Skip to Main content Skip to Navigation
Journal articles

8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi

Abstract : An antikinetoplastid pharmacomodulation study was done at position 8 of a previously identified pharmacophore in 3-nitroimidazo[1,2-a]pyridine series. Twenty original derivatives bearing an alkynyl moiety were synthesized via a Sonogashira cross-coupling reaction and tested in vitro, highlighting 3 potent (40 nM ≤ EC50 blood stream form≤ 70 nM) and selective (500 ≤ SI ≤ 1800) anti-T. brucei brucei molecules (19, 21 and 22), in comparison with four reference drugs. Among these hit molecules, compound 19 also showed the same level of activity against T. cruzi (EC50 amastigotes = 1.2 μM) as benznidazole and fexinidazole. An in vitro comet assay showed that nitroaromatic derivative 19 was not genotoxic. It displayed a low redox potential value (-0.68 V/NHE) and was shown to be bioactivated by type 1 nitroreductases both in Leishmania and Trypanosoma. The SAR study indicated that an alcohol function improved aqueous solubility while maintaining good activity and low cytotoxicity when the hydroxyl group was at position beta of the alkyne triple bond. Hit-compound 19 was also evaluated regarding in vitro pharmacokinetic data: 19 is BBB permeable (PAMPA assay), has a 16 min microsomal half-life and a high albumin binding (98.5%). Moreover, compound 19 was orally absorbed and was well tolerated in mouse after both single and repeated administrations at 100 mg/kg. Its mouse plasma half-life (10 h) is also quite encouraging, paving the way toward further efficacy evaluations in parasitized mouse models, looking for a novel antitrypanosomal lead compound.
Document type :
Journal articles
Complete list of metadata

https://hal.inrae.fr/hal-02899751
Contributor : Accord Elsevier CCSD Connect in order to contact the contributor
Submitted on : Monday, July 18, 2022 - 10:42:38 AM
Last modification on : Thursday, August 4, 2022 - 5:20:21 PM

File

S0223523420305304.pdf
Files produced by the author(s)

Licence


Distributed under a Creative Commons Attribution - NonCommercial 4.0 International License

Identifiers

Citation

Cyril Fersing, Clotilde Boudot, Caroline Castera-Ducros, Émilie Pinault, Sébastien Hutter, et al.. 8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi. European Journal of Medicinal Chemistry, Elsevier, 2020, 202, pp.112558. ⟨10.1016/j.ejmech.2020.112558⟩. ⟨hal-02899751⟩

Share

Metrics

Record views

86

Files downloads

3