hERG, Plasmodium Life Cycle, and Cross Resistance Profiling of New Azabenzimidazole Analogues of Astemizole

TY - JOUR

T1 - hERG, Plasmodium Life Cycle, and Cross Resistance Profiling of New Azabenzimidazole Analogues of Astemizole

AU - Mambwe, Dickson

AU - Coertzen, Dina

AU - Leshabane, Meta

AU - Mulubwa, Mwila

AU - Njoroge, Mathew

AU - Gibhard, Liezl

AU - Girling, Gareth

AU - Wicht, Kathryn J.

AU - Lee, Marcus C.S.

AU - Wittlin, Sergio

AU - Moreira, Diogo Rodrigo Magalhães

AU - Birkholtz, Lyn Marie

AU - Chibale, Kelly

N1 - Publisher Copyright: © 2024 The Authors. Published by American Chemical Society.

PY - 2024/4/11

Y1 - 2024/4/11

N2 - Toward addressing the cardiotoxicity liability associated with the antimalarial drug astemizole (AST, hERG IC50 = 0.0042 μM) and its derivatives, we designed and synthesized analogues based on compound 1 (Pf NF54 IC50 = 0.012 μM; hERG IC50 = 0.63 μM), our previously identified 3-trifluoromethyl-1,2,4-oxadiazole AST analogue. Compound 11 retained in vitro multistage antiplasmodium activity (ABS PfNF54 IC50 = 0.017 μM; gametocytes PfiGc/PfLGc IC50 = 1.24/1.39 μM, and liver-stage PbHepG2 IC50 = 2.30 μM), good microsomal metabolic stability (MLM CLint < 11 μL·min-1·mg-1, EH < 0.33), and solubility (150 μM). It shows a ∼6-fold and >6000-fold higher selectivity against human ether-á-go-go-related gene higher selectively potential over hERG relative to 1 and AST, respectively. Despite the excellent in vitro antiplasmodium activity profile, in vivo efficacy in the Plasmodium berghei mouse infection model was diminished, attributable to suboptimal oral bioavailability (F = 14.9%) at 10 mg·kg-1 resulting from poor permeability (log D7.4 = −0.82). No cross-resistance was observed against 44 common Pf mutant lines, suggesting activity via a novel mechanism of action.

AB - Toward addressing the cardiotoxicity liability associated with the antimalarial drug astemizole (AST, hERG IC50 = 0.0042 μM) and its derivatives, we designed and synthesized analogues based on compound 1 (Pf NF54 IC50 = 0.012 μM; hERG IC50 = 0.63 μM), our previously identified 3-trifluoromethyl-1,2,4-oxadiazole AST analogue. Compound 11 retained in vitro multistage antiplasmodium activity (ABS PfNF54 IC50 = 0.017 μM; gametocytes PfiGc/PfLGc IC50 = 1.24/1.39 μM, and liver-stage PbHepG2 IC50 = 2.30 μM), good microsomal metabolic stability (MLM CLint < 11 μL·min-1·mg-1, EH < 0.33), and solubility (150 μM). It shows a ∼6-fold and >6000-fold higher selectivity against human ether-á-go-go-related gene higher selectively potential over hERG relative to 1 and AST, respectively. Despite the excellent in vitro antiplasmodium activity profile, in vivo efficacy in the Plasmodium berghei mouse infection model was diminished, attributable to suboptimal oral bioavailability (F = 14.9%) at 10 mg·kg-1 resulting from poor permeability (log D7.4 = −0.82). No cross-resistance was observed against 44 common Pf mutant lines, suggesting activity via a novel mechanism of action.

KW - Astemizole

KW - gametocytocidal

KW - human ether-á-go-go-related gene (hERG)

KW - liver-stage activity

KW - Plasmodium berghei

KW - Plasmodium falciparum

KW - repositioning

KW - resistance phenotypes

UR - https://www.scopus.com/pages/publications/85188006501

U2 - 10.1021/acsmedchemlett.3c00496

DO - 10.1021/acsmedchemlett.3c00496

M3 - Article

C2 - 38628794

AN - SCOPUS:85188006501

SN - 1948-5875

VL - 15

SP - 463

EP - 469

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 4

ER -