Synthesis of Heterocycles of Biological Interest and their Combinatorial Chemistry

Abstract

Leishmaniasis is a vector born disease which is caused by many species of protozoan parasite leishmania. Depending on the causative species of leishmania parasite it is found in four major clinical manifestations. These are the cutaneous leishmaniasis, mucocutaneous leishmaniasis, visceral leishmaniasis and PKDL (post kala-azar dermal leishmaniasis). In all above forms of leishmaniasis, visceral leishmanaiasis (VL) is lethal, if left untreated. There are ≈ 70 000 deaths and 1.5 million new cases emerges per year due to VL. Majority of VL cases (≥ 90%) occurs in just six countries India, Nepal, Bangladesh, Sudan, Ethiopia and Brazil. Situation has become complicated by emergence of PKDL which appears in 0-6 months after successful cure of VL. The WHO has declared visceral leishmanaiasis (VL) a neglected and emerging disease. First line treatment option for visceral leishmanaiasis, the antimonials have suffered wide spread resistance problem. Second line treatment options are either of low therapeutic index or are highly costly. Hence, we decided to synthesize novel heterocycles, by both traditionally and combinatotial manner, in a hope to discover good hit or lead for leishmaniasis chemotherapy. In chapter 1 of present dissertation work we discussed about problem of leishmaniasis and recent development made in search of novel chemotherapeutic agent towards it. In first part of chapter 2 we described about our discovery of novel class of antileishmanial agents found in an effort to synthesize pentamidine aplysinopsin hybrid molecule, while in the second part of the chapter we discussed about another class of indole based novel antileishmanial agents discovered in an effort of multicomponent synthesis of an analogue of pentamidine aplysinopsin hybrid molecule. We reviewed various methodologies, drawbacks and recent trends of combinatorial chemistry in earlier part of chapter 3 and in later part of the chapter we discussed about development of diversity oriented synthetic route to 3-demethylaplysinopsin, a privileged natural product scaffold. In last chapter of present dissertation work, we described about our discovery of sulfur salts as transfer acylating agents which mimic biological acyl transfer mechanisms.