Synthesis of Certain Schiff Bases of 7-Hydroxy-3-Formyl Chromone as Thymidine Phosphorylase Inhibitors and Evaluation of Other Possible Biological Activities

INTRODUCTION:Carcinoma is the leading cause of premature death in the world. Due to the rapid advancement in cancer diagnosis and therapy, the life expectancy and survival rate of cancer patients have shown improvement. However, the overall clinical outcome of cancer is still unsatisfactory due to its high invasive and metastatic properties. In order to achieve therapeutic success in cancer patients, there is still room to develop new treatment strategies that target at various stages of tumour progression. A flurry of scientific investigations has identified angiogenesis as one of the important processes in cancer development. Angiogenesis was found to promote tumour growth and metastasis. Therefore antiangiogenesis might be an effective cancer treatment strategy.PURPOSE AND PLAN OF WORK:Enzyme inhibitors are used as potent therapeutic agents for the treatment of various diseases. More than 100 drugs used worldwide are enzyme inhibitors. Thymidine phosphorylase is a highly expressed protein in many solid human tumours. This has been identified as a potential target in the development of anti-cancer drugs. Abnormally the level of thymidine phosphorylase is highly expressed in various pathological disorders including pancreatic, gastric carcinoma, colon carcinoma, uterine sarcoma, renal carcinoma, breast and lung cancers, astrocytic tumors, cervical intraepithelial neoplasia, carcinomas of the ovary and bladder, Kaposi sarcoma, atherosclerosis, and in various inflammatory diseases. Identification of effective inhibitors of thymidine phosphorylase is, therefore, a need for the treatment of various types of neoplastic and non-neoplastic diseases. Currently only one TP inhibitor (tipiracil), in combination of trifluridine (a cytotoxin), is recently approved by U.S. FDA for clinical use for the treatment of metastatic colorectal cancer. This combination drug (trifluridine/ tipiracil), marketed as Lonsurf, is also associated with severe side effects, such as myelosuppression, anemia, and neutropenia. Therefore there is need to develop new TP inhibitory agents. Indeed, a potent inhibitor of TP, 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]uracil (TPI) entered phase II clinical trials in combination with 5-trifluoromethyl- 2α-deoxyuridine as an orally available anticancer treatment under the name of TAS-102. 3-Formylchromone is a fairly versatile molecule that is easily synthesized and its Schiff bases are associated with a wide range of biological activities including antimicrobial, anticancer, anti inflammatory, antioxidant activities. In addition literature review also revealed that Schiff bases of 3 formyl chromone exhibit thymidine phosphorylase inhibitory activity. Thiadiazole is also a potent nucleus which exhibits pharmacological activities such as antitumor, antiviral, antibacterial, amoebicidal, antiinflammatory, antitubercular, antipyretic, CNS depressant and hypoglycemic activities. Based on the above facts, the present work is focused on synthesis of Schiff bases of 7- hydroxyl - 3 formyl chromone using various 2- amino 5 aryl 1,3, 4 thiadiazole as novel thymidine phosphorylase inhibitors. 3- formyl chromone, 1,3,4 thiadiazole and Schiff bases have been reported to possess antimicrobial properties. Hence the synthesized compounds are screened for their invitro antimicrobial activity against selected strains of Gram positive and Gram negative bacteria and fungi.SUMMARY:The present work was focused on synthesis, thymidine phosphorylase inhibitory activity and antimicrobial screening of eight different Schiff bases of 7- hydroxyl- 3- formyl chromone with 2-amino 5-aryl 1,3,4- thiadiazole..LITERATURE REVIEW:The extensive literature review reports showed that Schiff bases of 3- formyl chromone are potent thymidine phosphorylase inhibitors and the chromone moiety, thiadiazole and Schiff bases posses excellent antimicrobial activity.SYNTHESIS:In the present work a total of eight new Schiff bases of 3- formyl chromone were synthesized.CONCLUSION:Based on the results of synthetic works, characterization data, enzyme inhibition studies and antimicrobial screening, the following conclusions were made. Using the schemes evolved, eight different Schiff bases of 7-hydroxy -3- formyl chromone were synthesized in good yields. The in vitro thymidine phosphorylase inhibitory activity studies indicated that compounds Ig and Ic showed excellent inhibitory activity against thymidine phosphorylase, more potent than standard. The compounds Id and Ie also showed inhibitory activity comparable with the standard. A general trend showed that more electron withdrawing substituents inserted on para position of phenyl ring will result in more potent compounds. The in vitro antimicrobial studies showed that all the compounds exhibited good antibacterial and anti fungal activity in which compound Ih showed the highest activity against Staphylococcus aureus and Pseudomonas aeruginosa. Ib, If and Ig showed highest activity against Bacillus subtilis and Escherichia coli respectively. The compound Id and Ic exhibited the highest anti fungal activities. Of the 8 compounds synthesized, Ig, Ic and Id can be chosen as lead moieties for the development of effective thymidine phosphorylase inhibitors. Similarly Ih and Id can be taken up for the development of ideal anti bacterial and anti fungal agents respectively