Identification of Fast-Acting 2,6-Disubstituted Imidazopyridines That Are Efficacious in the in Vivo Humanized Plasmodium falciparum NODscidIL2Rγ^null Mouse Model of Malaria

Abstract

Optimization of a chemical series originating from whole-cell phenotypic screening against the human malaria parasite, Plasmodium falciparum, led to the identification of two promising 2,6-disubstituted imidazopyridine compounds, 43 and 74. These compounds exhibited potent activity against asexual blood stage parasites that, together with their in vitro absorption, distribution, metabolism, and excretion (ADME) properties, translated to in vivo efficacy with clearance of parasites in the PfSCID mouse model for malaria within 48 h of treatment.

Identification of 2,4-Disubstituted Imidazopyridines as Hemozoin Formation Inhibitors with Fast-Killing Kinetics and In Vivo Efficacy in the Plasmodium falciparum NSG Mouse Model

“…Yield: 0.130 g (20%). 1 H NMR (600 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.14 -8.07 (m, 1H), 8.00 2- (3,4-difluorophenyl)-4-(piperazin-1-yl)-1H-imidazo [4,5-c]pyridine (6) Step 1: General procedure A. tert-butyl 4-( 2 Step 2: To a suspension of tert-butyl 4-(2-(3,4-difluorophenyl)-1H-imidazo [4,5-c]pyridin-4yl)piperazine-1-carbamate (58 mg, 0.140 mmol) in DCM (1 ml) was added TFA (0.1 ml) at 25 °C.…”

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

“…Another hit compound from the SoftFocus kinase library 2‐aryl imidazopyridine ( 478 ) led to the development of 479 and 480 , which possessed excellent pharmacokinetic characteristics and in vivo activity in a humanised mouse model of malaria . The 2‐aryl imidazopyridine scaffold as well as the related pyrrolopyridine features in four unreported Pathogen Box compounds (MMV032967, 481 ; MMV676260, 482 ; MMV393144, 483 ; MMV392832, 484 ).…”

The Plasmodium falciparum ABC transporter ABCI3 confers parasite strain-dependent pleiotropic antimalarial drug resistance

“…Compounds 2–5 were kindly provided by the Medicines for Malaria Venture (Geneva, Switzerland), and 1 and 6 were synthesized at the Drug Discovery and Development Centre (H3D) at the University of Cape Town in South Africa as part of the SoftFocusKinase 59 (SFK59) library ( Le Manach et al, 2018 ; Nchinda et al, 2018 ). Parasites resistant to 1 were obtained from single-step selections where 10 7 3D7-A10 parasites in triplicate were cultured with a continuous 3×IC 50 drug pressure.…”