Molecular modeling studies, synthesis, and biological evaluation of Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR) inhibitors.
The search for new antimalarial agents is necessary as current drugs in the market become vulnerable due to the emergence of resistance strains of Plasmodium falciparum (P. falciparum). The biosynthetic pathway for fatty acids has been recognized and validated as an important drug target in P.falciparum. One of the important enzymes in this pathway that has a determinant role in completing the cycles of chain elongation is Enoyl-ACP reductase (ENR) also popularly known as FabI. In this paper we report the design, synthesis, and microbial evaluation of inhibitors of Plasmodium enoyl reductase (PfENR). The search for inhibitors involved a virtual screening of the iResearch database with docking simulations. One of the hits was selected and modified to optimize its binding to PfENR; this resulted in the development of analogues of N-benzylidene-4-phenyl-1,3-thiazol-2-amine. The activity of these analogues was predicted from comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models constructed from a dataset of 43 known inhibitors of PfENR. The most promising molecules were synthesized and their structures characterized by spectroscopic techniques. The molecules were screened for in vitro antimalarial activity by whole-cell assay method. Two molecules, viz. VRC-007 and VRC-009, were found to be active at 4.67 and 7.01 microM concentrations, respectively.
Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai, India.
Varun A
VA
Morde
Mushtaque S
MS
Shaikh
Raghuvir R S
RR
Pissurlenkar
Evans C
EC
Coutinho
D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020134:Catalytic Domain; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D013055:Spectrophotometry, Infrared; D055672:Static Electricity
D000962:Antimalarials; D004791:Enzyme Inhibitors; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)