設計與合成具生物性的雜環小分子

Abstract

Small molecules can probe the biological systems thereby understanding of biological processes is possible. Hence, they have been exploited in designing drug molecules against various biological targets. The present thesis deals with the design and synthesis of heterocyclic small molecules of biological interest. The thesis is divided into three chapters for the sake of convenience and better understanding. The first chapter deals with a facile and efficient synthesis of novel oxo, thio and seleno hydantoin fused tetrahydroazepino [4, 5-b]indoles. Naturally occurring iboga class alkaloid inspired seven-member azepino[4,5-b]indole ring was synthesized as a new scaffold through Pictet-Spengler reaction followed by skeletal rearrangement of aziridine ring. To improve the efficiency of the synthetic route, the double bond of the rearranged olefinic product 1-45 was reduced and privileged hydantoin moiety was constructed on the core system through urea formation using variety of isocyanates, isothiocyanates and isoselenocyanates followed by intramolecular cyclization to incorporate elements of diversity. The regeneration of the double bond of intermediate 1-49 afforded hydantoin-fused tetrahydroazepino [4, 5-b]indoles. In the second chapter, an efficient and regioselective synthesis of novel 1,2,3-triazole-fused-1,5,-benzoxazocinones through intramolecular cyclization of substituted ethynyl triazoyl benzoic acids was explored. A crucial precursor 5-iodo-1,2,3-triazole benzoate was obtained from substituted anthranalic acid esters in a single step through CuAAC reaction using CuI/NBS catalytic system. Carbon-carbon triple bond was installed through Sonogashira coupling reaction by various terminal alkynes. Finally, the 1,4,5-substituted ethynyl triazoyl benzoic acids were obtained by AgOTf mediated intramolecular cyclization. The third chapter describes the design and synthesis of new biprivileged molecular scaffolds with diverse structural features. Commercially available, simple heterocyclic building blocks such as 4-fluoro-3-nitrobenzoic acid, 2-chloro-3-nitrobenzoic acid, and indoline were utilized for the synthesis of the novel heterocycles. Pictet–Spengler-type condensation was used as a key step to construct tetracyclic indolo-benzodiazepines and indolo-quinoxalines linked with substituted benzimidazoles. Analysis of single crystals of representative compounds showed that these molecular skeletons have the potential to present various substituents with distinct three-dimensional orientations.

Small molecules can probe the biological systems thereby understanding of biological processes is possible. Hence, they have been exploited in designing drug molecules against various biological targets. The present thesis deals with the design and synthesis of heterocyclic small molecules of biological interest. The thesis is divided into three chapters for the sake of convenience and better understanding. The first chapter deals with a facile and efficient synthesis of novel oxo, thio and seleno hydantoin fused tetrahydroazepino [4, 5-b]indoles. Naturally occurring iboga class alkaloid inspired seven-member azepino[4,5-b]indole ring was synthesized as a new scaffold through Pictet-Spengler reaction followed by skeletal rearrangement of aziridine ring. To improve the efficiency of the synthetic route, the double bond of the rearranged olefinic product 1-45 was reduced and privileged hydantoin moiety was constructed on the core system through urea formation using variety of isocyanates, isothiocyanates and isoselenocyanates followed by intramolecular cyclization to incorporate elements of diversity. The regeneration of the double bond of intermediate 1-49 afforded hydantoin-fused tetrahydroazepino [4, 5-b]indoles. In the second chapter, an efficient and regioselective synthesis of novel 1,2,3-triazole-fused-1,5,-benzoxazocinones through intramolecular cyclization of substituted ethynyl triazoyl benzoic acids was explored. A crucial precursor 5-iodo-1,2,3-triazole benzoate was obtained from substituted anthranalic acid esters in a single step through CuAAC reaction using CuI/NBS catalytic system. Carbon-carbon triple bond was installed through Sonogashira coupling reaction by various terminal alkynes. Finally, the 1,4,5-substituted ethynyl triazoyl benzoic acids were obtained by AgOTf mediated intramolecular cyclization. The third chapter describes the design and synthesis of new biprivileged molecular scaffolds with diverse structural features. Commercially available, simple heterocyclic building blocks such as 4-fluoro-3-nitrobenzoic acid, 2-chloro-3-nitrobenzoic acid, and indoline were utilized for the synthesis of the novel heterocycles. Pictet–Spengler-type condensation was used as a key step to construct tetracyclic indolo-benzodiazepines and indolo-quinoxalines linked with substituted benzimidazoles. Analysis of single crystals of representative compounds showed that these molecular skeletons have the potential to present various substituents with distinct three-dimensional orientations.