Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides

Abstract

The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-(2-phenylthiazol-4-yl)ethyl)amides, carbamates, and ureas, which rapidly, selectively, and potently kill both species of trypanosome. The mode of action of these compounds is unknown but does not involve CYP51 inhibition. They do, however, exhibit clear structure-activity relationships, consistent across both trypanosome species. Favorable physicochemical parameters place the best compounds in CNS drug-like chemical space but, as a class, they exhibit poor metabolic stability. One of the best compounds (64a) cleared all signs of T. cruzi infection in mice when CYP metabolism was inhibited, with sterile cure achieved in one mouse. This family of compounds thus shows significant promise for trypanosomiasis drug discovery.

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

“…Sykes’ screen also uncovered two related ethylamides ( 104 and 105 ) which displayed encouraging antikinetoplastid activity. A follow‐up SAR study conducted by Piggott and co‐workers led to a number of active 2‐phenylthiazole analogues including MMV688958 ( 106 ), which possessed improved activity against T.b. brucei and T. cruzi relative to 104 .…”

Synthesis and evaluation of novel 2,4-disubstituted arylthiazoles against T. brucei

“…New drugs are urgently required, as those that are currently available are characterized by sideeffects and treatment failures. 4,5 Various initiatives [6][7][8] have led to the discovery of promiscuous trypanocidal derivatives from phenotypic highthroughput screening of a number of compound libraries. These have been further refined and optimized to enhance drug-like properties.…”

“…1, as potent trypanocidals. 6,7 Based on these findings and our involvement in the adamantane chemistry, [9][10][11][12][13][14][15][16][17][18][19][20] we report herein on the chemistry and biology of thiazole derivatives of the general type scaffold IV. The thiazole moiety is an important pharmacophore in many compounds used against several tropical infectious diseases.…”

“…The length of the side chain of derivatives 2e, 2g and 3e was kept at the distance of three atoms (2C and 1N and vice versa), which in the derivatives I, II and III was found to be the optimal length for enhanced trypanocidal potency. [6][7][8] The length of the R group is different in adducts 2f, h and 3a, b. 2-Aminothiazole (adduct 3a), is a frequent-hitting fragment in biophysical binding assays.…”

Development of Predictive QSAR Models of 4‐Thiazolidinones Antitrypanosomal Activity Using Modern Machine Learning Algorithms

“…High throughput screening of the library of 80000 (Walter and Eliza Hall Institute) compounds inhibiting the growth of T brucei brucei allowed identifying a row of hit‐compounds, one of which was 2‐aryl‐4‐alkyl‐thiazol derivative. Optimization of the latter revealed a novel class of N‐(2‐(2‐phenylthiazol‐4‐yl)ethyl)amides, carbamates and ureas active against Tb rhodesiense and T cruzi . It should be mentioned that above described thiazolilhydrazones and 2,4‐substituted thiazole derivatives were characterized by low toxicity levels.…”