Identification and Evaluation of Bioactive Small Molecules as Antimalarials Via Phenotypic Based and Target-Based Drug Discovery | Shiv Nadar University
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Identification and Evaluation of Bioactive Small Molecules as Antimalarials Via Phenotypic Based and Target-Based Drug Discovery

Malaria is an infectious parasitic disease, which remains a major global health concern affecting billions of people worldwide. The existing chemotherapy, Artemisinin-based   combination therapy (ACT) is the mainstay of malaria chemotherapy. However, ACT is increasingly threatened by emergence of drug resistance in South-East Asia. Therefore, there is an urgent need for the development of novel antimalarial chemotherapy to control and eradicate malaria. In the current study, with the aim to integrate medicinal chemistry with the understanding of parasite biology, identification of new class of antimalarial drugs has been done. The thesis revolves around screening of libraries of chemically bioactive compounds which are synthesised by different strategies like diversity oriented synthesis (DOS), privileged scaffolds, hybrid systems and green chemistry. In this study, we have taken two strategies phenotype-based and target-based screening to investigate the novel libraries of chemically bioactive compounds for antimalarial activity. Here we present the synthesis and evaluation of antimalarial drugs against the erythrocytic stage of the malaria parasite by using various methods and techniques. We have screened library of novel chemical scaffolds which are synthesised by unique strategies such as diversity oriented synthesis (DOS), green chemistry, medicinal chemistry etc. A DOS-mediated exploration of substituted bicyclic lactams with novel structural motifs and natural product based DOS library of hybrid systems generated via “privileged scaffolds” was done. Upon screening, we have identified potential lead molecules against malaria parasite. These lead compounds were found to kill the parasite by mediating apoptotic like cell death by disrupting the mitochondrial membrane potential. We have also screened 1, 3 benzoxazine derivatives of phytophenol eugenol and its structural isomer isoeugenol, synthesised via green chemistry approach showing promising antimalarial activity by disrupting sodium homeostasis. In silico docking studies of the lead compound showed molecular interactions with the P-type cation ATPase PfATP4. Concurrently, we have screened the compounds against potential targets such as thioredoxin reductase having roles in the crucial mechanisms of the parasite like redox homeostasis and egress.

Department: 
Life Sciences
Year: 
2018
Student Name: 
Vijeta Sharma

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