Design and Molecular Docking Studies of N-Mannich Base Derivatives of
Primaquine Bearing Isatin on the Targets involved in the Pathophysiology
of Cerebral Malaria

Deepika      Purohit; Rohit      Dutt; Pawan      Kumar; Sahil      Kumar; Ajit      Kumar

doi:10.2174/1871527321666220430144232

Abstract

Background: Malaria is considered one of the life-threatening mosquito-borne infectious diseases responsible for approximately more than 4,00,000 deaths every year all over the world. Plasmodium falciparum and Plasmodium vivax are widespread species, but infections caused by the former are of great concern.

Objective: Among the various forms of infections associated with Plasmodium falciparum, cerebral malaria (CM) is the most severe neurological complication, accounting for almost 13% of all malariarelated mortality. The development of effective therapeutics is urgently needed to overcome the fatality of this dreadful disease.

Methods: The present work attempted to design and virtually screen a chemical library of 75 molecules (N-Mannich base derivatives of primaquine bearing isatin moiety as heterocyclic) by molecular docking studies against anti-malarial target proteins-Cystein Protease Falcipain-2; Dipeptidyl Aminopeptidase- 1; Dipeptidyl Aminopeptidase-3 and Glycogen synthase Kinase-3β receptors, for evaluating their anti-malarial potential. Among all studied anti-malarial target receptors, the designed molecules showed an overall higher affinity for Dipeptidyl Aminopeptidase-3. Furthermore, the molecules were analyzed for binding affinity and drug-like properties using Lipinski rules, and 30 best hits were shortlisted and analyzed for the pharmacokinetic profile.

Results: Two of these hits were found to be more toxic than primaquine, hence were omitted in further analysis. Later, these 28 hits were docked against two target proteins, (a) Plasmodium falciparum erythrocyte membrane protein-1 and (b) Intracellular adhesion molecule-1, to determine their efficiency against cerebral malaria, and the results were recorded. Analysis of docking results led to the identification of the 8 studied molecules as lead molecules which were selected for chemical synthesis, in vivo studies, and further preclinical evaluation.

Conclusion: The molecule DSR 11 was predicted as the most appropriate lead molecule for anti-CM activity in the present investigation apart from the other seven molecules (DSR4, DSR26, DSR38, DSR40, DSR49, DSR56, and DSR70).

Keywords: Cerebral malaria, cystein protease falcipain, dipeptidyl aminopeptidase, glycogen synthase kinase, molecular docking, pharmacokinetics.

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DOI https://dx.doi.org/10.2174/1871527321666220430144232	Print ISSN 1871-5273
Publisher Name Bentham Science Publisher	Online ISSN 1996-3181

CNS & Neurological Disorders - Drug Targets

Design and Molecular Docking Studies of N-Mannich Base Derivatives of Primaquine Bearing Isatin on the Targets involved in the Pathophysiology of Cerebral Malaria

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