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 proteins. The present study reported the design and synthesis of 4, 6 and 7-substituted quinoline-3-carboxylates - and carboxylic acids - for the inhibition of 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 NMT and -7.538 kcal/mol for 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 antimalarial efficacy against CQ-sensitive 3D7 and CQ-resistant INDO lines followed by cell toxicity evaluation. results highlighted the compound ethyl 6-methyl-4-(naphthalen-2-yloxy)quinoline-3-carboxylate () as a promising inhibitor with a glide score of -9.084 kcal/mol for NMT and -6.975 kcal/mol for NMT with IC values of 6.58 µM for 3D7 line. Furthermore, compounds and exhibited excellent anti-plasmodial activity (3D7 IC = 3.96, 6.71 µM, and INDO IC = 6.38, 2.8 µM, respectively). The conformational stability of with the active site of the target protein was analyzed through MD simulation and was found concordance with results. Thus, our study provides scaffolds for the development of potent antimalarials targeting both and .Communicated by Ramaswamy H. Sarma.