title: Design and synthesis of small molecular dual inhibitor of falcipain-2 and dihydrofolate reductase as antimalarial agent.
abstract: Resistance of malaria parasites has quickly developed to almost all used antimalarial drugs. Accordingly, the discovery of new effective drugs to counter the spread of malaria parasites that are resistant to existing agents, especially acting on multi-targets, is an urgent need. The cysteine protease falcipain-2 (FP-2) and dihydrofolate reductase (DHFR) play crucial roles in the Plasmodium life cycle. In this study, a series of first-gereration small molecular dual inhibitor of FP-2 and DHFR have been designed and synthesized based on the lead compound 1, which was randomly identified by screening FP-2 inhibitors in our laboratory. Six compounds (2f-g, 2j, and 2m-o) showed improved dual inhibitory activities against FP-2 (IC(50)=2.7-13.2μM) and DHFR (IC(50)=1.8-19.8μM), and the inhibitory capability of compound 2o against FP-2 and DHFR were increased ∼8 and ∼6 times than that of compound 1, respectively. Moreover, compound 2o exhibited moderate in vivo antimalarial activity in a dose dependent fashion, its safety and survival rate were slightly better than that of positive drug. The preliminary SAR was obtained, meanwhile, molecular modeling result provided the key structural information to maintain the dual inhibitory activity, and was helpful for future dual inhibitors design.
authors.affiliation: School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
authors.forename: Huang
authors.initials: H
authors.lastname: Huang
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Lu
authors.forename: Xi
authors.initials: X
authors.lastname: Li
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Cong
authors.forename: Hongmei
authors.initials: H
authors.lastname: Ma
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Che
authors.forename: Ruoqun
authors.initials: R
authors.lastname: Ma
authors.forename: Honglin
authors.initials: H
authors.lastname: Li
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Jin
authors.initials: J
authors.lastname: Huang
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D008970:Molecular Weight; D010962:Plasmodium berghei / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D013762:Tetrahydrofolate Dehydrogenase; D003546:Cysteine Endopeptidases; C416224:falcipain 2