Abstract
AbstractThe thesis consists of two parts: the first part is concerned with the synthesis and bioassay of promazine analogues and the second part describes the synthesis and anti-cancer activity of 3-phenoxy substituted indole analogues.The first part : The global outbreak of severe acute respiratory syndrome (SARS) caused by a novel coronavirus began in March 2003.An in-house chemical library consisting of 800 marketed drugs was evaluated for anti-SARS-CoV activities. We began our drug screening using porcine transmissible gastroenteritis virus (TGEV) as the surrogate system giving the similarities among several key viral proteins of TGEV and SARS-CoV. Hits that presented anti-TGEV activity then were subjected to the SARS-CoV assays. Several members of the phenothiazine drug class and niclosamide were found to inhibit SARS-CoV replication in cell culture at low concentration and thus both promazine and niclosamide were identified as the lead compounds for the structure optimization.For the lead optimization, we have synthesized 20 promazine analogues and subjected these to bioassay using TGEV and SARS –CoV for evaluating anti-viral activity. On the basis of these anti-viral assay, we have found compound 10 and 20 to exhibit good anti-SARS –CoV replication activities.During the synthesis of the promazine analogue, we tried to optimizeconditions and found out that microwave technique has the advantage for it decreased reaction time and provided considerable yields of products.The second part : Compound 31, a potent anti-cancer drug synthesized by bioisosterism of Combretastatin A-4, was subjected to further modification through the replacement of sulfur bridge with oxygen. Two synthetic methods were employed for the target molecule. First, a C-O coupling strategies of Ullman and Buchwald-Hartwig were employed, but failed. We successfuly synthesized seven phenoxy indole analogues using the second strategy, Fisher Indole synthesis. The compounds were subjected to cytotoxic activity using KB and MKN45 cancer cell lines; compound 32d showed the highest activity with IC50 = 1.2 ± 0.5 nM for KB, and IC50 = 1.1 ± 0.1 nM for MKN45.