High-Throughput Phenotypic Screening and Machine Learning Methods Enabled the Selection of Broad-Spectrum Low-Toxicity Antitrypanosomatidic Agents

Abstract

Broad-spectrum anti-infective chemotherapy agents with activity against Trypanosomes, Leishmania, and Mycobacterium tuberculosis species were identified from a high-throughput phenotypic screening program of the 456 compounds belonging to the Ty-Box, an in-house industry database. Compound characterization using machine learning approaches enabled the identification and synthesis of 44 compounds with broad-spectrum antiparasitic activity and minimal toxicity against Trypanosoma brucei, Leishmania Infantum, and Trypanosoma cruzi. In vitro studies confirmed the predictive models identified in compound 40 which emerged as a new lead, featured by an innovative N-(5-pyrimidinyl)­benzenesulfonamide scaffold and promising low micromolar activity against two parasites and low toxicity. Given the volume and complexity of data generated by the diverse high-throughput screening assays performed on the compounds of the Ty-Box library, the chemoinformatic and machine learning tools enabled the selection of compounds eligible for further evaluation of their biological and toxicological activities and aided in the decision-making process toward the design and optimization of the identified lead.

Identification of Innovative Folate Inhibitors Leveraging the Amino Dihydrotriazine Motif from Cycloguanil for Their Potential as Anti-Trypanosoma brucei Agents

“…Monocyclic and bicyclic aromatic systems such as pyrimidines, pteridines, quinolines, pyrrolo-pyrimidines, benzimidazoles, and benzothiazoles, mimicking the substrate pterin moiety, were extensively studied as molecular scaffolds for the design of Tb PTR1 and Tb DHFR inhibitors. ,− Also, the antimalarial drug cycloguanil (Cyc) (Figure a), featured by a dihydrotriazine core, was found to target Tb PTR1 besides Plasmodial and Trypanosoma DHFR . Interestingly, Cyc exhibited a superior affinity for Tb DHFR ( K i = 256 nM) than Tb PTR1 (IC 50 = 31.6 μM) and a low antiparasitic effect against T.…”