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

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.

Quinoline‐derivatives as privileged scaffolds for medicinal and pharmaceutical chemists: A comprehensive review

“…Although, there are multiple effective drugs available for treatment and management of this infectious disease, the treatment is a complex and challenging due to resistance development to the standard treatments regimens. Also, there has been a significant increase in drug‐resistant cases of antitubercular drugs have amplified radically; the number of extensively drug‐resistant (XDR) TB (resistance to at least one of the second‐line drugs, in addition to rifampicin and isoniazid) and multidrug‐resistant (MDR) TB (resistance to rifampicin and isoniazid; Bispo et al, 2017; Karthik Kumar et al, 2011). Considering the emergence of MDR/XDR‐TB on TB management, developing new chemical entities with anti‐TB activity is vital.…”