Síntese e avaliação de derivados benzoxazólicos do eugenol como potenciais agentes antifúngicos

Abstract

The search for new agents with antimicrobial activity is intensifying in recent years, mainly due to the increasing appearance of pathogenic micro-organisms strains resistant to available drugs. Natural substances such as eugenol, present in the essential oils of many plants, and some heterocyclic compounds such as benzoxazoles are known for their various biological properties, including antimicrobial activity. In order to obtain new active compounds against microorganisms, especially fungi, we applied the molecular hybridization strategy to prepare mixed molecules containing structural eugenol and benzoxazole cores. The final eight substances proposed have been successfully obtained from the oxidative cyclization of imines or cyclo-condensation of amides, both derived from o-aminophenols originated from eugenol or its analogue, diidroeugenol. The benzoxazoles obtained by amide intermediates was simpler and efficient. The products had their identities confirmed by infrared spectroscopy and nuclear magnetic resonance. These products were evaluated as antimicrobial agents against pathogenic or opportunistic species of Candida (C. albicans, C. krusei, C. glabrata, C. parapsilosis and C. tropicalis) and against Gram positive bacteria (Staphylococcus aureus) and gram negative (Escherichia coli). None of the benzoxazoles showed antibacterial activity up to 100 μg.mL-1. Moreover, four benzoxazoles, 9c, 9d, 10a and 10b, presented activity against at least one species of Candida sp. The product 10a was the most active against C. albicans and C. krusei (IC_50 = 321 μM) and benzoxazole 10b exhibited higher potency against C. glabrata (IC_50 = 332 μM). These four active substances showed better IC_50 values than those for eugenol, which was only active against C. krusei (IC_50 = 610 μM). In addition to this antifungal profile, it is noteworthy that these benzoxazoles were less cytotoxic than eugenol in human blood mononuclear cells assay. Although these derivatives have not shown greater potencies than that of the reference drug used in the test (fluconazole, IC_50 = 1.6 to 104.3 μM), they represent novel chemical entities capable of structural change for activity optimization.