Novel chromeneimidazole derivatives as antifungal compounds: synthesis and in vitro evaluation.

Over the past two decades a significant increase in fungal infections has been observed (1). More than any other antifungal class, the azoles have been steadily refined and improved upon over the course of almost 50 years. These antifungal compounds are chemically either an imidazole or a triazole group joined to carbon atom as their functional pharmacophore and working through blocking the active site of an enzyme variously known as lanosterol 14α-demethylase or cytochrome P450DM (2). More recently, a number of chlorinated imidazole compounds have been found to have antifungal as well as antibacterial activity. Among them, clotrimazole, miconazole, sulconazole and econazole have already been used in topical and in some cases systemic therapy. Ketoconazole is a newer dioxolane imidazole which shows promise as a broadspectrum antifungal agent effective by oral administration (3ñ6). Imidazole derivatives, including ketoconazole, miconazole, tioconazole, clotrimazole, and sulconazole, are recognized as potent ligands of the heme iron atom of P450s (Fig. 1) (7, 8), thereby inhibiting synthesis of normal membrane sterols in fungi. A lack of ergosterol in a fungal membrane seriously cripples the fungus and leaves it unable to grow and develop in the normal way. Resistance to azoles is emerging to Candida albicans, after longterm suppressive therapy (9, 10). There is an urgent need for newer potent antifungals to combat resistance developed against widely used azoles. Thus, much effort is devoted to develop novel antifungal agents, which are more safe and efficacious. Chromenes are naturally occurring benzopyrene derivatives known to exhibit wide spectrum of biological activities (11) like diuretic, analgesic myorelaxant (12) and antifungal (13). Naturally occurring angelicin (furanocoumarin) and its various synthetic derivatives were already reported to have good antifungal activity (14) Satyanarayana et al. reported the synthesis and antifungal screening of new Schiff base of chromenes under conventional and microwave conditions (15). It is suggested that chromene exhibit antifungal activity may be due to either killing the microbes or blocking their active sites (16). In the present paper, we have reported synthesis of various chromeneimidazole derivatives using conventionally synthesized coumarin and further derivatized using various substituted aldehydes. Chromene and imidazole derivatives have been considered to be an ideal requirement for exhibiting wide spectrum of antifungal activity. Thus, it was considered of interest to synthesize chromene derivatives having imidazole moiety attached through a spacer bearing different acceptor as well as donor functionalities and their evaluation against resistant Candida albicans strain.