Modulation of antimalarial activity at a putative bisquinoline receptor in vivo using fluorinated bisquinolines

Fielding, AJ; Lukinović, V; Evans, PG; Alizadeh-Shekalgourabi, S; Bisby, RH; Drew, MGB; Male, V; Del Casino, A; Dunn, JF; Randle, LE; Dempster, NM; Nahar, L; Sarker, SD; Cantú Reinhard, FG; de Visser, SP; Dascombe, MJ; Ismail, FMD

Abstract

Antimalarials can interact with heme covalently, by π⋅⋅⋅π interactions or by hydrogen bonding. Consequently, the prototropy of 4‐aminoquinolines and quinoline methanols was investigated by using quantum mechanics. Calculations showed mefloquine protonated preferentially at the piperidine and was impeded at the endocyclic nitrogen because of electronic rather than steric factors. In gas‐phase calculations, 7‐substituted mono‐ and bis‐4‐aminoquinolines were preferentially protonated at the endocyclic quinoline nitrogen. By contrast, compounds with a trifluoromethyl substituent on both the 2‐ and 8‐positions, reversed the order of protonation, which now favored the exocyclic secondary amine nitrogen at the 4‐position. Loss of antimalarial efficacy by CF3 groups simultaneously occupying the 2‐ and 8‐positions was recovered if the CF3 group occupied the 7‐position. Hence, trifluoromethyl groups buttressing the quinolinyl nitrogen shifted binding of antimalarials to hematin, enabling switching from endocyclic to the exocyclic N. Both theoretical calculations (DFT calculations: B3LYP/BS1) and crystal structure of (±)‐trans‐N1,N2‐bis‐(2,8‐ditrifluoromethylquinolin‐4‐yl)cyclohexane‐1,2‐diamine were used to reveal the preferred mode(s) of interaction with hematin. The order of antimalarial activity in vivo followed the capacity for a redox change of the iron(III) state, which has important implications for the future rational design of 4‐aminoquinoline antimalarials.

Citation

Fielding, A., Lukinović, V., Evans, P., Alizadeh-Shekalgourabi, S., Bisby, R., Drew, M., …Ismail, F. (2017). Modulation of antimalarial activity at a putative bisquinoline receptor in vivo using fluorinated bisquinolines. Chemistry - A European Journal, 23(28), 6811-6828. https://doi.org/10.1002/chem.201605099

• Journal Article Type: Article
• Online Publication Date: Apr 21, 2017
• Publication Date: Apr 21, 2017
• Deposit Date: Oct 18, 2019
• Journal: Chemistry - A European Journal
• Print ISSN: 0947-6539
• Electronic ISSN: 1521-3765
• Publisher: Wiley
• Volume: 23
• Issue: 28
• Pages: 6811-6828
• DOI: https://doi.org/10.1002/chem.201605099
• Keywords: General Chemistry
• Publisher URL: https://doi.org/10.1002/chem.201605099
• Related Public URLs: https://onlinelibrary.wiley.com/journal/15213765
• Additional Information: Additional Information : ** Article version: VoR ** From Crossref via Jisc Publications Router **Journal IDs: pissn 0947-6539 **History: published 17-05-2017; issued 21-04-2017; published_online 21-04-2017 **License for this article: starting on 21-04-2017, , http://onlinelibrary.wiley.com/termsAndConditions; Projects : 606831