TY - JOUR
T1 - SAR Guided Synthesis of Potent, Selective and Artemisinin Synergistic New Imidazole Derivatives with Promising In Vitro Antiplasmodial and In Vivo Antimalarial Activities
AU - Ratanlal, Malavath
AU - Mohankrishnan, Dinesh
AU - Jayaram, Vankudoth
AU - Sahal, Dinkar
AU - Sharma, Gangavaram V.M.
N1 - Publisher Copyright:
© 2024 Wiley-VCH GmbH.
PY - 2024/1/19
Y1 - 2024/1/19
N2 - 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).
AB - 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).
KW - Antiplasmodial activity
KW - FACS analysis
KW - Kill kinetics
KW - SYBR Green assay
KW - Stage specificity
KW - Synergy
KW - Testing in mouse model of malaria
KW - Tri and tetra-substituted imidazoles
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U2 - 10.1002/slct.202302636
DO - 10.1002/slct.202302636
M3 - Article
AN - SCOPUS:85182479703
SN - 2365-6549
VL - 9
JO - ChemistrySelect
JF - ChemistrySelect
IS - 3
M1 - e202302636
ER -