Discovery of N-(2-aminoethyl)-N-benzyloxyphenyl benzamides: New potent Trypanosoma brucei inhibitors

Abstract

A phenotypic screen of a compound library for antiparasitic activity on Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (HAT), led to the identification of N-(2-aminoethyl)-N-phenyl benzamides as a starting point for hit-to-lead medicinal chemistry. Eighty two analogues were prepared, which led to the identification of a set of highly potent N-(2-aminoethyl)-N-benzyloxyphenyl benzamides with the most potent compound 73 having an in vitro EC50 = 0.001 μM. The compounds displayed drug-like properties when tested in a number of in vitro assays. Compound 73 was orally bioavailable and displayed good plasma and brain exposure in mice, cured 2 out of 3 mice infected with Trypanosoma brucei in acute model when dosed orally at 50 mg/kg once per day for 4 days. Given its potent antiparasitic properties and its ease of synthesis, compound 73 represents a potential lead for the development of drug to treat Human African Trypanosomiasis.

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

“…The Pathogen Box contained two further antikinetoplastid pyridyl benzamides, 119 (MMV202553) and 120 (MMV688793), both of which are unreported in the literature and appear to conform to many of the SAR parameters described by Ferrins et al . Buckner and co‐workers identified the related phenyl benzamide 121 as a promising nontoxic antitrypanosomal compound with encouraging pharmacokinetic and pharmacodynamic properties . Further optimisation indicated that the inclusion of a 4‐chlorobenzyloxy substituent such as that observed in compound 122 (MMV688371) improved activity.…”

“…Further optimisation indicated that the inclusion of a 4‐chlorobenzyloxy substituent such as that observed in compound 122 (MMV688371) improved activity. Finally the pyridyl analogue 123 was found to cure 2/3 mice in an acute T. brucei infection model after oral dosing for four days, whilst retaining encouraging pharmacokinetic and pharmacodynamic properties . The Pathogen Box contains the related compound 124 (MMV688798), which is currently unreported in the literature.…”

Phenotypic Drug Discovery for Human African Trypanosomiasis: A Powerful Approach

“…For Scaffold 7, it was poor metabolic stability that precluded its further development. Finally, Scaffold 4 was discontinued because of a "static" killing mechanism [17]. This became apparent during in vivo efficacy experiments when administration of the compound resulted in temporary suppression of parasites followed by rebound.…”

“…This became apparent during in vivo efficacy experiments when administration of the compound resulted in temporary suppression of parasites followed by rebound. The "static mechanism could be recapitulated in vitro in "washout" experiments [17], which was latter incorporated into our screening routine to avoid repeating the problem.…”

“…One compound (11) had modest brain permeability of 9%, but was included for further chemistry despite this marginal activity. Four compounds (13)(14)(15)17) had minimal concentrations in the brain (< 2% of plasma levels) and were no longer pursued. One compound (16) had nearly undetectable plasma and brain levels at the 60-min time point and was also considered unsuitable for further development.…”