fentale District. Plant parts were prepared as infusions or decoctions. Leaf was the most commonly cited(44%) plant part, followed by stem(22%). Shrubs were the most frequently cited(63%) medicine source followed by trees(21%). Of the 17 plants, C. rotundifolia and A. trichosantha were the most frequently mentioned plants in the district. Ethanol extracts of the leaves of C. rotundifolia and A. trichosantha suppressed P. berghei parasitaemia significantly accounting for 53.73% and 49.07%, respectively at 900 mg/kg. The plants were found to be non-toxic up to a dose of 1 500 mg/kg. Conclusions: Seventeen plant species were reported to be used for treatment of malaria in the Awash Fentale Distinct, among which A. trichosantha and C. rotundifolia were the most preferred ones. P. berghei suppressive activity of these plants may partly explain their common use in the community.
文摘Objective:To evaluate the antimalarial activity of the aqueous extract of Euphorbia(E.)cordifolia Elliot against Plasmodium(P.)berghei-infected mice.Methods:Thirty healthy Swiss mice were intraperitoneally inoculated with 200μL of P.berghei parasitized-erythrocytes and divided into five groups,and then daily treated for 5 d with single dose of 10 mL/kg of distilled water for malaria control,10 mg/kg of chloroquine for the chloroquine control and 100,200 and 400 mg/kg of the aqueous extract of E.cordifolia for the three test groups.Parasitaemia was monitored by Giemsa-staining.At the end of the treatment,animals were sacrificed,and blood was collected for haematological and biochemical analyses.Organs were collected for biochemical and histopathological analyses.Statistical significance(P<0.05)was evaluated by analysis of variance followed by the Tukey post-test using Graphpad prism 7.0.Results:E.cordifolia extract decreased the parasite load to 2.46%,with an effective dose(ED50)of 113.07 mg/kg compared to the malaria group where the parasite load increased to(46.46±10.28)%.E.cordifolia extract prevented hypoglycaemia,anaemia,leucocytosis and thrombocytopenia,attenuated the increase of transaminases activities,bilirubin and creatinine rate,and improved catalase and superoxide dismutase activities,while reducing malondialdehyde contents in the liver and kidney.E.cordifolia extract significantly prevented histological damages observed in the malaria control group.No acute toxicity sign was observed in mice with plant extract at the dose up to 5000 mg/kg.Conclusions:E.cordifolia extract at 200 and 400 mg/kg showed significant antimalarial effects.This results support its traditional use in the treatment of malaria.
文摘Malaria is one of the most devastating infectious diseases that caused millions of clinical cases annually despite decades of prevention efforts. Recent cases of Plasmodium falciparum resistance against the only remaining class of effective antimalarial(artemisinin) in South East Asia may soon pose a significant threat. Hence, the identification of new antimalarial compounds with a novel mode of action is necessary to curb this problem. Protein kinase has been implicated as a valid target for drug development in diseases such as cancer and diabetes in humans. A similar approach is now recognized for the treatment of protozoan-related disease including malaria. Few Plasmodium protein kinases that are not only crucial for their survival but also have unique structural features have been identified as a potential target for drug development. In this review, studies on antimalarial drug development exploiting the size of Plasmodium protein kinase ATP gatekeeper over the past 15 years are mainly discussed. The ATP-binding site of Plasmodium protein kinases such as Pf CDPK1, Pf CDPK4, Pf PKG, Pf PK7, and Pf PI4K showed great potential for selective and multi-target inhibitions owing to their smaller or unique ATP-gatekeeper amino acid subunits compared to that of human protein kinase. Hence it is a feasible solution to identify a new class of active antimalarial agents with a novel mode of action and longer clinical life-span.
基金supported by the National Natural Science Foundation of China(Nos.81960637 and 81460532)the Innovation Team Project of Dali University for the Development and Utilization of Characteristic Medicinal Plants in Western Yunnan&Bai Nationality Medicines(No.ZKLX2019106).
文摘One previously undescribed angeloylated noreudesmane sesquiterpenoid,dobinin O(1),along with four known eudesmane sesquiterpenoids(2-5)were isolated from the peeled roots of Dobinea delavayi.Their structures were elucidated by extensive spectroscopic data analyses.In addition,compound 1 exhibited moderate antimalarial activity against Plasmodium yoelii BY265RFP with the inhibition ratio of 17.8±13.3%at the dose of 30 mg/kg/day.
基金funding support from the National Natural Science Foundation of China(No.82074251)the Hunan Natural Science Foundation of China(No.2018JJ2413)the Hunan Provincial Health and Health Commission Project(No.c2018032)。
文摘Objective Sulfanilamide,sulfadiazine,and dapsone were the first sulfonamides to be used to treat malaria by disrupting the folate biosynthesis process,which is essential for parasite survival.Therefore,we aimed to synthesize novel N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives through a rational drug design approach.Methods All compounds were synthesized by the conventional method,and the products were characterized by spectral analysis(1 H NMR and mass spectrometry).The progression of the reaction was monitored using thin-layer chromatography(TLC).All the derivatives were analyzed for their effective binding mode in the allosteric site of the plasmodium cysteine protease falcipain-2.Antibacterial and antifungal activities were determined using the broth dilution method.Results S6(N-(2-thiazol-4 yl)-acetyl-aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide and S9(N-(1 H-benzo[d]imidazol-2-yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide formed five hydrogen bonds;S8(N-(2-1 H-imidazol-2 yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide and S10(N-(1 H-benzo[d]imidazol-5-yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide formed four hydrogen bonds with the allosteric site of the enzyme.Considering the docking scores and formation of hydrogen bonds with the target enzyme,the novel derivatives were processed for wet lab synthesis.All the newly synthesized derivatives were subjected to in vitro antimalarial,antifungal,and antibacterial activities.All the derivatives exhibited sufficient sensitivity to the Plasmodium falciparum strain compared to the standards.Moreover,compounds S9 and S10 showed the most potent dual antimicrobial and antimalarial activities.They also exhibited powerful molecular interactions in molecular docking studies.Conclusion Based on the above results,it was concluded that N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives have excellent biological potential to act as antimalarial,antifungal,and antibacterial agents.
文摘Following highly prevalent Plasmodium resistant strains to antimalarial monotherapies in malaria endemic countries, uncomplicated malaria treatment policy changed to artemisinine-based combination therapies (ACTs). After adoption of this new treatment policy in a country, sufficient care is needed to be taken to prevent occurrence of resistance to the latest drugs. As Cameroon shifted to ACT in 2004, this study aimed to assess knowledge and practices of health workers in government health facilities of the Littoral region regarding mild malaria management in health facilities as well as according to prescription qualities of ACTs in leaflets received in pharmacies. A total of 66 physicians and 16 nurses were questioned in 10 health facilities and 503 medical leaflets with ACTs prescriptions were viewed in 17 pharmacies. All medical workers questioned correctly were defined mild malaria and were aware of the antimalarial policy change in Cameroon. Overall ACTs prescription for mild malaria management in children and adult patients was 72.2% and 87.8% respectively. An important proportion of health workers prescribed antimalarial monotherapies and non recommended antimalarial for uncomplicated malaria treatment. 31.7% of participants did not systematically recommend laboratory diagnostic test before antimalarial prescription. Of leaflets viewed in pharmacies, ACTs were prescribed by physicians, nurses and laboratory technicians. Age was the only criteria for ACTs prescription. Appropriate ACTs quality prescription ranged between 81.2% and 94.4%. Of the ACTs prescribed, blisters had the highest (92.9%) appropriate quality prescription and solutions the lowest (83.3%). According to qualification of prescribers, physicians had the highest score (93.1%) of appropriate quality prescription and laboratory technicians the lowest score (28.1%). For all ACTs containing medical leaflets, concomitant medications were recorded namely antipyretic (73.9%), antibiotic (21.9%), non steroid anti-inflammatory (19.9%) or vitamins (18.1%). Data gathered indicated that although health workers were aware of uncomplicated malaria treatment policy change in Cameroon, mild malaria mismanagement was prevailing in health facilities of the Littoral region and ACTs quality prescription in medical leaflets was not optimal. Therefore, awareness is still needed among prescribers in order to prevent or at least slow the occurrence of Plasmodium resistant strains to ACTs in Cameroon.
文摘Malaria is a real public health problem. It’s one of the pathologies that mobilize the scientific community. Resistance to existing treatments is the basis for the search for new treatments. Some molecules such as Manzamenones have shown important antimalarial properties. These molecules belong to the family of atypical fatty acid derivatives. This work presents the relative stabilities, some reactivity properties and the privileged sites of interaction by hydrogen bond of fourteen Manzamenones and two antimalarial drugs: quinine and Artemisinin. These analyses were performed using quantum chemical calculations. We employed the two-layer ONIOM calculation method;namely ONIOM (B3LYP/6-311++G (d, p): AM1) for the fourteen Manzamenones. The geometries of the two antimalarials are calculated at B3LYP/6-311++G (d, p). The electrostatic potential (ESP) calculation of all molecules is done at the B3LYP/6-31++G (d, p) level. The formation processes of the molecules are discussed from the thermodynamic quantities we have calculated. The relative stabilities, the energies of the frontier orbitals, the energy gaps, the dipole moment, etc., are evaluated and discussed. The electrostatic potential at the molecular surface has been used to identify the sites favorable to the formation of hydrogen bonds.
文摘Objective: To evaluate the antimalarial activity of the ethylacetate and butanol fractions of Combretum nigricans(C. nigricans) leaf extract in mice. Methods: C. nigricans solvent(butanol and ethylacetate) fractions were screened for their phytochemical constituents using standard procedures illustrated by Harborne and Evans. The Peters' 4-day suppressive test against early malaria infection, Rane's curative test against established malaria and prophylactic test for residual activity were employed for evaluating the antimalarial potential in mice. Results: The phytochemical screening revealed the presence of alkaloids, terpenoids, saponins, and flavonoids in both fractions at different intensity. Both fractions exhibited significant antimalarial activity in all test models(P<0.05). The ethylacetate fraction of C. nigricans had better chemosuppressive and curative effects compared to the butanol fraction, which however, elicited a better chemoprophylactic effect. The chemosuppressive effect of C. nigricans ethylacetate fraction(200-800 mg/kg) was 77.6%, 69.1% and 86.1%; curative effect was 62.3%, 71.3% and 72.4%; while the chemoprophylactic activity was 32.1%, 48.6% and 61.2% respectively. C. nigricans butanol fraction(200-800 mg/kg) had 40.3%, 54.1% and 69.1% chemosuppression; 26.2%, 36.9% and 34.5% curative effect; and 48.4%, 70.0% and 87.4% chemoprophylaxis. Conclusions: Both solvent fractions of C. nigricans possess antimalarial activity, and may be useful at different stages of malaria therapy.
文摘Cancer is a leading cause of death globally, while malaria is the leading cause of death from parasitic diseases in Nigeria. Historically, plant remedies have been used to manage both cancer and malaria.Interestingly, the possibility of treating cancer with antimalarial remedies has long been reported, even though the two diseases appear to have little in common. However, a body of research has indicated the potential anticancer activity of both synthetic and nature-derived antimalarials. In Nigeria, over 100 plants are used for the management of malaria, but little is known for their potential role in combatting cancer. Therefore, this review is to highlight the documented anticancer activities of plants used to treat malaria in Nigeria, with the goal of supporting anticancer drug discovery. Scientific databases were used to search for antimalarial plants using selected keywords. Of over 100 plants used to treat malaria in Nigeria, 56 have documented anticancer properties, containing alkaloids, flavonoids, tannins, terpenes,terpenoids, quinones, anthraquinones, saponins, steroids, sterols, organosulfur compounds and other polyphenols as the major bioactive components. The major mechanisms of anticancer activity include induction of apoptosis and autophagy, arrest of cell growth, generation of reactive oxygen species and inhibition of angiogenesis. However, mechanistic and clinical investigations of the anticancer properties of most of these plants are still lacking. Notwithstanding, the huge anticancer potential uncovered by the in vitro or in vivo studies and a few clinical studies, Nigerian antimalarial plants may provide a valuable resource, ready to be harnessed for anticancer drug development.
文摘Objective:To determine the suppressive and curative activity of aqueous leaf extract of Ageratum conyzoides(A.conyzoides) in combination with chloroquine and artesunate, respectively against Plasmodium berghei infection in mice.Methods:Using malaria(Plasmodium berghei) infected albino mice of both sexes,aqueous extracts of A.conyzoides in combination with chloroquine and artesunate were tested for antimalarial activity,respectively.Four-day suppressive test and Rane’s curative test were carried out.Results:Suppressive tests showed significant dose dependent reduction in parasitemia level produced by the extract-chloroquine and extract-artesunate combinations.Suppressive activities of both extract-drug combinations were greater than the individual drugs alone.Extract-chloroquine(100:5) produced the highest suppressive effect(98%suppression).Curative tests showed absolute survival in two extract-drug combinations.Two extract-drug combinations produced higher curative effects than the individual drugs alone.The highest dose combinations of extract-chloroquine(100:5) and extract-artesunate(100:5) produced absolute parasitemia clearance(cure) in the infected mice. Conclusions:The study indicated that aqueous extract of A.conyzoides had the ability to potentiate the antimalarial activity of chloroquine and artesunate against induced plasmodiasis in mice.It contributes a lot in the malaria endemic and poverty stricken tropics.
基金Financial support for this research provided by the National Natural Science Foundation of China (Nos. 21372001 and 21672064)the "Shu Guang" Project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (No. 14SG28)
文摘Resistance to malaria parasites has quickly developed to almost all used antimalarial drugs. Cysteine protease falcipain-2(FP-2) and Plasmodium falciparum dihydrofolate reductase(PfDHFR) have crucial roles, which are absolutely necessary, in the parasite life cycle. In this study, based on the uniform pharmacophores of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the identification of 14, which showed potent inhibition against FP-2 and PfDHFR enzyme(IC_(50)= 6.8 + 1.8 mmol/L and IC_(50)= 8.8 + 0.3 mmol/L) and P. falciparum 3D7 strain(IC50= 2.9mmol/L).Additionally, 14 exhibited more potent inhibition to the proliferation of chloroquine-resistant P.falciparum Dd2 strain(IC_(50)= 1.1 mmol/L) than pyrimethamine(IC_(50)>10 mmol/L), and 14 displayed micromolar inhibitory activities against two clinical isolated strains Fab9(IC_(50)= 2.6 mmol/L) and GB4(IC_(50)= 1.0 mmol/L). Collectively, these data demonstrated that 14 might be a good lead compound for the treatment of malaria.
基金financial assistance provided by Malaysia's Ministry of Higher Education (Grant number: FRGS/2/2010/SG/ UKM/01/9)the Universiti Kebangsaan Malaysia (Grant number: UKM_GUP-TKP-08-22-074) for making this study possible
文摘Objective: To determine ex vivo antimalarial activity and cytotoxicity of endophytic Streptomyces SUK 08 as well as the main core structure fractionated from its crude extract.Methods: The activities of SUK 08 crude extract were evaluated by using the Plasmodium lactate dehydrogenase assay and synchronization test against rodent malaria parasite Plasmodium berghei, instead of human malarial parasite Plasmodium falciparum. The cytotoxicity of the crude extract was determined by MTT assay. The crude extract was analyzed by thin-layer chromatography and gas chromatography–mass spectrophotometry.Results: The ethyl acetate crude extract showed very promising antimalarial activity with IC50 of 1.25 mg/m L. The synchronization tests showed that ethyl acetate extraction could inhibit all stages of the Plasmodium life cycle, but it was most effective at the Plasmodium ring stage. On the basis of a MTT assay on Chang Liver cells, ethyl acetate and ethanol demonstrated IC50 values of >1.0 mg/m L. The IC50 of parasitemia at 5% and30% for this extract was lower than chloroquine. Thin-layer chromatography, with 1: 9 ratio of ethyl acetate: hexane, was used to isolate several distinct compounds. Based on gas chromatography–mass spectrophotometry analysis, three core structures were identified as cyclohexane, butyl propyl ester, and 2,3-heptanedione. Structurally, these compounds were similar to currently available antimalarial drugs.Conclusions: The results suggest that compounds isolated from Streptomyces SUK 08 are viable antimalarial drug candidates that require further investigations.
基金We gratefully acknowledge the support provided by the Brazilian Agency National Council of Scientific and Technological Development(CNPq-Brazil)；The authors would like to thank the Scientific Initiation Program(IC/CNPq/UNIFAP)；and the Laboratory of Modeling and Computational Chemistry of Federal University of Amapáfor computational support.
文摘Malaria is a parasitic disease which has as etiological agents protozoa of the genus Plasmodium prevalent in tropical countries. The appearance of Plasmodium strains resistant to artemisinin has become necessary the development of new drugs using computational tools to combat this epidemic. Diverse transporter proteins can act as antimalarials targets, thereby being the enzyme deoxyhypusine synthase a promising antimalarial target. The present study aimed to investigate 15 most active inhibitors of deoxyhypusine synthase target, deposited in databases Binding DB, in order to trace a pattern of physicochemical, pharmacokinetic and toxicological properties of the inhibitors for this enzyme and propose new inhibitors of deoxyhypusine synthase target. The physicochemical properties were obtained according to the Lipinski parameters to evaluate oral absorption. Based on the certain properties were proposed three new inhibitors (A, B and C). The ADME/Tox properties were calculated for new inhibitors compared with results of the selected compounds. The fifteen inhibitors for oral administration showed satisfactory results, because they have adapted to the Lipinski parameters. In relation to the penetration of the blood-brain barrier the inhibitors analyzed showed penetration values less than 1, and ranged from 0.0411815 to 0.481764, being that the compound 1 showed value of CBrain/CBlood = 0.135467. Compound B showed a higher strength in plasma protein binding in relation to the compound 1, having a variation be-tween them of ±1.489344. Therefore, the compound B would present a longer halflife compared with compound 1. The proposed compounds showed positive and satisfactory results, being able to reach less adverse effects related to the central nervous system depending of administered dose.
基金financial support as an intramural activity provided by Director,ICMR-Regional Medical Research Centre,Dibrugarh(Assam),India for the study is gratefully acknowledged
文摘Objective:To obtain suitable artimisinin-based drug candidates with high antimalarial activity.Methods:Three different reaction schemes were used to synthesize a total of 15 artemisininbased compounds.The first synthetic scheme involved the synthesis of diazido aliphatic and aromatic compounds from commercially available dihalides and azido derivatives of artemisinin.The second scheme consisted of the reaction of dibromoaliphatic compounds with sodium azide in dimethylformamide which yielded the desired compounds.Artemisinin-based compounds on treatment with sodium azide and bromotrimethylsilane in dichloromethane produced the most potent compound GB-2.Another potent compound GB-1 was synthesized from artemisinin by treatment with alcohols in the presence of Aberlyst-15 in anhydrous dichloromethane.The third scheme involved the Huisgen 1,3-dipolar cycloaddition between the synthesized aliphatic and aromatic diazides and two alkyne derivatives of artemisinin to obtain the desired artemisinin dimers with average yields.Results:The best in vitro antiplasmodial activity was shown by the compound GB-2 registering IC_(50)value 0.066μg/mL against chloroquine-sensitive and 0.865μg/mL against chloroquineresistant strains of Plasmodium falciparum.It suppressed 59.0%parasitaemia in vivo of rodent malaria parasite Plasmodium berghei in Swiss albino model at 50μg/kg body weight dosage.Molecular docking interactions of Plasmodium falciparum ATP6(PfATP6)protein revealed strong bonding of GB-2 with Thr255 residue which is likely to be the reason for excellent antimalarial activity of this compound.Conclusion:Two compounds GB-1 and GB-2 exhibited excellent in vitro antiplasmodial activity and fair in vivo antimalarial activity.Of the two,GB-2 showed better activity which could be attributed to its strong bonding interactions with Thr255 as evidenced from the molecular docking study.Study helped in identifying artemisinin analogues possessing good antimalarial properties and further research in structural alterations of the selected molecules should be carried out which may result in obtaining potent drug candidates against the malarial parasite.
文摘Six new ent-abietane diterpenoids,abientaphlogatones A−F(1−6),along with two undescribed ent-abietane diterpenoid glucosides,abientaphlogasides A−B(7−8)and four known analogs were isolated from the aerial parts of Phlogacanthus curviflorus(P.curviflorus).The structures of these compounds were determined using high-resolution electrospray ionization mass spectrometry(HR-ESI-MS),one-dimensional and two-dimensional nuclear magnetic resonance(NMR)spectroscopy,electronic circular dichroism(ECD)spectra,and quantum chemical calculations.Notably,compounds 5 and 6 represented the first reported instances of entnorabietane diterpenoids from the genus Phlogacanthus.In theβ-hematin formation inhibition assay,compounds 2,4,7−10,and 12 displayed antimalarial activity,with IC_(50) values of 12.97−65.01μmol·L−1.Furthermore,compounds 4,5,8,and 10 demonstrated neuroprotective activity in PC12 cell injury models induced by H_(2)O_(2) and MPP+.
