Identification and evaluation of bioactive small molecules as antimalarials via phenotypic based and target based drug discovery

Abstract

Malaria is an infectious parasitic disease, which remains a major global health concern newlineaffecting billions of people worldwide. The existing chemotherapy, Artemisinin-based newlinecombination therapy (ACT) is the mainstay of malaria chemotherapy. However, ACT is newlineincreasingly threatened by emergence of drug resistance in South-East Asia. Therefore, there newlineis an urgent need for the development of novel antimalarial chemotherapy to control and newlineeradicate malaria. In the current study, with the aim to integrate medicinal chemistry with the newlineunderstanding of parasite biology, identification of new class of antimalarial drugs has been newlinedone. The thesis revolves around screening of libraries of chemically bioactive compounds newlinewhich are synthesised by different strategies like diversity oriented synthesis (DOS), newlineprivileged scaffolds, hybrid systems and green chemistry. In this study, we have taken two newlinestrategies phenotype-based and target-based screening to investigate the novel libraries of newlinechemically bioactive compounds for antimalarial activity. Here we present the synthesis and newlineevaluation of antimalarial drugs against the erythrocytic stage of the malaria parasite by using newlinevarious methods and techniques. We have screened library of novel chemical scaffolds which newlineare synthesised by unique strategies such as diversity oriented synthesis (DOS), green newlinechemistry, medicinal chemistry etc. A DOS-mediated exploration of substituted bicyclic newlinelactams with novel structural motifs and natural product based DOS library of hybrid systems newlinegenerated via privileged scaffolds was done. Upon screening, we have identified potential newlinelead molecules against malaria parasite. These lead compounds were found to kill the parasite newlineby mediating apoptotic like cell death by disrupting the mitochondrial membrane potential. newlineWe have also screened 1, 3 benzoxazine derivatives of phytophenol eugenol and its structural newlineisomer isoeugenol, synthesised via green chemistry approach showing promising antimalarial newlineactivity by disrupting sodium homeostasis. In silico