Identification of new oxospiro chromane quinoline-carboxylate antimalarials that arrest parasite growth at ring stage.

Malaria still threatens half the globe population despite successful Artemisinin-based combination therapy. One of the reasons for our inability to eradicate malaria is the emergence of resistance to current antimalarials. Thus, there is a need to develop new antimalarials targeting Plasmodium proteins. The present study reported the design and synthesis of 4, 6 and 7-substituted quinoline-3-carboxylates 9(a - o) and carboxylic acids 10(a - b) for the inhibition of Plasmodium N-Myristoyltransferases (NMTs) using computational biology tools followed by chemical synthesis and functional analysis. The designed compounds exhibited a glide score of -9.241 to -6.960 kcal/mol for Pv NMT and -7.538 kcal/mol for Pf NMT model proteins. Development of the synthesized compounds was established via NMR, HRMS and single crystal X-ray diffraction study. The synthesized compounds were evaluated for their in vitro antimalarial efficacy against CQ-sensitive Pf 3D7 and CQ-resistant Pf INDO lines followed by cell toxicity evaluation. In silico results highlighted the compound ethyl 6-methyl-4-(naphthalen-2-yloxy)quinoline-3-carboxylate ( 9a ) as a promising inhibitor with a glide score of -9.084 kcal/mol for Pv NMT and -6.975 kcal/mol for Pf NMT with IC 50 values of 6.58 µM for Pf 3D7 line. Furthermore, compounds 9n and 9o exhibited excellent anti-plasmodial activity ( Pf 3D7 IC 50 = 3.96, 6.71 µM, and Pf INDO IC 50 = 6.38, 2.8 µM, respectively). The conformational stability of 9a with the active site of the target protein was analyzed through MD simulation and was found concordance with in vitro results. Thus, our study provides scaffolds for the development of potent antimalarials targeting both Plasmodium vivax and Plasmodium falciparum .Communicated by Ramaswamy H. Sarma.