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

التفاصيل البيبلوغرافية
العنوان: Novel aroyl guanidine anti-trypanosomal compounds that exert opposing effects on parasite energy metabolism.
المؤلفون: Varghese S; Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia., Srivastava A; Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia., Wong SW; Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia., Le T; Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia., Pitcher N; Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia., Mesnard M; Ensemble Scientifique des Cézeaux, 24 avenue des Landais, 63170, Aubière, France., Lallemand C; Ensemble Scientifique des Cézeaux, 24 avenue des Landais, 63170, Aubière, France., Rahmani R; Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia., Moawad SR; The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3052, Victoria, Australia., Huang F; School of Pharmaceutical Sciences, Nanjing Tech University, No. 30 South Puzhu Road, Nanjing, 211816, China., He T; School of Pharmaceutical Sciences, Nanjing Tech University, No. 30 South Puzhu Road, Nanjing, 211816, China., Sleebs BE; The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3052, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia., Barrett MP; Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom., Sykes ML; Discovery Biology, Centre for Cellular Phenomics, Griffith University, Nathan, Queensland, 4111, Australia., Avery VM; Discovery Biology, Centre for Cellular Phenomics, Griffith University, Nathan, Queensland, 4111, Australia; School of Environment and Science, Griffith University, Nathan, QLD, 4111, Australia., Creek DJ; Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia. Electronic address: darren.creek@monash.edu., Baell JB; Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia; School of Pharmaceutical Sciences, Nanjing Tech University, No. 30 South Puzhu Road, Nanjing, 211816, China. Electronic address: jonathan@lyterian.com.
المصدر: European journal of medicinal chemistry [Eur J Med Chem] 2024 Mar 15; Vol. 268, pp. 116162. Date of Electronic Publication: 2024 Jan 17.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Paris : Editions Scientifiques Elsevier
Original Publication: Paris, S.E.C.T. [etc.]
مواضيع طبية MeSH: Trypanocidal Agents*/chemistry , Parasites* , Trypanosomiasis, African*/drug therapy , Trypanosomiasis, African*/parasitology , Trypanosoma* , Trypanosoma brucei brucei*, Animals ; Humans ; Trypanosoma brucei rhodesiense ; Guanidine/pharmacology ; Guanidines/pharmacology ; Energy Metabolism ; Mammals
مستخلص: 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, high throughput screening (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 (IC 50  ≤ 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
معلومات مُعتمدة: MR/S019650/1 United Kingdom MRC_ Medical Research Council
المشرفين على المادة: 0 (Trypanocidal Agents)
JU58VJ6Y3B (Guanidine)
0 (Guanidines)
تواريخ الأحداث: Date Created: 20240223 Date Completed: 20240318 Latest Revision: 20240318
رمز التحديث: 20240318
DOI: 10.1016/j.ejmech.2024.116162
PMID: 38394930
قاعدة البيانات: MEDLINE
الوصف
تدمد:1768-3254
DOI:10.1016/j.ejmech.2024.116162