Synthesis of small organic molecules and their therapeutic potential towards drug development

The thesis describes 20 years of research in the field of development of small organic molecules that are drug candidates for combating various diseases. In particular the thesis focuses on the use of small organic molecules as anti-HIV agents. In the preliminary studies, we synthesized two class of compounds, the first class comprising of nucleoside derivatives and the second class of compounds which comprising of non-nucleoside derivatives. Although nucleoside derivatives are well known to act as anti-HIV agents in the past, the development of drug-resistant viral strains hampered the use of these agents on a continuous basis for patients who is harbouring with AIDS. To circumvent this problem, we focused our attention in altering the structure of the nucleoside derivative with a hope that the vital enzyme reverse transcriptase will not recognize this change. Accordingly, we synthesized nucleoside analog with a phosphoramidate side chain since it is well known that the ordinary nucleoside derivatives gets phosphorylated with thymidine kinases present in the cells. Our goal was to avoid the first step of phosphorylation which may in turn result in the formation of the active metabolite d4T-Aia-Phosphate which subsequently converts in to the di- and triphosphate respectively. Thus we obtained our lead compound stampidine which showed extraordinary antiviral activity in normal HIV -strains in nanomolar concentrations. Based on the successful outcome, we examined the potential of this compound to act against other mutant viral strains which are resistance to multi-drug treatment. Exposure of RT-MDR strains to stampidine resulted in inhibition of HIV-replication demonstrating that our agent was powerful anti-HIV drug. Once we established this, we extended our investigations towards other mutant strains derived from AIDS patients. Remarkably stampidine inhibited the viral replication providing a land mark opportunity to further understand the mechanism of action of this novel agent. We further advanced our research in conducting a pharmacokinetic study in mouse model, rat model and proceeded with a dog and feline model. In all the cases, the viral replication was halted and this provided the basis for preparing the compound under cGMP conditons. Accordingly the cGMP product was prepared at Cardinal Health, North Carolina under the direction of myself and subsequently formulated to a gel capsule form at University of Iowa, Pharmaceutical department. Administration of the formulated capsules to the cats and dogs resulted in the total inhibition of HIV demonstrating the usefulness of this compound for further clinical studies. Thus we have achieved the first research goal in the development of an anti-HIV agent. On the similar ground, we also developed a non-nucleoside agent, namely a thiophene ring attached thiourea which also acted very similar to the stampidine profile. We further extended our investigations towards rodent and animal species and finally formulated this compound also under cGMP conditions. During the entire course of the research study, we gained the knowledge about the usefulness of these small molecules serving as potential drug candidates. We studied the mechanism of action of these agents using a systematic approach and the thesis represents the results obtained. All these research work was done initially at the Biotherapy Program of University of Minnesota, followed by Parker Hughes Cancer Center and at Paradigm Pharmaceuticals.