Guanidinium compounds with sub-micromolar activities against Mycobacterium tuberculosis. Synthesis, characterization and biological evaluations

Bioorg Med Chem. 2015 Sep 1;23(17):5410-8. doi: 10.1016/j.bmc.2015.07.053.

Hugues Massimba-Dibama ¹, Maxime Mourer ², Patricia Constant ³, Mamadou Daffé ³, Jean-Bernard Regnouf-de-Vains ⁴

Affiliations

1 CNRS, SRSMC, UMR 7565, équipe MoBAT, F-54506, France.
2 CNRS, SRSMC, UMR 7565, équipe MoBAT, F-54506, France; Université de Lorraine, SRSMC, UMR 7565, équipe MoBAT, Vandœuvre-lès-Nancy F-54506, France.
3 CNRS, IPBS (Institut de Pharmacologie et Biologie Structurale), Département Mécanismes Moléculaires des Infections Mycobactériennes, 205 route de Narbonne, F-31077 Toulouse Cedex 04, France; Université de Toulouse, UPS, 118 route de Narbonne, F-31062 Toulouse Cedex 9, France.
4 CNRS, SRSMC, UMR 7565, équipe MoBAT, F-54506, France; Université de Lorraine, SRSMC, UMR 7565, équipe MoBAT, Vandœuvre-lès-Nancy F-54506, France. Electronic address: jean-bernard.regnouf@univ-lorraine.fr.

PMID: 26254828 DOI: 10.1016/j.bmc.2015.07.053

Abstract

Seven polycharged species, incorporating 1, 2, 3, 4 and 6 guanidine arms organized around a benzene core were synthesized and assayed as anti-mycobacterial agents against Mycobacterium tuberculosis. They display MIC values comprised between 25 and 12.5 μM (close to ethambutol EMB) for the mono- and the hexa-substituted derivatives, and 0.8 μM (close to isoniazid and streptomycin) for the tri-substituted derivative. The three bi- and the tetra-substituted analogs displayed MIC values of CA. 6.5-3.0 μM. The latter were also evaluated against the isoniazid-resistant MYC5165 strain, resulting in highly interesting micromolar or sub-micromolar MIC, CA. 4-125 times more active than isoniazid. These preliminary results are attractive for the development of new anti-TB agents.

Keywords

Ammonium; Anti-mycobacterial; Guanidinium; Mycobacterium tuberculosis; Tuberculosis.

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