Mapping the electronic and biological landscape of halogenated aryl quinoline derivatives via computational approaches

Abstract

Tuberculosis is caused by the bacterium Mycobacterium tuberculosis and is the leading cause of death from infectious diseases worldwide, being considered a granulomatous infection. The quinoline molecules were chosen because they possess antifungal and antimicrobial properties, which are normally related to their biological activities, being a privileged structure in medicinal chemistry, capable of modulating multiple targets, including kinases. The target prediction revealed a strong association with vascular endothelial growth factor receptor 2 (KDR), with 1300 and 1447 similar compounds. This article shows the structural reactivity of the four derivatives of 1,4-dihydro-4-oxo-quinoline-3-carbohydrazide, evaluated through DFT calculations in vacuum and DMSO (B3LYP/6–311 +  + G(d,p)), using the ORCA 5.04 program. In addition, this study also used computational approaches of virtual screening and ADMET prediction to evaluate pharmacokinetic properties. The analyses were performed using the softwares SwissADME, ADMETlab 3.0, admetSAR 3.0, pkCSM, Pred-hERG 5.0, StopTox, and ADMET Prediction Service—LMC, and involved the evaluation of oral bioavailability (0.55 for all compounds), intestinal permeability (Caco-2: −4.708 to −4.756), toxicity (non-toxic), and pharmacokinetic profile, selecting the compounds with the best characteristics for absorption and distribution. The results showed that the QNL1 and QNL3 derivatives were the most favorable due to high intestinal absorption (> 95%) and apparent permeability (Papp > 1.0 × 10 cm/s), showing potential as a future drug. In summary, the findings show these compounds as promising candidates for the treatment of tuberculosis, E. coli bacteria, and the fungus Aspergillus fumigatus.