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. 2017 Jun 9;10(2):52.
doi: 10.3390/ph10020052.

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

Marcelle L F Bispo  1   2   3 , Camilo H S Lima  4   5   6 , Laura N F Cardoso  7   8 , André L P Candéa  9 , Flávio A F M Bezerra  10 , Maria C S Lourenço  11 , Maria G M O Henriques  12 , Ricardo B Alencastro  13 , Carlos R Kaiser  14 , Marcus V N Souza  15   16 , Magaly G Albuquerque  17
Affiliations

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

Marcelle L F Bispo et al. Pharmaceuticals (Basel). .

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.

Keywords: 4-aminoquinoline; Mycobacterium tuberculosis; amino–imino tautomerism; anti-mycobacterial activity; cytotoxicity; drug design; hologram quantitative structure–activity relationship (HQSAR); molecular modeling.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Series A–D of 7-chloro-4-aminoquinoline derivatives synthesized and evaluated against the Mycobacterium tuberculosis wild-type H37Rv strain (minimum inhibitory concentration, MIC) by our research group and their respective lead compounds.
Figure 2
Figure 2
Plot of the experimental versus predicted pMIC values of the training and test sets of the tautomers I (amino) (A) and II (imino) (B) datasets.
Figure 3
Figure 3
The HQSAR contribution maps of the most (A08, B05, C03, and D06) and least (A09, B03, C07, and D03) potent compounds according to the tautomer II model from each series (A, B, C, and D) along with the experimental (and calculated) pMIC values.
Figure 4
Figure 4
The HQSAR contribution maps of the outliers (A01 and D09) and similar compounds that belong to the training set.
See this image and copyright information in PMC

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