Gemfibrozil is a widely used lipid modifying drug with well-established hypolipidemic and anti-atherosclerotic benefits; however, the presence of a carboxylic acid moiety in its structure is responsible for side effec...Gemfibrozil is a widely used lipid modifying drug with well-established hypolipidemic and anti-atherosclerotic benefits; however, the presence of a carboxylic acid moiety in its structure is responsible for side effects in the gastrointestinal tract. The principle of bioisosterism was applied to design derivatives replacing the carboxylic acid group. The carboxylic acid group was replaced with bioisoteric groups, such as 1,2,4-triazole-3-thiol and hydroxamic acid. The derivatives were then synthesized, characterized, and evaluated in rats for reduced gastrointestinal irritation and hypolipidemic effects. Gemfibrozil was used as standard for comparison. The derivatives demonstrated less gastric irritation and retained hypolipidemic effects, however the hypolipidemic affects were significantly less than that of Gemfibrozil. The results of this study offers a direction for further research on the application of bioisosterism for the design of new derivatives of Gemfibrozil and other fibric acid derivatives.展开更多
2-Azabicyclo[2.1.1]hexanes(aza-BCHs)are constrained pyrrolidine analogues with improved physicochemical characteristics in drug design.Here,we report a direct visible light-mediated photocycloaddition of 4-aza-coumari...2-Azabicyclo[2.1.1]hexanes(aza-BCHs)are constrained pyrrolidine analogues with improved physicochemical characteristics in drug design.Here,we report a direct visible light-mediated photocycloaddition of 4-aza-coumarins with mono-or disubstituted bicyclo[1.1.0]butanes for synthesizing aza-BCHs without an external catalyst.The introduction of the ester group on 4-aza-coumarin is critical for direct imine excitation and versatile synthetic utility.Preliminary mechanistic studies indicated that the reaction took place primarily at the triplet hypersurface.展开更多
Small molecule sodium ion channel blockers with a pharmacophore of a-aminoamide have exhibited anti-allodynia effects on neuropathic pain. A library of new a-aminoamide derivatives containing a scaffold of substituted...Small molecule sodium ion channel blockers with a pharmacophore of a-aminoamide have exhibited anti-allodynia effects on neuropathic pain. A library of new a-aminoamide derivatives containing a scaffold of substituted benzene were designed and synthesized. These compounds were evaluated in mice formalin model and they exhibited significant analgesic activities. However, the anti-allodynia mechanism of these compounds remains unclear; some of the target compounds can only moderately inhibit the sodium ion channel, Navl.7, in a whole-cell patch clamp assay. These results suggest that introduction of the moiety of substituted benzene to a-aminoamide derivatives can improve their bioactivity and further study is warranted.展开更多
In view of the isosterism of sulfonyl group (-SO2-) and phosphoryl group [-P(O)(OR)-,R=H, CH3, C2H5, etc], a new type of ureas, that is, N-phosphoryl-N'-(4,6-dimethoxypyrimidin-2yl) ureas 2 were synthesized and sh...In view of the isosterism of sulfonyl group (-SO2-) and phosphoryl group [-P(O)(OR)-,R=H, CH3, C2H5, etc], a new type of ureas, that is, N-phosphoryl-N'-(4,6-dimethoxypyrimidin-2yl) ureas 2 were synthesized and shown to be a new class of acetolactate synthase (ALS) inhibitors.展开更多
In view of the isosterism of the sulfonyl (-SO2-) and phosphoryl groups [-P(O)(OR)-,R=H, CH3, C2H5, etc], two new types of ureas, N-(N-aryl-O-alkyl phosphoryl)-N'-(4, 6-dimethoxypyrinddin-2-yl) ureas 2 and N-(N-ar...In view of the isosterism of the sulfonyl (-SO2-) and phosphoryl groups [-P(O)(OR)-,R=H, CH3, C2H5, etc], two new types of ureas, N-(N-aryl-O-alkyl phosphoryl)-N'-(4, 6-dimethoxypyrinddin-2-yl) ureas 2 and N-(N-aryl-N-alkyl phosphoryl)-N'-(4, 6-dimethoxy pyrimidin-2-yl)ureas 3, were synthesized by treating N- (arylandnochlorophosphoryl ) - N'- (4, 6-dimethoxypyriAndinyl-2-) ureas 4 with alcohols or amines. Compounds 4 were obtained by reactingdichlorophosphoryl isocyanate with 4,6 - di meth oxy- 2-aminopyrimidine, and then with aromaticamines. The enzyme tests (in vitro) indicated that compounds 2 and 3 were two novel classes ofacetolactate synthase (ALS) inhibitors, which showed that the phosphoryl group, [-P(O)(OR)-], or[-P(O)(NHR)-], was a good bioisostere of the sulfonyl group (-SO2-) in sulfonylurea.展开更多
Bicyclo[2.1.1]hexanes(BCHs) are structurally unique C(sp^(3))-rich bicyclic hydrocarbons that are gaining prominence in the field of medicinal chemistry as bioisosteres of benzenoids.The nitrile is an important functi...Bicyclo[2.1.1]hexanes(BCHs) are structurally unique C(sp^(3))-rich bicyclic hydrocarbons that are gaining prominence in the field of medicinal chemistry as bioisosteres of benzenoids.The nitrile is an important functionality in drug development due to its ability to improve physicochemical and pharmacokinetic properties and facilitate potential noncovalent interactions with drug targets.Consequently,cyanoarene motifs are commonly found in drug development.The introduction of cyano-BCHs as potential bioisosteres of cyano-arenes shows great promise;however,there are currently no catalytic methods available for their synthesis.Herein,we report a palladium-catalyzed enantioselective [2σ+2π] cycloadditions of bicyclo[1.1.0]butanes with arylidenemalononitriles for the preparation of chiral cyano-BCHs.This method accommodated a wide range of substrates and tolerated various functional groups.The cyano-BCH products could be transformed to molecules with diverse functionality.Control experiments suggest that the reaction proceeds via a zwitterionic intermediate generated by palladium-mediated ring opening of vinyl-carbonyl bicyclo[1.1.0]butanes followed by stereoselective 1,2-addition and intramolecular allylic substitution reactions.展开更多
Current methods to access aryl/alkyl thiol-substituted bicyclo[1.1.1]pentane(BCP)derivatives(valuable bioisosteres for thiophenols/thioethers)remain underdeveloped.Herein,we report a photocatalytic multicomponent reac...Current methods to access aryl/alkyl thiol-substituted bicyclo[1.1.1]pentane(BCP)derivatives(valuable bioisosteres for thiophenols/thioethers)remain underdeveloped.Herein,we report a photocatalytic multicomponent reaction via consecutive photoinduced electron transfer(ConPET)to enable simultaneous Csp3-C and Csp3-Y(Y=S,Se,Te)bond formation on[1.1.1]pentanes.This strategy delivers diverse alkyl halides(Cl,Br,I;primary,secondary,tertiary).Late-stage derivatization of drug molecules(e.g.,aspirin,methylprednisolone)and oxidations to sulfoxides/sulfones demonstrate synthetic versatility.Mechanistic studies support a radical relay pathway initiated by ConPET-mediated alkyl radical generation.The method establishes a robust platform for constructing chalcogen-rich BCP bioisosteres,addressing a critical gap in medicinal chemistry and offering significant potential for drug discovery.展开更多
This study aimed to identify ideal pharmaceutical candidates featuring strong anti-HIV-1 activity and desirable drug-like characteristics.Our endeavor involved the implementation of a bioisosterism strategy,leading to...This study aimed to identify ideal pharmaceutical candidates featuring strong anti-HIV-1 activity and desirable drug-like characteristics.Our endeavor involved the implementation of a bioisosterism strategy,leading to the discovery of an assemblage of halogen-containing biphenyldiarylpyrimidines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors.Notably,compound A12 demonstrated exceptional efficacy against both WT HIV-1(EC_(50)=1.9 nmol/L)and seven mutant strains(EC_(50)=1.7-157 nmol/L),surpassing that of the lead compound 6 and comparable to etravirine.Furthermore,this analog exhibited minimal adverse effects with significantly reduced cytotoxicity(CC_(50)=195μmol/L)and a high selectivity index(SI=102,608),superior to those of etravirine(CC_(50)>4.6μmol/L,SI>1436)and rilpivirine(CC_(50)=3.98μmol/L,SI=3989).It displayed low inhibition of CYP(IC_(50)=6.99-25μmol/L)and hERG(IC_(50)>40μmol/L),indicating a safer profile compared to etravirine and rilpivirine.No acute toxicity or organ pathological damage was observed at a single dose of 2 g/kg.Additionally,A12 exhibited favorable oral bioavailability(F=29.2%)and an extended elimination half-life(T _(1/2)=13.56 h),enabling convenient oral administration at minimal doses.These findings indicated that A12 could serve as a promising drug candidate for HIV treatment.展开更多
Owing to their diverse reactivity resulting from their inherent high strain energy,bicyclo[1.1.0]butanes(BCBs)have garnered increasing attention as versatile building blocks for constructing racemic and achiral cyclob...Owing to their diverse reactivity resulting from their inherent high strain energy,bicyclo[1.1.0]butanes(BCBs)have garnered increasing attention as versatile building blocks for constructing racemic and achiral cyclobutane and bicyclo[n.1.1]alkane scaffolds.These structures,particularly bicyclo[n.1.1]alkanes show potential as valuable C(sp^(3))-rich bioisosteres for substituted arenes in modern drug design.Over the past two years,innovative strategies have been employed to harness these“spring-loaded”molecules for efficient and enantioselective synthesis of chiral four-membered carbocycles and chiral bicyclo[n.1.1]alkanes.In this review,we highlight the latest advancements in asymmetric transformations of BCBs,with a particular focus on innovative stereoselective catalytic strategies,catalyst systems,and activation modes.We anticipate that this review will inspire researchers to pay more attention to this emerging field,thereby enabling catalytic asymmetric transformations of BCBs to become a reliable method for further expanding the chemical space of pharmaceutically valuable chiral molecules.展开更多
In order to search for potent and environmental friendly insecticides with new modes of action, a series of pyranoside derivatives mimicking D-myo-inositol 1,4,5-trisphosphate （IP3） were designed and synthesized acc...In order to search for potent and environmental friendly insecticides with new modes of action, a series of pyranoside derivatives mimicking D-myo-inositol 1,4,5-trisphosphate （IP3） were designed and synthesized according to the bioisosterie approach. The biological assay indicated that most of the new compounds showed moderate to good insecticidal activities against oriental armyworm （Mythimna separata） and diamondback moth （PluteIla xylostella）. Especially, compound 5g displayed 80% larvicidal activity against oriental armyworm at 50 mg/L. Meanwhile, 5a showed 100% and 70% larvicidal activities against diamondback moth at 50 and 25 nag/L, respectively. To further explore the mode of action, calcium imaging technique was applied to study the effects of 5a, 5g, and 5i on the intracellular calcium ion concentration （[Ca^2＋]i） in central neurons isolated from Spodoptera exigua. The results indicated that the tested compounds released stored calcium ions from endoplasmic reticulum.展开更多
Human immunodeficiency virus(HIV)is the primary infectious agent of acquired immunodeficiency syndrome(AIDS),and non-nucleoside reverse transcriptase inhibitors(NNRTIs)are the cornerstone of HIV treatment.In the last ...Human immunodeficiency virus(HIV)is the primary infectious agent of acquired immunodeficiency syndrome(AIDS),and non-nucleoside reverse transcriptase inhibitors(NNRTIs)are the cornerstone of HIV treatment.In the last 20 years,our medicinal chemistry group has made great strides in developing several distinct novel NNRTIs,including 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine(HEPT),thio-dihydro-alkoxy-benzyl-oxopyrimidine(S-DABO),diaryltriazine(DATA),diarylpyrimidine(DAPY)analogues,and their hybrid derivatives.Application of integrated modern medicinal strategies,including structure-based drug design,fragment-based optimization,scaffold/fragment hopping,molecular/fragment hybridization,and bioisosterism,led to the development of several highly potent analogues for further evaluations.In this paper,we review the development of NNRTIs in the last two decades using the above optimization strategies,including their structure-activity relationships,molecular modeling,and their binding modes with HIV-1 reverse transcriptase(RT).Future directions and perspectives on the design and associated challenges are also discussed.展开更多
Strobilurins are one of the most important natural products with fungicidal activities and well known for their novel action mode, broad fungicidal spectrum, lower toxicity against mammalian cells, and environmentally...Strobilurins are one of the most important natural products with fungicidal activities and well known for their novel action mode, broad fungicidal spectrum, lower toxicity against mammalian cells, and environmentally benign characteristics. Design and syntheses of strobilurin analogues therefore have attracted great attention in the field of agrochemistry. Previously, we successfully developed a new molecular design method of pharmacophore-linked fragment virtual screening （PFVS） and discovered a lead compound （E）-methyl-2-（2-（（（3-（imino-（phenyl）- methyl）phenyl）thio）methyl）phenyl）-3-methoxyacrylate （1）. To discover new strobilurin analogues with higher fun- gicidal activity, the structural modification of compound 1 was carried out guided by bioisosterism. A series of benzophenone derivatives 2a--2j were synthesized, among which compound 2j with a Ki value of 1.89 nmol/L was identified as the most promising inhibitor of porcine cytocbrome bcl complex, 157-fold improved binding affinity compared to the commercially available bCl inhibitor Azoxystrobin （AZ）. In addition, most of the new compounds displayed excellent fungicidal activity against Sphaerothecafuliginea at the concentration of 200μmol/L. The pre- sent work indicates that strobilurin analogues containing benzophenone side chains may be the ideal leads for future fungicide discovery.展开更多
Rational design of new bioisosteres through introduction of high-value functional groups to bicyclo[1.1.1]pentane(BCP)is of particular use for drug discovery.Disclosed herein is the first access to valuable fluoroalky...Rational design of new bioisosteres through introduction of high-value functional groups to bicyclo[1.1.1]pentane(BCP)is of particular use for drug discovery.Disclosed herein is the first access to valuable fluoroalkylthio(seleno)-functionalized BCPs.A range of SCF3,SCF2H,SCFH2,SeCF3,SeC4F9,and SeC8F17 groups are readily incorporated to BCPs under mild conditions.Concomitant installation of a sulfone provides a platform for incorporation of the BCP motif to bioactive molecules.This practical protocol features novel BCP scaffolds,broad substrate scope,excellent atom-economy,simple operation,and gramscale preparation.展开更多
The cofactor nicotinamide adenine dinucleotide(NAD+)plays a key role in a wide range of physiological processes and maintaining or enhancing NAD+levels is an established approach to enhancing healthy aging.Recently,se...The cofactor nicotinamide adenine dinucleotide(NAD+)plays a key role in a wide range of physiological processes and maintaining or enhancing NAD+levels is an established approach to enhancing healthy aging.Recently,several classes of nicotinamide phosphoribosyl transferase(NAMPT)activators have been shown to increase NAD+levels in vitro and in vivo and to demonstrate beneficial effects in animal models.The best validated of these compounds are structurally related to known urea-type NAMPT inhibitors,however the basis for the switch from inhibitory activity to activation is not well understood.Here we report an evaluation of the structure activity relationships of NAMPT activators by designing,synthesising and testing compounds from other NAMPT ligand chemotypes and mimetics of putative phosphoribosylated adducts of known activators.The results of these studies led us to hypothesise that these activators act via a through-water interaction in the NAMPT active site,resulting in the design of the first known urea-class NAMPT activator that does not utilise a pyridine-like warhead,which shows similar or greater activity as a NAMPT activator in biochemical and cellular assays relative to known analogues.展开更多
Pentafluorosulfanylated(SF_(5^(-))) aromatics have shown great potential in drugs, and the bioisosteric replacement of aromatic ring with bicyclo[1.1.1]pentane(BCP) unit has attracted considerable attention recently. ...Pentafluorosulfanylated(SF_(5^(-))) aromatics have shown great potential in drugs, and the bioisosteric replacement of aromatic ring with bicyclo[1.1.1]pentane(BCP) unit has attracted considerable attention recently. Consequently, pentafluorosulfanylated bicyclo[1.1.1]pentanes(SF_(5^(-))BCPs) should have application in the realm of drug discovery. In this study, a one-pot iodopentafluorosulfanylation of [1.1.1]propellane with SF_(5)Cl and CH_(2)I_(2)for the practical synthesis of iodopentafluorosulfanylated bicyclo[1.1.1]pentane(SF_(5^(-))BCP-I) was developed. SF_(5^(-))BCP-I was the first example of SF_(5^(-))BCPs that could be transformed. The first general method to access SF_(5^(-))substituted bicyclo[1.1.1]pentane derivatives was demonstrated through photoredox-catalyzed radical addition of SF_(5^(-))BCP-I to alkenes and alkynes.展开更多
N-Hydroxyphthalimide(NHPI)esters have emerged as powerful sources of alkyl radicals generated by single-electron transfer,but homolysis of NHPI ester to produce an alkyl radical and a phthalimide nitrogen radical is s...N-Hydroxyphthalimide(NHPI)esters have emerged as powerful sources of alkyl radicals generated by single-electron transfer,but homolysis of NHPI ester to produce an alkyl radical and a phthalimide nitrogen radical is still in its infancy.In this study,we developed a light-induced method for generation of alkyl and phthalimide nitrogen radicals from NHPI esters and subsequent reactions of the radicals with[1.1.1]propellane and aryl aldehydes for rapid generation of bicycle[1.1.1]pentane ketones.This method does not require metals or photosensitizers,features a broad substrate scope(90 examples)and excellent functional group tolerance,and can be used for the functionalization of structurally complex natural products and drugs.Mechanistic investigations indicate that the reaction involves photoinduced homolytic cleavage of the Cs_(2)CO_(3)-NHPI ester complex to produce alkyl and phthalimide nitrogen radicals and subsequent hydrogen atom transfer between the phthalimide nitrogen radical and the aldehyde to generate an acyl radical.展开更多
文摘Gemfibrozil is a widely used lipid modifying drug with well-established hypolipidemic and anti-atherosclerotic benefits; however, the presence of a carboxylic acid moiety in its structure is responsible for side effects in the gastrointestinal tract. The principle of bioisosterism was applied to design derivatives replacing the carboxylic acid group. The carboxylic acid group was replaced with bioisoteric groups, such as 1,2,4-triazole-3-thiol and hydroxamic acid. The derivatives were then synthesized, characterized, and evaluated in rats for reduced gastrointestinal irritation and hypolipidemic effects. Gemfibrozil was used as standard for comparison. The derivatives demonstrated less gastric irritation and retained hypolipidemic effects, however the hypolipidemic affects were significantly less than that of Gemfibrozil. The results of this study offers a direction for further research on the application of bioisosterism for the design of new derivatives of Gemfibrozil and other fibric acid derivatives.
基金supported by the National Key R&D Program of China(No.2022YFA1503200)the National Natural Science Foundation of China(Nos.22071028,21921003)。
文摘2-Azabicyclo[2.1.1]hexanes(aza-BCHs)are constrained pyrrolidine analogues with improved physicochemical characteristics in drug design.Here,we report a direct visible light-mediated photocycloaddition of 4-aza-coumarins with mono-or disubstituted bicyclo[1.1.0]butanes for synthesizing aza-BCHs without an external catalyst.The introduction of the ester group on 4-aza-coumarin is critical for direct imine excitation and versatile synthetic utility.Preliminary mechanistic studies indicated that the reaction took place primarily at the triplet hypersurface.
基金the Beijing Municipal Science and Technology Project(No.Z131100002713004)National Science and Technology Major Project of China(No.2012ZX09301003)
文摘Small molecule sodium ion channel blockers with a pharmacophore of a-aminoamide have exhibited anti-allodynia effects on neuropathic pain. A library of new a-aminoamide derivatives containing a scaffold of substituted benzene were designed and synthesized. These compounds were evaluated in mice formalin model and they exhibited significant analgesic activities. However, the anti-allodynia mechanism of these compounds remains unclear; some of the target compounds can only moderately inhibit the sodium ion channel, Navl.7, in a whole-cell patch clamp assay. These results suggest that introduction of the moiety of substituted benzene to a-aminoamide derivatives can improve their bioactivity and further study is warranted.
文摘In view of the isosterism of sulfonyl group (-SO2-) and phosphoryl group [-P(O)(OR)-,R=H, CH3, C2H5, etc], a new type of ureas, that is, N-phosphoryl-N'-(4,6-dimethoxypyrimidin-2yl) ureas 2 were synthesized and shown to be a new class of acetolactate synthase (ALS) inhibitors.
文摘In view of the isosterism of the sulfonyl (-SO2-) and phosphoryl groups [-P(O)(OR)-,R=H, CH3, C2H5, etc], two new types of ureas, N-(N-aryl-O-alkyl phosphoryl)-N'-(4, 6-dimethoxypyrinddin-2-yl) ureas 2 and N-(N-aryl-N-alkyl phosphoryl)-N'-(4, 6-dimethoxy pyrimidin-2-yl)ureas 3, were synthesized by treating N- (arylandnochlorophosphoryl ) - N'- (4, 6-dimethoxypyriAndinyl-2-) ureas 4 with alcohols or amines. Compounds 4 were obtained by reactingdichlorophosphoryl isocyanate with 4,6 - di meth oxy- 2-aminopyrimidine, and then with aromaticamines. The enzyme tests (in vitro) indicated that compounds 2 and 3 were two novel classes ofacetolactate synthase (ALS) inhibitors, which showed that the phosphoryl group, [-P(O)(OR)-], or[-P(O)(NHR)-], was a good bioisostere of the sulfonyl group (-SO2-) in sulfonylurea.
基金funding support from the National Key R&D Program of China (Nos.2022YFA1503703,2023YFA1506700)the National Natural Science Foundation of China (Nos.22071118,22271162)the Haihe Laboratory of Sustainable Chemical Transformations and the Fundamental Research Funds for the Central Universities for financial support。
文摘Bicyclo[2.1.1]hexanes(BCHs) are structurally unique C(sp^(3))-rich bicyclic hydrocarbons that are gaining prominence in the field of medicinal chemistry as bioisosteres of benzenoids.The nitrile is an important functionality in drug development due to its ability to improve physicochemical and pharmacokinetic properties and facilitate potential noncovalent interactions with drug targets.Consequently,cyanoarene motifs are commonly found in drug development.The introduction of cyano-BCHs as potential bioisosteres of cyano-arenes shows great promise;however,there are currently no catalytic methods available for their synthesis.Herein,we report a palladium-catalyzed enantioselective [2σ+2π] cycloadditions of bicyclo[1.1.0]butanes with arylidenemalononitriles for the preparation of chiral cyano-BCHs.This method accommodated a wide range of substrates and tolerated various functional groups.The cyano-BCH products could be transformed to molecules with diverse functionality.Control experiments suggest that the reaction proceeds via a zwitterionic intermediate generated by palladium-mediated ring opening of vinyl-carbonyl bicyclo[1.1.0]butanes followed by stereoselective 1,2-addition and intramolecular allylic substitution reactions.
基金the Natural Science Foundation of Zhejiang Province(No.LMS25B060007)the Key Research&Development Project of Science Technology Department of Zhejiang Province(No.2024C01203)for financial support.
文摘Current methods to access aryl/alkyl thiol-substituted bicyclo[1.1.1]pentane(BCP)derivatives(valuable bioisosteres for thiophenols/thioethers)remain underdeveloped.Herein,we report a photocatalytic multicomponent reaction via consecutive photoinduced electron transfer(ConPET)to enable simultaneous Csp3-C and Csp3-Y(Y=S,Se,Te)bond formation on[1.1.1]pentanes.This strategy delivers diverse alkyl halides(Cl,Br,I;primary,secondary,tertiary).Late-stage derivatization of drug molecules(e.g.,aspirin,methylprednisolone)and oxidations to sulfoxides/sulfones demonstrate synthetic versatility.Mechanistic studies support a radical relay pathway initiated by ConPET-mediated alkyl radical generation.The method establishes a robust platform for constructing chalcogen-rich BCP bioisosteres,addressing a critical gap in medicinal chemistry and offering significant potential for drug discovery.
基金financially supported by National Natural Science Foundation of China(Nos.82304297 and 22077018).
文摘This study aimed to identify ideal pharmaceutical candidates featuring strong anti-HIV-1 activity and desirable drug-like characteristics.Our endeavor involved the implementation of a bioisosterism strategy,leading to the discovery of an assemblage of halogen-containing biphenyldiarylpyrimidines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors.Notably,compound A12 demonstrated exceptional efficacy against both WT HIV-1(EC_(50)=1.9 nmol/L)and seven mutant strains(EC_(50)=1.7-157 nmol/L),surpassing that of the lead compound 6 and comparable to etravirine.Furthermore,this analog exhibited minimal adverse effects with significantly reduced cytotoxicity(CC_(50)=195μmol/L)and a high selectivity index(SI=102,608),superior to those of etravirine(CC_(50)>4.6μmol/L,SI>1436)and rilpivirine(CC_(50)=3.98μmol/L,SI=3989).It displayed low inhibition of CYP(IC_(50)=6.99-25μmol/L)and hERG(IC_(50)>40μmol/L),indicating a safer profile compared to etravirine and rilpivirine.No acute toxicity or organ pathological damage was observed at a single dose of 2 g/kg.Additionally,A12 exhibited favorable oral bioavailability(F=29.2%)and an extended elimination half-life(T _(1/2)=13.56 h),enabling convenient oral administration at minimal doses.These findings indicated that A12 could serve as a promising drug candidate for HIV treatment.
基金National Natural Science Foundation of China(grant no.22471068)the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang(grant no.2022R01007)the Fundamental Research Funds for the Central Universities for financial support.
文摘Owing to their diverse reactivity resulting from their inherent high strain energy,bicyclo[1.1.0]butanes(BCBs)have garnered increasing attention as versatile building blocks for constructing racemic and achiral cyclobutane and bicyclo[n.1.1]alkane scaffolds.These structures,particularly bicyclo[n.1.1]alkanes show potential as valuable C(sp^(3))-rich bioisosteres for substituted arenes in modern drug design.Over the past two years,innovative strategies have been employed to harness these“spring-loaded”molecules for efficient and enantioselective synthesis of chiral four-membered carbocycles and chiral bicyclo[n.1.1]alkanes.In this review,we highlight the latest advancements in asymmetric transformations of BCBs,with a particular focus on innovative stereoselective catalytic strategies,catalyst systems,and activation modes.We anticipate that this review will inspire researchers to pay more attention to this emerging field,thereby enabling catalytic asymmetric transformations of BCBs to become a reliable method for further expanding the chemical space of pharmaceutically valuable chiral molecules.
基金This work was financially supported by the National Natural Science Foundation of China （No. 31370039）, 973 Program （No. 2010CB 126106）, the Tianjin Natural Science Foundation （No. 16JCYBJC29400） and the ＂111＂ Project of Ministry of Education of China （Project No. B06005）.
文摘In order to search for potent and environmental friendly insecticides with new modes of action, a series of pyranoside derivatives mimicking D-myo-inositol 1,4,5-trisphosphate （IP3） were designed and synthesized according to the bioisosterie approach. The biological assay indicated that most of the new compounds showed moderate to good insecticidal activities against oriental armyworm （Mythimna separata） and diamondback moth （PluteIla xylostella）. Especially, compound 5g displayed 80% larvicidal activity against oriental armyworm at 50 mg/L. Meanwhile, 5a showed 100% and 70% larvicidal activities against diamondback moth at 50 and 25 nag/L, respectively. To further explore the mode of action, calcium imaging technique was applied to study the effects of 5a, 5g, and 5i on the intracellular calcium ion concentration （[Ca^2＋]i） in central neurons isolated from Spodoptera exigua. The results indicated that the tested compounds released stored calcium ions from endoplasmic reticulum.
基金funded by grants from the National Natural Science Foundation of China(81872791 and 21372050)the Young Elite Scientists Sponsorship Program by the China Association forScience and Technology(2017QNRC061)+1 种基金National Key R&D Program of China(2017YFA0506000)the Key Research and Development Program of Ningxia(2019BFG02017 and 2018BFH02001,China)
文摘Human immunodeficiency virus(HIV)is the primary infectious agent of acquired immunodeficiency syndrome(AIDS),and non-nucleoside reverse transcriptase inhibitors(NNRTIs)are the cornerstone of HIV treatment.In the last 20 years,our medicinal chemistry group has made great strides in developing several distinct novel NNRTIs,including 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine(HEPT),thio-dihydro-alkoxy-benzyl-oxopyrimidine(S-DABO),diaryltriazine(DATA),diarylpyrimidine(DAPY)analogues,and their hybrid derivatives.Application of integrated modern medicinal strategies,including structure-based drug design,fragment-based optimization,scaffold/fragment hopping,molecular/fragment hybridization,and bioisosterism,led to the development of several highly potent analogues for further evaluations.In this paper,we review the development of NNRTIs in the last two decades using the above optimization strategies,including their structure-activity relationships,molecular modeling,and their binding modes with HIV-1 reverse transcriptase(RT).Future directions and perspectives on the design and associated challenges are also discussed.
文摘Strobilurins are one of the most important natural products with fungicidal activities and well known for their novel action mode, broad fungicidal spectrum, lower toxicity against mammalian cells, and environmentally benign characteristics. Design and syntheses of strobilurin analogues therefore have attracted great attention in the field of agrochemistry. Previously, we successfully developed a new molecular design method of pharmacophore-linked fragment virtual screening （PFVS） and discovered a lead compound （E）-methyl-2-（2-（（（3-（imino-（phenyl）- methyl）phenyl）thio）methyl）phenyl）-3-methoxyacrylate （1）. To discover new strobilurin analogues with higher fun- gicidal activity, the structural modification of compound 1 was carried out guided by bioisosterism. A series of benzophenone derivatives 2a--2j were synthesized, among which compound 2j with a Ki value of 1.89 nmol/L was identified as the most promising inhibitor of porcine cytocbrome bcl complex, 157-fold improved binding affinity compared to the commercially available bCl inhibitor Azoxystrobin （AZ）. In addition, most of the new compounds displayed excellent fungicidal activity against Sphaerothecafuliginea at the concentration of 200μmol/L. The pre- sent work indicates that strobilurin analogues containing benzophenone side chains may be the ideal leads for future fungicide discovery.
基金supported by the National Natural Science Foundation of China(21722205,21971173)the Project of Scientific and Technologic Infrastructure of Suzhou(SZS201905)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)。
文摘Rational design of new bioisosteres through introduction of high-value functional groups to bicyclo[1.1.1]pentane(BCP)is of particular use for drug discovery.Disclosed herein is the first access to valuable fluoroalkylthio(seleno)-functionalized BCPs.A range of SCF3,SCF2H,SCFH2,SeCF3,SeC4F9,and SeC8F17 groups are readily incorporated to BCPs under mild conditions.Concomitant installation of a sulfone provides a platform for incorporation of the BCP motif to bioactive molecules.This practical protocol features novel BCP scaffolds,broad substrate scope,excellent atom-economy,simple operation,and gramscale preparation.
基金funded by the China Sponsorship Council(No.201709110169)support by the SGC,a registered charity(number 1097737)that receives funds from AbbVie,Bayer Pharma AG,Boehringer Ingelheim,Canada Foundation for Innovation,Eshelman Institute for Innovation,Genome Canada,Innovative Medicines Initiative(EU/EFPIA),Janssen,Merck KGaA Darmstadt Germany,MSD,Novartis Pharma AG,Ontario Ministry of Economic Development and Innovation,Pfizer,S?o Paulo Research Foundation-FAPESP and Takeda+2 种基金supported by the Frankfurt Cancer Institute(FCI)the DKTK translational cancer networkfinancial support by the European Union Horizon 2020 research and innovation program under grant agreement number 730872,project CALIPSOplus。
文摘The cofactor nicotinamide adenine dinucleotide(NAD+)plays a key role in a wide range of physiological processes and maintaining or enhancing NAD+levels is an established approach to enhancing healthy aging.Recently,several classes of nicotinamide phosphoribosyl transferase(NAMPT)activators have been shown to increase NAD+levels in vitro and in vivo and to demonstrate beneficial effects in animal models.The best validated of these compounds are structurally related to known urea-type NAMPT inhibitors,however the basis for the switch from inhibitory activity to activation is not well understood.Here we report an evaluation of the structure activity relationships of NAMPT activators by designing,synthesising and testing compounds from other NAMPT ligand chemotypes and mimetics of putative phosphoribosylated adducts of known activators.The results of these studies led us to hypothesise that these activators act via a through-water interaction in the NAMPT active site,resulting in the design of the first known urea-class NAMPT activator that does not utilise a pyridine-like warhead,which shows similar or greater activity as a NAMPT activator in biochemical and cellular assays relative to known analogues.
基金supported by the National Natural Science Foundation of China (21991121)the National Key Research and Development Program of China (2021YFF0701700)。
文摘Pentafluorosulfanylated(SF_(5^(-))) aromatics have shown great potential in drugs, and the bioisosteric replacement of aromatic ring with bicyclo[1.1.1]pentane(BCP) unit has attracted considerable attention recently. Consequently, pentafluorosulfanylated bicyclo[1.1.1]pentanes(SF_(5^(-))BCPs) should have application in the realm of drug discovery. In this study, a one-pot iodopentafluorosulfanylation of [1.1.1]propellane with SF_(5)Cl and CH_(2)I_(2)for the practical synthesis of iodopentafluorosulfanylated bicyclo[1.1.1]pentane(SF_(5^(-))BCP-I) was developed. SF_(5^(-))BCP-I was the first example of SF_(5^(-))BCPs that could be transformed. The first general method to access SF_(5^(-))substituted bicyclo[1.1.1]pentane derivatives was demonstrated through photoredox-catalyzed radical addition of SF_(5^(-))BCP-I to alkenes and alkynes.
基金supported by the National Natural Science Foundation of China(22171174)the Fundamental Research Funds for the Central Universities(GK202207015,GK202304033,GK202401008)+5 种基金the Innovation Capability Support Program of Shaanxi(2023-CX-TD-28)the Fundamental Science Research Project of Shaanxi for Chemistry,Biology(22JHZ002)the Natural Science Foundation of Shaanxi Province(2023-JC-YB-100)the China Postdoctoral Science Foundation(2023M732165)the Shaanxi Province Postdoctoral Science Foundation(2023BSHYDZZ107)the Young Talent Fund of Association for Science and Technology in Shaanxi,China(20240606)。
文摘N-Hydroxyphthalimide(NHPI)esters have emerged as powerful sources of alkyl radicals generated by single-electron transfer,but homolysis of NHPI ester to produce an alkyl radical and a phthalimide nitrogen radical is still in its infancy.In this study,we developed a light-induced method for generation of alkyl and phthalimide nitrogen radicals from NHPI esters and subsequent reactions of the radicals with[1.1.1]propellane and aryl aldehydes for rapid generation of bicycle[1.1.1]pentane ketones.This method does not require metals or photosensitizers,features a broad substrate scope(90 examples)and excellent functional group tolerance,and can be used for the functionalization of structurally complex natural products and drugs.Mechanistic investigations indicate that the reaction involves photoinduced homolytic cleavage of the Cs_(2)CO_(3)-NHPI ester complex to produce alkyl and phthalimide nitrogen radicals and subsequent hydrogen atom transfer between the phthalimide nitrogen radical and the aldehyde to generate an acyl radical.
