In vitro trypanocidal activities and structure–activity relationships of ciprofloxacin analogs

• Published in: Molecular diversity Vol. 28; no. 4; pp. 2667 - 2680
• Main Authors: Janse van Rensburg, Helena D., Suganuma, Keisuke, N’Da, David D.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.08.2024; Springer Nature B.V
• Subjects: Animals; Bacterial infections; Biochemistry; Biomedical and Life Sciences; Cattle; Cell Line; Chemotherapy; Ciprofloxacin - analogs & derivatives; Ciprofloxacin - chemistry; Ciprofloxacin - pharmacology; Drug development; Drug resistance; Life Sciences; Mitochondrial DNA; Organic Chemistry; Original Article; Pharmacokinetics; Pharmacy; Polymer Sciences; Protozoa; Structure-Activity Relationship; Toxicity; Tropical diseases; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma - drug effects; African trypanosomes; 1,2,3-Triazole; Trypanocidal activity; Ciprofloxacin
• ISSN: 1381-1991; 1573-501X; 1573-501X
• DOI: 10.1007/s11030-023-10704-9

Tropical diseases, such as African trypanosomiasis, by their nature and prevalence lack the necessary urgency regarding drug development, despite the increasing need for novel, structurally diverse antitrypanosomal drugs, using different mechanisms of action that would improve drug efficacy and safety. Traditionally antibacterial agents, the fluoroquinolones, reportedly possess in vitro trypanocidal activities against Trypanosoma brucei organisms. During our research, the fluroquinolone, ciprofloxacin ( 1 ), and its analogs ( 2 – 24 ) were tested against bloodstream forms of T. brucei brucei , T. b. gambiense , T. b. rhodesiense , T. evansi , T. equiperdum , and T. congolense and Madin-Darby bovine kidney cells (cytotoxicity). Ciprofloxacin [CPX ( 1 )] demonstrated selective trypanocidal activity against T. congolense (IC 50 7.79 µM; SI 39.6), whereas the CPX derivatives ( 2 – 10 ) showed weak selective activity (25 < IC 50  < 65 µM; 2 < SI < 4). Selectivity and activity of the CPX and 1,2,3-triazole (TZ) hybrids ( 11 – 24 ) were governed by their chemical functionality at C-3 (carboxylic acid, or 4-methylpiperazinyl amide) and their electronic effect (electron-donating or electron-withdrawing para-benzyl substituent), respectively. Trypanocidal hits in the micromolar range were identified against bloodstream forms of T. congolense [CPX ( 1 ); CPX amide derivatives 18 : IC 50 8.95 µM; SI 16.84; 22: IC 50 5.42 µM; SI 25.2] and against T. brucei rhodesiense (CPX acid derivative 13: IC 50 4.51 µM; SI 10.2), demonstrating more selectivity toward trypanosomes than mammalian cells. Hence, the trypanocidal hit compound 22 may be optimized by retaining the 4-methylpiperazine amide functional group (C-3) and the TZ moiety at position N-15 and introducing other electron-withdrawing ortho -, meta -, and/or para -substituents on the aryl ring in an effort to improve the pharmacokinetic properties and increase the trypanocidal activity. Graphical abstract Structure–activity relationships of ciprofloxacin-1,2,3-triazole hybrids were governed by the chemical functionality at C-3 and electronic effect.