우수한 항균 활성을 나타내는 aryl phenyl ether pyrazole계 화합물의 합성

Abstract

The incidence of invasive fungal infections caused by opportunistic pathogens, often characterized by high mortality rates, has been increasing over the past two decades. Patients that become severely immunocompromised because of underlying diseases such as leukemia or, recently, acquired immunodeficiency syndrome or patients who undergo cancer chemotherapy or organ transplantation are particularly susceptible to opportunistic fungal infections. A matter of concern in the treatment of fungal infections is the limited number of efficacious antifungal drugs. Many of the currently available drugs are toxic, produce recurrence because they are fungistatic and not fungicides or lead to the development of resistance due in part to the prolonged periods of administration of the available antifungal drugs. There is, therefore, a clear need for the discovery of new structures with antifungal properties, which could lead to the development of new drugs for the management of fungal infections and treatment of systemic mycoses. Up to only 30 years ago the choice of systemically available antimycotics was between two drugs, amphotericin B and flucytosine, neither of which was satisfactory. Then a series of inhibitors of the biosynthesis of ergosterol, the major sterol of the fungal cell membrane, were found to have excellent antifungal activity, improved safety, and some were also active after oral or parenteral application. Starting with miconazole and ketoconazole, and improving through fluconazole and itraconazole, the imidazole and triazole inhibitors of lanosterol l4α-ademethylation have been the most successful. Although the use of a new generation of triazoles, the available polyenes in lipid formulations, the use of echinocandins or the combination therapy have been introduced as alternatives in the last 10 years, the number of available preparations to treat systemic fungal infections is still limited and more alternatives are needed, particularly with improved efficacy against emerging pathogens with limited susceptibility to the available preparations. We find out that the imidazole derivatives have shown potent antifungal activity associated with good antimycobacterial activity. In addition, aryl phenyl ether group is a widely used in pesticide and drug molecular design. With the reference to above information and help of bioisoterism, we have synthesized a series of compounds in which the imidazole moiety is directly linked at position 4 and aryl phenyl ether at the position 3 of pyrazole ring to improve antifungal activity.