Síntese e avaliação biológica de cromanonas, homoisoflavonoides e derivados

Abstract

Dysregulated inflammation and the increase in microbial resistance represent significant challenges to public health, requiring the search for new therapeutic alternatives. In this context, natural products and their derivatives stand out in the discovery of new drugs, as they exhibit broad structural diversity and multiple biological activities. Among these classes, chromanones and homoisoflavonoids have attracted increasing interest due to their relevant pharmacological properties, including anti-inflammatory and antimicrobial activities. Thus, a collection of thirty-two synthetic compounds (1–32), structurally related, comprising eleven chroman-4-ones (1–11) and twenty-one homoisoflavonoids (12–32), was prepared, among which twenty-four are new compounds (5, 8, 9, 10, 11, 13, 15–32). The structural characterization of the compounds was perfomed using Infrared Spectroscopy, Nuclear Magnetic Resonance of ¹H and ¹³C-APT, and High-Resolution Mass Spectrometry. Subsequently, the compounds were evaluated for their anti-inflammatory activity, through assays measuring the reduction of O₂•⁻, NO, and TNF-α production, and for their antimicrobial activity against medically relevant fungi and bacteria, using the broth microdilution method to determine the Minimum Inhibitory Concentration (MIC). Compounds exhibiting the best biological activities were selected for molecular docking studies. In the anti-inflammatory assays, compounds 24, 25, 26, and 29 stood out, showing the highest percentages of inhibition of TNF-α production (46.2±3.1%; 46.4±0.8%; 82.0±0.5%; and 45.7±1.8%, respectively) and NO production (38.0±3.1%; 47.3±2.3%; 31.4±2.6%; and 39.9±2.5%, respectively) at a concentration of 10 μM. Molecular docking studies suggest 5-lipoxygenase (5-LOX) as the most likely molecular target for these compounds. Structure–activity relationship analysis revealed that substitution of the phenolic hydroxyl group of compound 1 with alkyl or benzyl groups favored the reduction of reactive species O₂•⁻ and NO production, whereas the introduction of a methoxy group at the meta position of ring B in homoisoflavonoids promoted increased anti-inflammatory activity, particularly in TNF-α inhibition. Regarding antimicrobial activity, compounds 1, 2, and 26 exhibited greater potency compared to the positive control against several microorganisms, with MIC values ranging from 64 to 256 μg/mL (359.2–1559.5 μM) for bacteria (S. epidermidis, P. aeruginosa, and S. enterica) and yeasts (C. albicans, C. tropicalis, and N. glabratus), and from 256 to 512 μg/mL (1452.8–2873.6 μM) against filamentous fungi (A. flavus and P. citrinum). In silico studies against C. albicans indicated that these compounds may act through different mechanisms of action: compound 1 showed affinity for the enzyme CS1, whereas compounds 2 and 26 acted on HOG1 and FBA1, all of which are essential enzymes for fungal virulence and survival. The results suggest that the addition of alkyl or benzyl chains to the phenolic hydroxyl group of compound 1 reduces antimicrobial activity, while the introduction of a methoxy group at the meta position of ring B in homoisoflavonoids increases bioactivity, similarly to the anti-inflammatory activity. Thus, it is concluded that compound 26 stood out by exhibiting both anti-inflammatory and antimicrobial activities, acting through multiple mechanisms. The results obtained allowed the identification of important chemical features that may guide the rational design of new molecules with anti-inflammatory and antimicrobial potential.