1. A Core-Linker-Polyamine (CLP) Strategy Enables Rapid Discovery of Antileishmanial Aminoalkylquinolinecarboxamides That Target Oxidative Stress Mechanism.
- Author
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Shah AP, Hura N, Kishore Babu N, Roy N, Krishna Rao V, Paul A, Kumar Roy P, Singh S, and Guchhait SK
- Subjects
- Humans, Oxidative Stress, Polyamines pharmacology, Structure-Activity Relationship, Antiprotozoal Agents chemistry, Antiprotozoal Agents pharmacology, Leishmania, Leishmania donovani
- Abstract
A Core-Linker-Polyamine (CLP) strategy has been exploited to develop new antileishmanial agents. It involves the linker-based assembly of alkyl-polyamine side chain as a potential pharmacophore motif with a privileged heterocyclic motif, 4-arylquinoline. A series of aminoalkyl 4-arylquinoline-2-carboxamides and their analogs were synthesized and tested against L. donovani promastigotes. Among all synthesized derivatives, 10 compounds showed significant antipromastigote activities with more efficacy (IC
50 : 4.75-8 μM) than an antileishmanial oral drug Miltefosine (IC50 : 8.9±1.55 μM). Most active aminoalkyl-quinoline-carboxamides 9 a and 9 b, displayed negligible cytotoxicity towards human monocytic (THP-1) macrophages. The compounds show antileishmanial activity by generating mitochondrial superoxide radicals. However, they did not show interference with trypanothione reductase, a redox enzyme of Leishmania. Significant change in the morphology of the L. donovani promastigote by the compounds was observed. The Structure-activity relationship analysis suggest the pharmacophoric importance of alkylpolyamine and carboxamide motifs. In silico evaluation indicated that the investigated active molecules 9 a and 9 b possess important drug-likeness, physicochemical and pharmacokinetic-relevant properties., (© 2022 Wiley-VCH GmbH.)- Published
- 2022
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