Design, synthesis and biological evaluation of small molecule inhibitors for treatment of diseased states

Abstract

Complex natural molecules often consist of small molecular entities in a systematic arrangement, and these architectural units usually make them useful as an overall bio-construct. Fused pyridine compounds belong to the largest family of aza-heteroaromatics. These are extensively distributed in nature in plants, marine organisms, insects, mammalians, and human tissues body fluids. These heterocycles modulate a diverse set of biological activities by interacting with biomolecules like proteins in living systems. Hence, significant biological processes can be manipulated by cautious alteration of protein expressions using these external ligands (agonists and antagonists) as molecular tools. Often structural analogs of newly discovered molecules with the known ligands play a pivotal role in solving this riddle. Azaindoles (pyrrollo-pyridines) are the closest bio-isosteres of indoles and purines and play an indispensable role in mimicking the natural ligand-target interactions. Recently, pyrrollo-pyridines have become an integral core unit in some critical drug candidates. However, their synthesis in the laboratory has always been a challenge for chemists. Due to the pyridine ring's electron-deficient nature, classical indole synthesis such as Fischer and Madelung cyclization are inefficient in azaindole synthesis. The recent advances in organometallic chemistry have enabled us to devise efficient methodologies for azaindole synthesis and functionalization. However, the developed protocols have not been realized sufficiently in the pharmaceutical industries. The use of the heavy metal catalyst in the synthetic strategy may lead to unwanted toxicity and inaccuracy in the biological studies. Fused indolopyridines or carbolines are widely attributed to their DNA intercalation properties, inhibition of cyclin-dependent kinases (CDKs), topoisomerases, monoamine oxidase, interaction with benzodiazepine and 5-hydroxy serotonin receptors. This class of heterocycles has demonstrated a broad spectrum of pharmacological properties, including sedative, anxiolytic, hypnotic, anti-convulsant, anti-viral, anti-parasitic, and anti-microbial activities. Although the synthesis of tailored carboline derivatives still remains a challenge to synthetic chemists, the overall assessment of existing protocols reveals low yield, limited substrate scope, use of specific substrates, and involvement of extreme thermal conditions, corrosive reagents, and toxic heavy metal catalysts. Over the last two decades, the furopyridines have been extensively studied as bio-isosteres of indoles. Hence, these heterocycles have emerged as useful pharmacophores in therapeutic agents for treating cognitive or autoimmune disorders, migraine, irritable bowel syndrome, and asthma. Benzofuropyridine, another intriguing member of the fused pyridine class, has also found attention grabbing applications in the pharmaceutical and OLED industry. The synthetic procedures for these important heterocyclic-cores have remained confined due to limited substrate scope and lack of innovative approaches. Azabenzofuran or pyridofuran has attracted more attention after the recent success of TAM16 against drug susceptible and drug-resistant clinical isolates of Mycobacterium tuberculosis. The in vitro and in vivo studies of TAM16 have displayed comparable efficacy to the first-line TB drug isoniazid. In the process, polyketide synthase (Pks13) has emerged as a prime target for potential drug candidates in the field. It is essential for the synthesis of mycolic acids required for the cell wall of the pathogen. The present thesis work describes the development of an unprecedented methodology for the synthesis of fused-pyridine heterocycles such as substituted 5-azaindoles, γ-carbolines, furo[3,2- c]pyridines, and benzofuro[3,2-c]pyridines. Subsequently, these nitrogen-heterocycles have been transformed into potential bio constructs for therapeutic applications. The thesis work comprises of following chapters: 1. Serendipitous base-catalyzed condensation-heteroannulation of iminoesters: A regioselective route to the synthesis of 4,6- disubstituted 5-azaindoles Synthesis of 1-indolyl-3,5,8-substituted -carbolines: One-pot metal-solvent free protocol and biological evaluation 3. One-pot synthesis of furo[3,2-c]pyridines and benzofuro[3,2- c]pyridines: Development of isatin molecular hybrids for treatment of tuberculosis