Síntese e avaliação farmacocinética in silico de compostos híbridos com potencial bioativo: chalconas quinolínicas e derivados heterocíclicos do ácido salicílico

Abstract

The growing demand for therapeutics with higher efficacy and lower toxicity has driven the development of innovative synthetic strategies in medicinal chemistry. In this context, molecular hybridization emerges as a promising approach, enabling the design of compounds that combine different pharmacophoric nuclei into a single structure, thereby expanding their bioactive potential. This study aimed to perform the rational design, synthesis, and in silico pharmacokinetic evaluation of novel hybrid molecules belonging to the classes of quinoline-based chalcones and heterocyclic derivatives of salicylic acid. Chalcones, traditionally known for their broad spectrum of biological activities (antitumor, antibacterial, and anti-inflammatory), yet limited by intrinsic pharmacokinetic drawbacks (poor water solubility, low bioavailability, and potential toxicity), were functionalized with the quinoline scaffold, recognized for improving physicochemical properties such as lipophilicity and metabolic stability. In parallel, salicylic acid, due to its versatile bioactivity, was modified through halogenation and cyclization strategies, yielding unprecedented structures. The methodology involved classical organic synthesis routes, including Claisen-Schmidt condensations and nucleophilic substitutions, as well as computational predictions using the Deep-PK server to assess pharmacokinetic parameters. Five compounds were synthesized: the intermediate 4-((7-chloroquinolin-4-yl)oxy)-3- methoxybenzaldehyde (GAD1), two chalcone derivatives of GAD1 (GAD2 and GAD3), a cyclic salicylic acid dimer (GAD4), and a brominated heterocyclic derivative (GAD5), all obtained with yields above 75% through precipitation. In silico analyses suggested favorable pharmacokinetic profiles, particularly for the quinoline-chalcones GAD2 and GAD3, which exhibited predicted good intestinal absorption, low hepatotoxicity, and reduced CYP450 isoform inhibition compared with their non-quinoline analogues. Similarly, GAD4 and GAD5 demonstrated trends toward improved metabolic stability and toxicity parameters relative to salicylic acid. Despite the inherent limitations of computational predictions, the findings highlight the feasibility of these structural modifications as a starting point for future in vitro and in vivo investigations.