Design and Synthesis of Potential Antileishmanial Agents

Abstract

Leishmania is one of the most neglected tropical diseases in the world, about 1.5 million new cases of Cutaneous Leishmaniasis and 500000 new cases of Visceral Leishmaniasis occur each year. Cutaneous Leishmaniasis is endemic in more than 70 countries worldwide. Visceral Leishmaniasis occurs in 65 countries; the majority (90%) of cases occur in agricultural areas and among the suburban poor countries. The number of cases is increasing globally at an alarming rate. Ecological chaos caused by humans has enabled the Leishmaniasis to expand beyond their natural ecotopes, and this in turn affects the level of human exposure to the sandfly vectors. Cases of Leishmania and human immunodeficiency virus (HIV) co-infection have also recently increased. The classical treatment of Leishmaniasis requires the administration of toxic and poorly tolerated drugs. However, parasite resistance greatly reduces the efficacy of conventional medications. High toxicity, emergence of resistance and lack of cost effectiveness are the main drawbacks of the present drugs. Moreover, there are no effective vaccines to prevent Leishmaniasis. Therefore it is utmost importance to look for effective new drugs to treat Leishmaniasis. Azole antifungal agents have been used as antileishmanial agents since 1980s, inhibit the growth of Leishmania amastigotes in culture systems by inhibiting the cytochrome P-450- mediated 14α-demethylation of lanosterol, blocking ergosterol synthesis, and causing accumulation of 14α-methyl sterols. Metronidazole and N-substituted azoles (ketoconazole, miconazole, econazole, fluconazole, and itraconazole) are well-tolerated drugs that are potentially active against Leishmania, but their use in the treatment of cutaneous and visceral Leishmaniasis has produced conflicting results. Some recent encouragement has been given by the oral activity of posoconazole in a Leishmania amazonensis experimental model. The orally active azoles, are at various stages of development, offer potential for Leishmania chemotherapy. Based on the above reports and following the traditional approach of generating synthetic analogues of existing drugs, we designed and synthesized a series of azole based compounds The thesis entitled “Design and Synthesis of Potential Antileishmanial Agents” describes our synthetic efforts towards the development of novel and potential antileishmanial agents. This thesis consists of five chapters. Chapter 1 is a review on Leishmaniasis, current treatment options, promising lead molecules, drug targets and recent advances in the development of novel therapeutics and future prospective of leishmanial chemotherapy. Chapter 2 is divided into two parts. Chapter 2.1 deals with the design, synthesis and antileishmanial activity of fluoxetine based azole. Chapter 2.2 deals the synthesis and evaluation of Oxiconazole-Fluoxetine azole hybrids as antileishmanial agents. Chapter 3 presents the synthesis and evaluation of new Furanyl and Thiophenyl azoles as antileishmanial agents. Chapter 4 illustrates the antileishmanial and antimycobacterial activity of novel aryloxy azolyl chalcones. Chapter 5 describes the trisubstituted pyrimidines with potent antileishmanial and antimycobacterial activity.