Synthesis and anticancer evaluation of pyridazine derivatives

Lengwe, Chilufya

Synthesis and anticancer evaluation of pyridazine derivatives

Date

2020-11-11

Authors

Lengwe, Chilufya

Publisher

Kamuzu University of Health Sciences

Abstract

Type of Study Synthetic and Characterization Problem Statement The WHO reports that cancer is a leading cause of death worldwide, accounting for an estimated 9.6 million deaths in 2018.1 The global burden of cancer has increased significantly such that, according to WHO, it estimated that the number of new cases in the next 20 years is expected to rise to approximately 70%.2Drug resistance in the treatment of cancer is a frequent clinical challenge for cancer patients.68 Several drug resistance mechanisms have emerged such that some drugs can be prevented from entering the cell; they can be pumped out of the cells; drug activity can also be compromised by mutations or altered expression of the target. Although some therapies have shown remarkable clinical success, emergence of drug resistance has posed problems more especially in advanced stages of cancer.69,70 Therefore, it is paramount that efforts to understand the principle underlining mechanisms of cancer resistance and identifying therapies that can treat cancers no longer susceptible to the current treatments are explored.71Unwanted toxicity profiles of the current therapiesis also another motivating factor for the need to develop alternative chemotherapeutic regimens.72 Furthermore, the cost of cancer drugs, has risen concomitantly with the shift from the use of conventional cytotoxic chemotherapy to newer targeted agents -from about $12,000 before 2000 to more than $120,000 median annual price by 2015.73 Therefore, there is a critical need for structurally novel and cheaper anticancer drugs with new mechanisms of action. Aim of the Study To utilize the pyridazine scaffold as a template for the design and synthesis of novel anticancer agents. Specific Objectives i) To perform synthesis and characterization of target compounds using physical andspectroscopic techniques. ii) To perform in vitro antitumor structure-activity relationship (SAR) studies of various pyridazine analogues. iii) Undertake in vitro profiling with respect to solubility, permeability and metabolic stability: include standard deviations. iv) To evaluate the most promising compounds for in vivo efficacy in relevant disease models and pharmacokinetics Methodology Two classes of pyridanzine compounds will be synthesized. In the first case 6- chloropyridazin-3-amine will be coupled with substituted benzoic acids to form N-(6- chloropyridazin-3-yl)-substituted benzamide which will be then coupled with asubstituted boronic acid to formthe target compounds. The second class involves the dichlorinated pyridazine starting material, 3,6-dichloropyridanze,been coupled with excess boronic acid. Expected Findings IC50 values for all the compounds to be synthesized will be determined. Spectroscopy data i.e. NMR, MS and IR as well as the Physical properties such as melting points of all compounds will be generated. Solubility and permeability data of all promising compounds will be generated. Efficacy data of all promising compounds in animals will be generated Dissemination The report of this research will be submitted to the COM and UNZA as host institutions and also presented to College of Medicine Research and Ethics Committee (COMREC). Further, the results of this research will be disseminated through local conferences, workshops and symposia. If possible, a dissemination workshop will be organized.