Plasmodium parasites causing malaria have developed resistance to most of the antimalarials in use,in-cluding the artemisinin-based combinations,which are the last line of defense against malaria.This ne-cessitates th...Plasmodium parasites causing malaria have developed resistance to most of the antimalarials in use,in-cluding the artemisinin-based combinations,which are the last line of defense against malaria.This ne-cessitates the discovery of new targets and the development of novel antimalarials.Plasmodium falciparum alanyl aminopeptidase(PfA-M1)and leucyl aminopeptidase(PfA-M17)belong to the M1 and M17 family of metalloproteases respectively and play critical roles in the asexual erythrocytic stage of development.These enzymes have been suggested as potential antimalarial drug targets.Herein we describe the devel-opment of peptidomimetic hydroxamates as PfA-M1 and PfA-M17 dual inhibitors.Most of the compounds described in this study display inhibition at sub-micromolar range against the recombinant PfA-M1 and PfA-M17.More importantly,compound 26 not only exhibits potent malarial aminopeptidases inhibitory activities(PfA-M1 K i=0.11±0.0002μmol/L,PfA-M17 K_(i)=0.05±0.005μmol/L),but also possesses remarkable selectivity over the mammalian counterpart(pAPN K_(i)=17.24±0.08μmol/L),which endows 26 with strong inhibition of the malarial parasite growth and negligible cytotoxicity on human cell lines.Crystal structures of PfA-M1 at atomic resolution in complex with four different compounds including compound 26 establish the structural basis for their inhibitory activities.Notably,the terminal ureidoben-zyl group of 26 explores the S2' region where differences between the malarial and mammalian enzymes are apparent,which rationalizes the selectivity of 26.Together,our data provide important insights for the rational and structure-based design of selective and dual inhibitors of malarial aminopeptidases that will likely lead to novel chemotherapeutics for the treatment of malaria.展开更多
A palladium-catalyzed tandem carbonylative lactonization and cycloaddition reaction of 2-vinyl acetophenones with alkenes and CO has been established.This reaction enables an efficient conversion of the easily availab...A palladium-catalyzed tandem carbonylative lactonization and cycloaddition reaction of 2-vinyl acetophenones with alkenes and CO has been established.This reaction enables an efficient conversion of the easily available alkenes to various bridged lactones through intermolecular cycloaddition.展开更多
基金supported by University Grants Commission (UGC), New Delhi, India and Bharati Reddi by Department of Science and Technology, New Delhi, India for their research fellowshipsCSIR-IICT manuscript number is IICT/Pubs./2018/299+6 种基金Anthony Addlagatta thanks Science and Engineering Research Board (SERB), New Delhi, India for research grants (Nos. EMR/2015/000461 and CRG/2019/006013)Natural Science Foundation of Shandong Province (No. ZR2018QH007, China)Key Research and Development Program of Shandong Province (No. 2017CXGC1401, China)Young Scholars Program of Shandong University (No. YSPSDU, 2016WLJH33, China) for research fellowshipsRenu Sudhakar is the recipient of the fellowship from the Department of Biotechnology (India)Puran Singh Sijwali lab is supported with funds from the Department of Biotechnology, India (Nos. SR/SO/BB/-0124/2012 and BT/COE/34/SP15138/2015)the Council of Scientific & Industrial Research, India
文摘Plasmodium parasites causing malaria have developed resistance to most of the antimalarials in use,in-cluding the artemisinin-based combinations,which are the last line of defense against malaria.This ne-cessitates the discovery of new targets and the development of novel antimalarials.Plasmodium falciparum alanyl aminopeptidase(PfA-M1)and leucyl aminopeptidase(PfA-M17)belong to the M1 and M17 family of metalloproteases respectively and play critical roles in the asexual erythrocytic stage of development.These enzymes have been suggested as potential antimalarial drug targets.Herein we describe the devel-opment of peptidomimetic hydroxamates as PfA-M1 and PfA-M17 dual inhibitors.Most of the compounds described in this study display inhibition at sub-micromolar range against the recombinant PfA-M1 and PfA-M17.More importantly,compound 26 not only exhibits potent malarial aminopeptidases inhibitory activities(PfA-M1 K i=0.11±0.0002μmol/L,PfA-M17 K_(i)=0.05±0.005μmol/L),but also possesses remarkable selectivity over the mammalian counterpart(pAPN K_(i)=17.24±0.08μmol/L),which endows 26 with strong inhibition of the malarial parasite growth and negligible cytotoxicity on human cell lines.Crystal structures of PfA-M1 at atomic resolution in complex with four different compounds including compound 26 establish the structural basis for their inhibitory activities.Notably,the terminal ureidoben-zyl group of 26 explores the S2' region where differences between the malarial and mammalian enzymes are apparent,which rationalizes the selectivity of 26.Together,our data provide important insights for the rational and structure-based design of selective and dual inhibitors of malarial aminopeptidases that will likely lead to novel chemotherapeutics for the treatment of malaria.
基金We are grateful for the financial support from the National Natural Science Foundation of China(21790333 and 21925111)the Strategic Priority Research Program of the CAS(XDPB14).
文摘A palladium-catalyzed tandem carbonylative lactonization and cycloaddition reaction of 2-vinyl acetophenones with alkenes and CO has been established.This reaction enables an efficient conversion of the easily available alkenes to various bridged lactones through intermolecular cycloaddition.
