Molecular Modeling QSAR studies and Synthesis of Novel Azolo Cinnoline Analogs as Antitubercular Agents

Hurmath Unnissa, S (2016) Molecular Modeling QSAR studies and Synthesis of Novel Azolo Cinnoline Analogs as Antitubercular Agents. Doctoral thesis, The Tamilnadu Dr. M.G.R. Medical University, Chennai.

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Abstract

A library of two hundred and two compounds containing pyrazolo cinnoline, pyrazole based cinnolines, oxadiazole based cinnolines and imidazothiadiazole based derivatives were designed, and for pre-selection of promising compounds, the compounds were optimized and docked into the active pocket of cytochrome P450 sterol 14α-demethylase from Mycobacterium tuberculosis MtbCYP51 (PDB id: 1EA1) in complex with fluconazole for antimycobacterial studies and into the homology model of Candida albicans CACYP51 for antifungal studies. In principle all docking applications included four steps, i.e. identification and preparation of the receptor site, preparation of the ligands, docking the ligands and evaluation of the docked orientations. According to their docking scores and their interaction with receptor the compounds were selected for synthesis. Based on the docking scores and feasibility of synthesis, forty three compounds were selected, synthesised and screened for its antitubercular against Mycobacterium tuberculosis H37Rv and for its antifungal activity against Candida albicans. All the synthesised compounds have shown good antitubercular and antifungal activity. Among the synthesised candidates the promising antitubercular lead molecules were identified based on their MIC values.The compound 1C (7-chloro derivative of pyrazolo cinnoline series), 6D (6-chloro substituted phenyl derivative of pyrazolo cinnoline), OX-4 (7-chloro and nitro substituted oxadiazole based cinnoline), OX-5 (6-flouro substituted oxadiazole based cinnoline), IMT-6 (6-carboxyl substituted derivative of imidazothiadiazolo based cinnoline), IMT-8 (6-sulphonamido substituted derivative of imidazothiadiazole based cinnoline) and IMT-10 (6-sulphonamido substituted derivative of imidazo thiadiazolo based cinnoline) with excellent antitubercular activity were found to be promising candidate as antitubercular agent. The promising antifungal lead molecules among the synthesized compounds were identified based on their MIC values. The compound 1C (7-chloro derivative of pyrazolo cinnoline), 2C (unsubstituted derivative of pyrazolo cinnoline), 4C (7 nitro derivate of pyrazolo cinnoline), 6D (6-chloro substituted phenyl pyrazolo cinnoline), PY-7(6-chloro derivative of pyrazole based cinnoline), PY-9 (6-nitro substituted pyrazole based cinnoline), OX-1 (3-chloro substituted oxadiazole based cinnoline), OX-2 (3-chloro and hydroxyl substituted oxadiazole based cinnoline), OX-5 (6-flouro substituted oxadiazole based cinnoline),OX-7(4-chloro derivative of oxadiazole), OX-8 (6-chloro and nitro substituted oxadiazole based cinnoline), IMT-12 (un substituted derivative of imidazothiadiazole based cinnoline), IMT-13 (alkyl substituted derivative of imidazothiadiazole based cinnoline) and IMT-14 (6-carboxyl derivative of imidazothiadiazole based cinnoline) with good antifungal activity were found to be promising candidate as antifungal agent. In this study In-silico design was developed to accelerate and assist hit identification, hit-to-lead selection, and lead optimisation. The computational tools were found to advance efficiency and effectiveness of drug discovery process, reduce use of animals and increase predictability of biological action. Computer-aided drug discovery and development utilised here was based on the incerebro-in silico-chemico-biological approach. Thus the molecular modelling studies of azolo cinnoline analogs by targeting the inhibition of enzyme cytochrome P450 14α-sterol demethylase followed by its synthesis and in vitro screening for antitubercular and antifungal activity shown that azolo cinnoline analogs will be safe, fast acting, less toxic and potent antitubercular and antifungal agents. The azolo cinnoline analogs synthesised through molecular modelling studies will potentiate the target oriented attack on the microorganisms without affecting the normal tissues and these molecules can be utilised as potent antitubercular and antifungal drug candidate.

Item Type: Thesis (Doctoral)
Additional Information: 00404/2012
Uncontrolled Keywords: Molecular Modelling, Quantitative Structure Activity Relationship studies, Novel Azolo Cinnoline Analogs, Antitubercular Agents.
Subjects: PHARMACY > Pharmaceutics
Depositing User: Subramani R
Date Deposited: 20 Sep 2019 15:17
Last Modified: 24 Oct 2022 04:56
URI: http://repository-tnmgrmu.ac.in/id/eprint/11536

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