Novel aroyl guanidine anti-trypanosomal compounds that exert opposing effects on parasite energy metabolism

Varghese, S. et al. (2024) Novel aroyl guanidine anti-trypanosomal compounds that exert opposing effects on parasite energy metabolism. European Journal of Medicinal Chemistry, 116162. (doi: 10.1016/j.ejmech.2024.116162) (In Press)

Abstract

Human African trypanosomiasis (HAT), or sleeping sickness, is a neglected tropical disease with current treatments marred by severe side effects or delivery issues. To identify novel classes of compounds for the treatment of HAT, a high throughput screen (HTS) had previously been conducted on bloodstream forms of T. b. brucei, a model organism closely related to the human pathogens T. b. gambiense and T. b. rhodesiense. This HTS had identified a number of structural classes with potent bioactivity against T. b. brucei (IC50 ≤ 10 μM) with selectivity over mammalian cell-lines (selectivity index of ≥10). One of the confirmed hits was an aroyl guanidine derivative. Deemed to be chemically tractable with attractive physicochemical properties, here we explore this class further to develop the SAR landscape. We also report the influence of the elucidated SAR on parasite metabolism, to gain insight into possible modes of action of this class. Of note, two sub-classes of analogues were identified that generated opposing metabolic responses involving disrupted energy metabolism. This knowledge may guide the future design of more potent inhibitors, while retaining the desirable physicochemical properties and an excellent selectivity profile of the current compound class.

• Item Type: Articles
• Additional Information: This research was supported by the National Health and Medical Research Council of Australia (NHMRC), IRIISS grant no. 361646, and through NHMRC project grants 1025581 and 1079351, and through Fellowship support for J.B. B. (2012-2016 Senior Research Fellowship #1020411; 2017-2021 Principal Research Fellowship). The authors acknowledge the Australian Federal Government Education Investment Fund Super Science Initiative and the Victorian State Government (OIS grant), Victoria Science Agenda Investment Fund for infrastructure support. The authors acknowledge the facilities, and the scientific and technical assistance of the Australian Translational Medicinal Chemistry Facility (ATMCF), Monash Institute of Pharmaceutical Sciences (MIPS). ATMCF is supported by Therapeutic Innovation Australia (TIA). TIA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program.
• Status: In Press
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Barrett, Professor Michael
• Authors: Varghese, S., Srivastava, A., Wong, S. W., Le, T., Pitcher, N., Mesnard, M., Lallemand, C., Rahmani, R., Moawad, S. R., Huang, F., He, T., Sleebs, B. E., Barrett, M. P., Sykes, M. L., Avery, V. M., Creek, D. J., and Baell, J. B.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: European Journal of Medicinal Chemistry
• Publisher: Elsevier
• ISSN: 0223-5234
• Published Online: 17 January 2024