Abstract
Organic chemistry is the major field in chemistry, which links many scientific disciplines and allows for collaboration with other scientists in researching, new methodologies, and developing new drugs. Carbon–carbon bond formation is the essence of organic synthesis. These reactions are fundamental transformations for constructing structurally complex organic building blocks, especially in the realm of natural products, medicinal chemistry, and agrochemical synthesis. Developing new and efficient method for carbon–carbon and carbon–oxygen bond formation, have solved fundamental problem in organic chemistry. Na@SiO2 was developed as a powerful reagent for a solution to one of the most important themes in organic synthesis, carbon to carbon bond formation. In the presence of Na@SiO2 organohalides to give alcohols in good to excellent yield. A broad selection of carbonyl derivatives undergoes efficient CC and CO bond formation. Less reactive Grignard reagent undergoes smooth CC bond formation. Na@SiO2 also assisted α-halocarbonyl compounds to react with aldehydes in the formation epoxides through an unprecedented radical pathway. Alternative to Darzen’s method brings time economic, high yield and trans- selectivity in epoxides. In comparison with myriad available methods, advantages associated with the newly developed methods include: (1) the desired adducts were often obtained in very good yields, (2) reactions were complete at ambient temperature within 2.0 hours, (3) requirement for anhydrous solvent was not necessary, and (4) manipulation of the heterogeneous reaction was simple. Application of Na@SiO2 in organic synthesis fits into five of twelve guidelines of green chemistry. Our methodology offers a good alternative to Darzens reaction. Darzens reaction usually takes 1−7 days with low yield of diastereoselective product, which is due to base catalyzed racemization. But in our case, all of the reactions completed within 2.0 hours and we got exclusively trans-epoxides. Unlikely to Darzens reaction, prolonged reaction time didn't isomerize the product in our methodology. Over the past years it has been observed that a number of new viruses ("RNA viruses and emerging viruses") and other pathogens has spread worldwide, introducing since then unknown diseases into previously unaffected regions. So, for the development of new anti-viral leads, novel coumarin-epoxide conjugates with high anti-HCV potency and selectivity were synthesized by newly developed method. These conjugates were tested against HCV in huh 5-2 cells with minimum EC50 of 0.9 μM and maximum SI value of 102. Moreover, two libraries of doubly and triply conjugated compounds were designed and synthesized with anti-CHIKV activity. Establishment of structure-activity relationship was done on the basis of chemically synthesized 60 new compounds, in which uracil, coumarin, and arene was allowed to possess various substituents. The uracil moiety can be 5-methyl-2-thiouracil, 2-thiobenzouracil, and 4-anilino-2-thiobenzouracil. 4-Chloromethyl coumarin was allowed to possess different substituent on it. Arene moiety can be linked to coumarin or pyrimidine via –OSO2–, –OCH2–, and –NH joint. The structure of all chemically synthesized compounds were confirmed by spectroscopic methods (NMR, Mass, and IR) and by X-ray crystallography. In this new library, their anti-CHIKV assay, cytostatic determination assays were performed and the structure−activity relationship was established. Several new compounds were found to inhibit CHIKV (899 strain) in Vero cells subtype A. The most appealing results were associated with conjugates 87, 88, 89, and 102, which inhibited CHIKV (899 strain) at minimum EC50 of 1.96 μM and maximum SI value of 37. 4-Anilinoquinazoline was proved to be potent pyrimidine nucleus. Furthermore, conjugation of 4-anilinoquinazolinone with coumarin offers high selectivity in CHIKV inhibition. Arene-sulfo joint with benzouracil-coumarin conjugate was proved to be potent in anti-CHIKV leads. Moreover, 14 guidelines were deduced from the analysis of their structures, lipophilicity, and anti-CHIKV activity. Two major issues has been discussed and solved in this dissertation, which includes the development of new method of CC bond formation and potent anti- CHIKV leads. Na@SiO2 mediated CC and CO bond formation offers good alternative to Grignard and Darzens reaction, which are the prominent and most useful reaction in laboratory. Anti-CHIKV leads with minimum EC50 value of 1.96 μM was obtained in our compound library, which is best among reported CHIKV inhibitor. By developing new CC bond formation method and novel anti-CHIKV leads, significant contribution has been made in organic and medicinal chemistry field, which may helpful for the researchers around the globe for the development of new methodologies and new drugs.