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HYPOTHESIS AND THEORY article

Front. Drug Discov.
Sec. Technologies and Strategies to Enable Drug Discovery
Volume 4 - 2024 | doi: 10.3389/fddsv.2024.1430927

Multiparameter Ranking of Carbazoles for Anti-Trypanosome Lead Discovery

Provisionally accepted
Amrita Sharma Amrita Sharma 1Carlos E. Sanz-Rodriguez Carlos E. Sanz-Rodriguez 2Michael Pollastri Michael Pollastri 3Andrei Purmal Andrei Purmal 4Kojo Mensa-Wilmot Kojo Mensa-Wilmot 1*
  • 1 Kennesaw State University, Kennesaw, United States
  • 2 University of Georgia, Athens, Georgia, United States
  • 3 Northeastern University, Boston, Massachusetts, United States
  • 4 Incuron, LLC, Buffalo, NY, United States

The final, formatted version of the article will be published soon.

    Criteria for progression of hits in discovery of leads for Human African trypanosomiasis (HAT), a neglected disease caused by the microbial eukaryote Trypanosoma brucei, are not standardized. Hits are advanced upon meeting thresholds for drug-like molecules. Following those principles pharmacokinetics (Cmax and AUC0-6h) and anti-trypanosome characteristics predicted arrest of T. brucei proliferation in mice by three curaxins. Unexpectedly, while CBL0137 cured HAT in a mouse model, CBL0174 and CBL0187, structure analogs of CBL0137 with similar drug-like properties failed to control division of T. brucei. Herein, we propose an alternative strategy that integrates physicochemical, metabolic, pharmacokinetic, pharmacodynamic, tissue distribution and trypanocidality parameters into calculation of a score for ranking compounds in hit-to-lead campaigns. Data from our studies of curaxins support feasibility of the goal. Serum dropped anti-trypanosome potency of CBL0174 and CBL0187 considerably. Delayed trypanocidal concentrations (DTC25 and DTC90) were used to study modes of curaxin actions in trypanosomes. Efficacy of CBL0137 in mice correlated with (i) high AUC0-6h:DTC90 ratio, (ii) blocking of transferrin endocytosis, and (iii) inhibition of protein synthesis. Hydroxylation of the carbazole prevented CBL0137 from inhibiting endocytosis of Tf. A multiparametric score termed "Curaxin HAT Lead Efficacy (CHLE)" was calculated using pharmacokinetic, physicochemical, metabolism, brain exposure, and pharmacodynamic data; CBL0137 was the highest scoring hit. Complementing these observations, and predictive of performance of curaxins in mice, CBL0137, but not CBL0174 or CBL0187, was trypanocidal after exposure of trypanosomes to AUC0-6h amounts of the hits for six hours in vitro. We discuss a role for CHLE scores in ranking of curaxins for anti-HAT lead discovery. Principles used to develop CHLE scores may be used to calculate new ones for other scaffolds during discovery of leads for HAT or other infectious diseases.

    Keywords: Trypanosomiasis, Mouse model of disease, hit-to-lead selection, drug modes of action, parasite, Infectious Disease

    Received: 10 May 2024; Accepted: 13 Jun 2024.

    Copyright: © 2024 Sharma, Sanz-Rodriguez, Pollastri, Purmal and Mensa-Wilmot. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Kojo Mensa-Wilmot, Kennesaw State University, Kennesaw, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.