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

Marcelle Bispo,Maria Lourenço,Laura Cardoso,André Candéa,Ricardo Alencastro,Flávio Bezerra,Carlos Kaiser,Maria Henriques,Camilo Lima,Magaly Albuquerque,Marcus Souza

doi:10.3390/ph10020052

Abstract

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 (D01–D21). Considering the active compounds of series A (A01–A13), B (B01–B13), C (C01–C07), and D (D01–D09), 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.

Highlights

Tuberculosis (TB), a severe infectious bacterial disease caused by Mycobacterium tuberculosis (MTB), infected almost 9.6 million of people around the world and caused 1.5 million deaths in 2014 [1]
The antimycobacterial activities of D01–D21 were evaluated against the M. tuberculosis H37Rv strain susceptible to streptomycin, isoniazid, rifampin, and ethambutol (S.I.R.E.) drugs (American Type Culture Collection, ATCC® 27294TM), using the microplate Alamar blue assay (MABA) [21,22], and Pharmaceuticals 2017, 10, 52 this current work, we report the biological evaluation of series D against the MTB wild-type H37Rv strain (Figure 1, Table 1), composed of polysubstituted phenyl 7-chloro-4-quinolinyl-hydrazones (D01–D21) previously synthesized by our research group [3]
The antimycobacterial activities of D01–D21 were evaluated against the M. tuberculosis H37Rv strain susceptible to streptomycin, isoniazid, rifampin, and ethambutol (S.I.R.E.) drugs (American Type Culture Collection, ATCC® 27294TM), using the microplate Alamar blue assay (MABA) [21,22], and the results are expressed in terms of minimum inhibitory concentration (MIC, μM) (Table 1)

Summary

Introduction

Tuberculosis (TB), a severe infectious bacterial disease caused by Mycobacterium tuberculosis (MTB), infected almost 9.6 million of people around the world and caused 1.5 million deaths in 2014 [1]. The antimycobacterial activities of D01–D21 were evaluated against the M. tuberculosis H37Rv strain susceptible to streptomycin, isoniazid, rifampin, and ethambutol (S.I.R.E.) drugs (American Type Culture Collection, ATCC® 27294TM), using the microplate Alamar blue assay (MABA) [21,22], and Pharmaceuticals 2017, 10, 52 this current work, we report the biological evaluation of series D against the MTB wild-type H37Rv strain (Figure 1, Table 1), composed of polysubstituted phenyl 7-chloro-4-quinolinyl-hydrazones (D01–D21) previously synthesized by our research group [3] This series promotes an increase in the structural diversity allowing the utilization of the ligand-based strategy analysis using the hologram quantitative structure–activity relationship (HQSAR) method [16] with the purpose of driving the structural modification to improve the anti-mycobacterial (anti-MTB) activity of these series of compounds. This method avoids the need for molecular alignment or knowledge of bioactive conformation inherent in the current 3D-QSAR methods, such as the Comparative Molecular Field Analysis (CoMFA) [20], and is a good choice for datasets lacking a defined biological target

Biological Activities

D16 D17D12

D14 D15D15

Chemical and Biological Dataset

Molecular Modeling

HQSAR Modeling

Conclusions