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Open AccessArticle

Anti-Mycobacterial Evaluation of 7-Chloro-4-Aminoquinolines and Hologram Quantitative Structure–Activity Relationship (HQSAR) Modeling of Amino–Imino Tautomers

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Departamento de Química, Universidade Estadual de Londrina (UEL), Londrina 86057-970, Brazil
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Faculdade de Farmácia, Laboratório de Química Medicinal (LQMed), Programa de Pós-Graduação em Ciências Aplicadas a Produtos para Saúde, Universidade Federal Fluminense (UFF), Niterói 24241-000, Brazil
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Programa de Pós-Graduação em Química (PGQu), Instituto de Química (IQ), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21949-900, Brazil
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Fundação Oswaldo Cruz (FioCruz), Instituto de Tecnologia em Fármacos (Far-Manguinhos), Rio de Janeiro 21041-250, Brazil
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Fundação Oswaldo Cruz (FioCruz), Instituto de Pesquisas Clínicas Evandro Chagas (IPEC), Rio de Janeiro 21040-360, Brazil
*
Authors to whom correspondence should be addressed.
Academic Editor: Osvaldo A. Santos-Filho
Pharmaceuticals 2017, 10(2), 52; https://doi.org/10.3390/ph10020052
Received: 8 May 2017 / Revised: 5 June 2017 / Accepted: 6 June 2017 / Published: 9 June 2017
(This article belongs to the Special Issue Chemoinformatics and Drug Design)
In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized three series (A, B, and C) of 7-chloro-4-aminoquinolines, which were evaluated in vitro against Mycobacterium tuberculosis (MTB). Now, we report the anti-MTB and cytotoxicity evaluations of a new series, D (D01D21). Considering the active compounds of series A (A01A13), B (B01B13), C (C01C07), and D (D01D09), we compose a data set of 42 compounds and carried out hologram quantitative structure–activity relationship (HQSAR) analysis. The amino–imino tautomerism of the 4-aminoquinoline moiety was considered using both amino (I) and imino (II) forms as independent datasets. The best HQSAR model from each dataset was internally validated and both models showed significant statistical indexes. Tautomer I model: leave-one-out (LOO) cross-validated correlation coefficient (q2) = 0.80, squared correlation coefficient (r2) = 0.97, standard error (SE) = 0.12, cross-validated standard error (SEcv) = 0.32. Tautomer II model: q2 = 0.77, r2 = 0.98, SE = 0.10, SEcv = 0.35. Both models were externally validated by predicting the activity values of the corresponding test set, and the tautomer II model, which showed the best external prediction performance, was used to predict the biological activity responses of the compounds that were not evaluated in the anti-MTB trials due to poor solubility, pointing out D21 for further solubility studies to attempt to determine its actual biological activity. View Full-Text
Keywords: Mycobacterium tuberculosis; 4-aminoquinoline; amino–imino tautomerism; molecular modeling; hologram quantitative structure–activity relationship (HQSAR); drug design; anti-mycobacterial activity; cytotoxicity Mycobacterium tuberculosis; 4-aminoquinoline; amino–imino tautomerism; molecular modeling; hologram quantitative structure–activity relationship (HQSAR); drug design; anti-mycobacterial activity; cytotoxicity
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MDPI and ACS Style

Bispo, M.L.F.; Lima, C.H.S.; Cardoso, L.N.F.; Candéa, A.L.P.; Bezerra, F.A.F.M.; Lourenço, M.C.S.; Henriques, M.G.M.O.; Alencastro, R.B.; Kaiser, C.R.; Souza, M.V.N.; Albuquerque, M.G. Anti-Mycobacterial Evaluation of 7-Chloro-4-Aminoquinolines and Hologram Quantitative Structure–Activity Relationship (HQSAR) Modeling of Amino–Imino Tautomers. Pharmaceuticals 2017, 10, 52.

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