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1H-Benzo[d]imidazoles and 3,4-dihydroquinazolin-4-ones: Design, synthesis and antitubercular activity.

Authors :
Macchi, Fernanda Souza
Pissinate, Kenia
Villela, Anne Drumond
Abbadi, Bruno Lopes
Rodrigues-Junior, Valnês
Nabinger, Débora Dreher
Altenhofen, Stefani
Sperotto, Nathalia
da Silva Dadda, Adílio
Subtil, Fernanda Teixeira
de Freitas, Talita Freitas
Erhart Rauber, Ana Paula
Borsoi, Ana Flávia
Bonan, Carla Denise
Bizarro, Cristiano Valim
Basso, Luiz Augusto
Santos, Diógenes Santiago
Machado, Pablo
Source :
European Journal of Medicinal Chemistry. Jul2018, Vol. 155, p153-164. 12p.
Publication Year :
2018

Abstract

Using a classical hybridization approach, a series of 1 H -benzo[ d ]imidazoles and 3,4-dihydroquinazolin-4-ones were synthesized (39 examples) and evaluated as inhibitors of Mycobacterium tuberculosis growth. Chemical modification studies yielded potent antitubercular agents with minimum inhibitory concentration (MIC) values as low as 0.24 μM against M. tuberculosis H37Rv strain. Further, the synthesized compounds were active against four drug-resistant strains containing different levels of resistance for the first line drugs. These molecules were devoid of apparent toxicity to HepG2, HaCat, and Vero cells with IC 50s  > 30 μM. Viability in mammalian cell cultures was evaluated using MTT and neutral red assays. In addition, some 3,4-dihydroquinazolin-4-ones showed low risk of cardiac toxicity, no signals of neurotoxicity or morphological alteration in zebrafish ( Danio rerio ) toxicity models. 3,4-Dihydroquinazolin-4-ones 9q and 9w were considered the lead compounds of these series of molecules with MIC values of 0.24 μM and 0.94 μM against M. tuberculosis H37Rv, respectively. Taken together, these data indicate that this class of compounds may furnish candidates for future development of novel anti-TB drugs. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
02235234
Volume :
155
Database :
Academic Search Index
Journal :
European Journal of Medicinal Chemistry
Publication Type :
Academic Journal
Accession number :
130858393
Full Text :
https://doi.org/10.1016/j.ejmech.2018.06.005