Synthesis and Antimycobacterial Activity of 2,5-Disubstituted and 1,2,5-Trisubstituted Benzimidazoles

• Published in: Frontiers in chemistry Vol. 8; p. 433
• Main Authors: Jiménez-Juárez, Rogelio, Cruz-Chávez, Wendy, de Jesús-Ramírez, Nayeli, Castro-Ramírez, Guadalupe Ivonne, Uribe-González, Itzel, Martínez-Mejía, Gabriela, Ruiz-Nicolás, Ricardo, Aguirre-Alvarado, Charmina, Castrejón-Jiménez, Nayeli Shantal, García-Pérez, Blanca Estela
• Format: Journal Article
• Language: English
• Published: Frontiers Media S.A 19-06-2020
• Subjects: benzimidazole derivatives; Chemistry; docking study; FtsZ protein; mycobacterial intracellular activity; Mycobacterium tuberculosis
• ISSN: 2296-2646; 2296-2646
• DOI: 10.3389/fchem.2020.00433

The appearance of drug-resistant strains of
Mycobacterium tuberculosis
and the dramatic increase in infection rates worldwide evidences the urgency of developing new and effective compounds for treating tuberculosis. Benzimidazoles represent one possible source of new compounds given that antimycobacterial activity has already been documented for some derivatives, such as those bearing electron-withdrawing groups. The aim of this study was to synthesize two series of benzimidazoles, di- and trisubstituted derivatives, and evaluate their antimycobacterial activity. Accordingly,
5a
and
5b
were synthesized from hydroxymoyl halides
3a
and
3b
, and nitro-substituted o-phenylenediamine
4
. Compound
11
was synthesized from an aromatic nitro compound, 4-chloro-1,2-phenylenediamine
9
, mixed with 3-nitrobenzaldehyde
10
, and bentonite clay. Although the synthesis of
11
has already been reported, its antimycobacterial activity is herein examined for the first time. 1,2,5-trisubstituted benzimidazoles
7a
,
7b
, and
12
were obtained from N-alkylation of
5a
,
5b
, and
11
. All benzimidazole derivatives were characterized by FT-IR, NMR, and HR-MS, and then screened for their
in vitro
antimycobacterial effect against the
M. tuberculosis
H37Rv strain. The N-alkylated molecules (
7a
,
7b
, and
12
) generated very limited
in vitro
inhibition of mycobacterial growth. The benzimidazoles (
5a
,
5b
, and
11
) showed
in vitro
potency against mycobacteria, reflected in minimal inhibitory concentration (MIC) values in the range of 6.25–25 μg/mL. Consequently, only the 2,5-disubstituted benzimidazoles were assessed for biological activity on mouse macrophages infected with
M. tuberculosis
. A good effect was found for the three compounds. The cytotoxicity assay revealed very low toxicity for all the test compounds against the macrophage cell line. According to the docking study, 2,5-disubstituted benzimidazoles exhibit high affinity for an interdomain cleft that plays a key role in the GTP-dependent polymerization of the filamentous temperature-sensitive Z (FtsZ) protein. The ability of different benzimidazoles to impede FtsZ polymerization is reportedly related to their antimycobacterial activity. On the other hand, the 1,2,5-trisubstituted benzimidazoles docked to the N-terminal of the protein, close to the GTP binding domain, and did not show strong binding energies. Overall,
5a
,
5b
, and
11
proved to be good candidates for
in vivo
testing to determine their potential for treating tuberculosis.