Drug Design, Docking Studies And Synthesis of Certain Coumarinyl Azetidin-2-Ones and Evaluation of their Antimycobacterial Activity

Tuberculosis (TB) is the most common cause of the death from infectious disease world-wide, which affects mainly the poorest countries of the world. Cell wall of Mycobacterium tuberculosis includes peptidoglycans and complex lipids (mycolic acids) which are significant determinant of its virulence. Novel antitubercular drugs are urgently needed because TB remains a global health priority [110]. Coumarin compounds as medicinal drugs have been increasingly attracting special interest due to their potential outstanding contributions in the prevention and treatment of diseases, and the related researches and developments have received an increasing attention to synthetic organic chemists [110]. A great deal of effort has been made directly or indirectly towards the discovery and development of coumarin-based antitubercular drugs and some excellent achievements have been acquired. Azetidinone is an exciting pharmaceutical fragment in drug discovery. The strong activity of the famous antibiotics such as penicillins, cephalosporins, thienamycins, nocardicins, aztreonams as well as carbapenems is attributed to the presence of the 2 -azetidinone ring [110]. Mycobacterium tuberculosis genome has high number of cytochrome P450 enzymes and parallel studies indicated that cytochrome P450 inhibiting azole drugs has potent antitubercular activity. Recent research explains potential drug target on Mycobacterium tuberculosis P450 and provides evidence for roles of selected P450 isoforms in host lipid and sterol or steroid transformations Drug discovery tools help in designing new molecular entities which are safe and effective without consuming much of the research hours. The purpose of the present work was to design and synthesize new azetidine-2-one derivatives containing coumarin moiety in order to explore the extent of their antitubercular activity. The compounds were designed by in silico method using MT-CYP51 as the target molecule.SUMMARY: The present work was focused on the designing of novel azetidin-2-one derivatives with coumarin moiety having antitubercular activity. For this, following approach has been adopted. PHASE I: DRUG DESIGN APPROACH: It involves the following stages: Stage 1: Identification of target Cytochrome P450 lanosterol 14α-demethylase in Mycobacterium tuberculosis (MT-CYP51) was selected as the target enzyme as its inhibition will prevent synthesis of the membrane lipids. This compromises membrane integrity and induces Mycobacterial cell lysis.Stage 2: Lead Identification The lead coumarin was selected based on several literature reviews. 150 compounds including a series of azetidinone, imidazolidinone, thiazolidinone and oxazolidinone derivatives of coumarin were subjected to molecular docking studies. All the compounds were found to have binding energy lesser than that of the standard fluconazole. A series of twelve azetidinone (az31-az42) derivatives were selected from these compounds on the basis of their binding energy. az37 (P1) and az38 (P2) was found to have the least binding energy of -11.28 and - 11.24, respectively. Safety and efficacy of the lead molecules were evaluated by observing the in silico ADME studies and computation of drug like properties. Twelve ligands (N1-6 and P1-6) were subjected to in silico lead optimization. Oral bioavailability was evaluated was evaluated by using Molinspiration server and ADMET data were obtained from Accelry’s Accord for Excel. All the compounds possessed good bioavailability and permeability.CONCLUSION: The present study establishes that computational tools help in minimizing the tedious process of drug discovery and delivers new drug candidate more quickly. Cytochrome P450 lanosterol 14α-demethylase in Mycobacterium tuberculosis (MT-CYP51) was selected as the target and coumarin as the lead, which was optimized based on drug likeness score. The proposed twelve compounds were synthesized and their structures were established based on spectral data. The compounds were evaluated for antibacterial and antimycobacterial activity. The synthesized compounds showed poor to moderate antibacterial activity. Five synthesized derivatives (N2, N6, P3, P4 and P6) showed equipotent antitubercular activity compared to the standards Pyrazinamide and Ciprofloxacin at concentration of 3.12µg/ml. Two synthesized derivatives (P3 and P6) exhibited higher level of antitubercular activity even at a low concentration of 1.6µg/ml. Among the synthesized compounds, 3-phenyl substituted azetidin-2-ones showed promising antimycobacterial activity. Among the synthesized compounds, P3 and P6 can be taken as the lead molecule and acute toxicity studies are to be done on these promising compounds