SAR Guided Synthesis of Potent, Selective and Artemisinin Synergistic New Imidazole Derivatives with Promising In Vitro Antiplasmodial and In Vivo Antimalarial Activities.

Autor: Ratanlal, Malavath, Mohankrishnan, Dinesh, Jayaram, Vankudoth, Sahal, Dinkar, Sharma, Gangavaram V. M.
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Zdroj: ChemistrySelect; 1/19/2024, Vol. 9 Issue 3, p1-12, 12p
Abstrakt: Guided by Structural Activity Relationship (SAR), a series of synthetic tri‐ and tetra‐substituted imidazoles were studied for in vitro antiplasmodial activities against erythrocytic stages of chloroquine sensitive and resistant strains of Plasmodium falciparum using SYBR green I assay. This led to the identification of three potent (IC50 μM) derivatives : Im2 (0.75), Im5 (0.75) and Im22 (0.5). These three lead molecules present unique structural features with a common molecular architecture. Thus, Im2 and Im22 have phenyl rings at positions 4 and 5 of imidazole ring along with n‐hexyl at N3 position, and differ in the C2 substituent (3‐cyclopentyloxy‐4‐methoxy phenyl for Im2) versus naphthyl for Im22. In contrast, positions 4 and 5 in Im5 have pyridyl rings, with unsubstituted N3. Further, curative antimalarial studies with Im2 and Im5 in a Plasmodium berghei (ANKA) infected mouse model of malaria, revealed an increase in average survival time to 28.6±4.2 and 27.4±4 days respectively, as compared to 20.2±2.3 days for untreated control mice. Results of in vitro combination (Im22+Artemisinin) with ΣFIC50: 0.34–0.79, indicated promising synergy and prospects for the use of Im22 as a new constituent in Artemisinin combination therapy (ACT). [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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