Antiprotozoal Selectivity of Diimidazoline N-Phenylbenzamides

Abstract

We discovered three diimidazolines with high antiplasmodial selectivity that had IC50 values of 1.9-28 nM against cultured Plasmodium falciparum. We also identified a gem-dimethyl diimidazoline with high antitrypanosomal selectivity that had an IC50 value of 26 nM against cultured Trypanosoma brucei rhodesiense. Two 2-imidazoline heterocycles in a para orientation on a N-phenylbenzamide or similar core structure were required for high antiprotozoal activity. Ring expansion of the imidazoline as well as heterocyclic variants with pKa values of <7 all decreased activity significantly.

Imidazoline- and Benzamidine-Based Trypanosome Alternative Oxidase Inhibitors: Synthesis and Structure–Activity Relationship Studies

“…To do so, we tried to prepare the "keto" analogue of 1d, with a carbonyl bond linking the methylene chain to the 5-methylresorcinol scaffold instead of an amide bond (Scheme 3a). 16 1.…”

“…In the present work, we tested the benzamidinium ( 1a – d ), 2-phenylimidazolin-3-ium ( 2c ), and 2-(phenylamino)­imidazolin-3-ium ( 3c ) cations as less bulky surrogates of TPP + (Chart ). Compounds containing these cationic groups, which are found in many trypanocidal drugs (e.g., pentamidine, diminazene) and investigational compounds, are known to strongly accumulate in the mitochondrial matrix of trypanosomes, against considerable concentration gradients. − We hypothesized that smaller cations would insert themselves deeper into the enzyme cavity to promote favorable interactions of the 2,4-dihydroxy-6-methylbenzoic head with the enzyme active site. With the previous 4-hydroxybenzoate series, a methylene linker of less than C-14 between the TPP or quinolin-1-ium cation and the head region was detrimental to TAO inhibition. , However, the imidazoline- and benzamidine-based cations used in this study are structurally different (i.e., shape, size, and electronic properties) to these cations and may present a different SAR.…”

Tribute to Jonathan Vennerstrom

“…In addition to his foundational work on malaria and schistosomiasis, Jonathan has developed a novel class of diimidazolines for the treatment of African trypanosomiasis with an improved safety profile compared to the current standard of care pentamidine for the first stage of the disease. 8 In his 2008 speech to the United Nations on the UN Millennium Development Goals, Bill Gates highlighted Jonathan's antimalarial project as a pioneering medical advance stating "In early animal studies, a single dose of this drug cured malariasomething we've never seen before". In recognition of his accomplishments, Jonathan received the 2019 ACS Award for Creative Invention established "to recognize a single inventor for the successful application of research in chemistry and/or chemical engineering that contributes to the material prosperity and happiness of people.…”

“…In parallel efforts, his laboratories have explored a novel series of aryl hydantoins and diarylureas with impressive antischistosomal activity. In addition to his foundational work on malaria and schistosomiasis, Jonathan has developed a novel class of diimidazolines for the treatment of African trypanosomiasis with an improved safety profile compared to the current standard of care pentamidine for the first stage of the disease …”