Design, Synthesis and Pharmacological Evaluation of Small Organic Molecules for Therapeutic Agents

Abstract

The role played by modern organic synthesis in the pharmaceutical industry sustains to be one of the main drivers in the drug discovery process. The problem of the limited availability of natural products in bio-evaluation has been tackled in many cases by modern methods of organic synthesis with which small molecules including natural products can be prepared in sufficient quantities. Small molecules include new drugs and drug candidates and reagents and these have proven to be invaluable tools for investigating biological systems. Synthetic small molecules make up a major portion of the modern screening palette. Advances in the field of synthetic organic chemistry have led to the development of many stereoselective methodologies for proficient assemblage of small organic molecules. Much endeavor has been applied on the development of asymmetric variants of well-established reactions, and upon finding of a new reaction that generates new stereogenic centers, development of stereoselective versions using chiral auxiliaries, reagents, or catalysts. The use of small molecules by ‘Chemical Genetics’ approach provide fast, conditional, dosedependent, and often reversible control of biological functions. Thus, dynamic processes such as the cell cycle and development can be dissected in details by adding or removing the small molecule at appropriate times. Moreover, in contrast to Classical Genetic approach (gene knockouts and RNA knockdowns), selective small molecule probes can be used to study the individual functions of multifunctional proteins and can distinguish between different conformational and post-translational modification states of their targets. Thus, the use of small molecules to activate or inactivate proteins by direct interactions has come out as a powerful tool for the study of complex biological systems. Small molecules can also be used to illuminate new potential therapeutic targets and provide a direct means of validating these targets in model systems. Thus, the identification of new, highly specific small molecule probes remains a significant current challenge in chemical biology and drug discovery. The thesis entitled “Design, Synthesis and Pharmacological Evaluation of Small Organic Molecules for Therapeutic Agents” is arranged under seven chapters: Chapter 1: Utilization of enantiopure 2,3-epoxyalcohols and syn-2,3-dihydroxy esters in the synthesis of natural products and natural product-like molecules Chapter 1 includes an overview of selected literature reports covering synthesis of natural products (NPs) and natural product-like molecules (NPLMs) involving 1,2- aminoalcohol, 2,3-dihydrobenzofuran & 1-benzopyran moieties employing the Sharpless asymmetric dihydroxylation and epoxidation as the key chirality inducing steps. Chapter 2: Synthesis and Pharmacological Evaluation of a series of Aryl aryl methyl thio arenes (AAMTAs) as Antimalarial Therapeutics Chapter 2 deals with our study with Aryl aryl methyl thio arenes (AAMTAs) showing antimalarial activity in vivo in animal model. Interestingly, AASMPs exhibit acceptable selectivity against the malaria parasite and show antimalarial activity in vivo against the MDR rodent malaria parasite P. yoelii. Chapter 3: Stereoselective Synthesis of Functionalized 2,3-Dihydrobenzofurans and 1-Benzopyrans by Phenoxide ion-Mediated Carbocyclization This chapter is divided into two sections: Sections 3A and Section 3B. Sections 3A deals with efficient asymmetric synthesis of 2-isopropenyl-2,3- dihydrobenzofurans and 4-(2,3-dihydrobenzofuran-2-yl)-2-methylbut-3-en-2-ols. Key steps include Sharpless asymmetric epoxidation reaction on suitable allyl alcohols and construction of the 2,3-dihydrobenzofuran nucleus by phenolate ion-mediated intramolecular 5-exo-tet epoxide ring opening reactions. The simplicity of the reaction sequence, as well as the commercial accessibility of large array of starting 2- hydroxyaromatic aldehydes, makes this process a convenient method for the preparation of “natural-product-like” 2-substituted 2,3-dihydrobenzofuran frameworks. In addition, the scope the reaction sequence is much broader, and synthesis of various substituted aromatic and heteroaromatic nuclei can be envisioned from the starting aldehydes. Section 3B deals with efficient asymmetric synthetic methods of enantiomerically pure 2-hydroxymethyl chromans and 4-chroman-2-yl-2-methyl-but-3-en-2-ols. Key steps include Sharpless asymmetric epoxidation reaction on suitable allyl alcohol and construction of the benzopyran nucleus by phenoxide ion mediated intramolecular 6- exo-tet epoxide ring opening. The ease of the reaction sequence, as well as the rapid accessibility of the starting 2-allylphenols, makes this process a practical method for the preparation of optically active 2-hydroxymethyl-chromans. Chapter 4: Asymmetric Total Syntheses of Spisulosine, Its Diastereo- and Regioisomers Chapter 4 illustrates the first protecting group-free syntheses of spisulosine, an anticancer marine natural product and its diastereo- and regioisomers employing Sharpless asymmetric epoxidation reaction as the source of chirality. The other merits of this synthesis are high-yielding reaction steps, high enantioselectivity and various possibilities available for structural modification and thus it might be considered as a general synthetic strategy to enantiomerically pure 2-amino-3-alkanols. Chapter 5: Stereoselective Synthesis of Functionalized 1-Benzoxepines Chapter 5 deals with an asymmetric synthesis of 2,3-disubstituted 1-benzoxepines by an easy and high yielding reaction sequence. Key steps include Sharpless asymmetric dihydroxylation reaction on suitable α,β-unsaturated esters and construction of the 1- benzoxepine nuclei by phenoxide ion-directed intramolecular 7-endo-tet carbocyclization of syn-2,3-dihydroxy ester-derived cyclic sulphates. Presence of methoxy group ortho to the phenolic –OH functionality on the phenyl ring rendered the cyclization reaction completely regioselective producing 1-benzoxepine derivatives only. In the absence of a methoxy group on the phenyl ring, the reaction furnished both 1-benzoxepine and 1-benzopyran derivatives with the former being the major one. Chapter 6. An Enantioselective Approach towards Synthesis of a potent C17,20- Lyase Inhibitor Chapter 6 deals with our preliminary studies for enatioselective synthesis of a potent C17,20-lyase inhibitor and its other analogues. Notable features of this approach include the use of Sharpless asymmetric dihydroxylation to synthesize the enantiomerically pure 1,2-diol and and thus both enatiomers could be obtained by varying the ligands. The other merits of this synthesis are high-yielding reaction steps, high enantioselectivity and various possibilities available for structural modification and thus it might be considered as a general synthetic strategy to enantiomerically pure tertiary alcohols bearing the two aromatic rings. Chapter 7. Design and Synthesis of Small Organic Molecules for P2X ion and P2Y G Protein-Coupled Receptors (GPCRs) Chapter 7 deals with our preliminary studies for the quest to improve the bioavailability of Suramin related molecules, a polysulfonated naphthylurea, that served as a highly successful chemical lead for the development of potent and selective P2X antagonists. We have successfully replaced the sulfonate group of suramin analogs with esters and acids. Furthermore, the position of bis-urea has also been replaced by different spacers as shown in the chaper 7. It is also suggested that the size of the molecule might play a vital role in approaching the P2 receptors. In this quest, the bulk of the suramin has been reduced to small organic molecules having requisite functional groups with different spacers like amides (-CONH-), saturated amines, acids and esters.