Quantitative Structure Activity Relationship, Molecular Docking Study and Synthesis of Some Quinoline Derivatives

Abstract

Several quinoline derivatives have an important role in the biological activities field. This importance leads to investigate of newly designed and synthesized of quinoline derivatives against mycobacterium tuberculosis (TB). Chapter one of this thesis deals basically with chemistry of quinoline moiety and deals also with quinoline compounds together with review of their biological properties, in addition, a short concise synthesized quinoline methods was conducted. In the present study the quantitative structure activity relationship (QSAR) studies were carried out to get model that can be used to predict the anti-mycobacterium tuberculosis activity for designed compounds. Data set compounds composed of quinoline derivatives were collected and their anti-mycobacterium tuberculosis (TB) activity with physiochemical descriptors using multiple linear regression methods was correlated. The model obtained was estimated by internal and external predictivity methods. The results of QSAR study showed very good predictive and statistically significant descriptors model (r2 = 0.8231, r = 0.9071 for training set, Q2 = 0.8015 for cross validation and r2= 0.9792, r = 0.9896 for test set), and all statistical parameter were found in acceptable range (RMSE= 0.1236, S = 0.1646, F = 37.173, P = 0.0001. The obtained model showed positive correlated with logP (o/w) partition coefficient and (DCASA) Absolute different in charge-weighted areas. This model was used to predict the biological activity of designed 34 quinoline derivatives and this result compared with rifamycin. Drug ability of designed compounds was evaluated using Lipinski’s rule of five to select compounds for synthesis. Therefore, 8 out of 34 compounds were selected for synthesis. The selected compounds for the synthesis were found to have less ant-mycobacterium tuberculosis (TB) than rifampicin. Molecular docking study also was carried out to find out the binding affinity of target compounds with mycobacterium tuberculosis (TB) protein that was obtained from protein data bank (PDB). The docking scores were calculated, fewness energy indicated the force binding adjective of ligand and receptor. Compounds (C9, C10, C30, C6, C20, C25 and C17) have showed excellent docking score (-21.8094, -21.3433, -21.3289, -20.7235, -19.6866, -19.3230 and -19.1307 kcal/mol respectively) comparing with rifampicin as references drug (-25.2369 kcal/mol). 6KGH protein was selected for docking study of quinoline derivatives and rifampicin as reference drug. The result study from this study showed that some of compounds were capable of forming interaction with amino acid in mycobacterium tuberculosis cells and their docking score ranged between (-21.8094 to -15.7230) kcal/mol. In synthetic work, different aromatic aryl amine derivatives were react with sodium nitrite and hydrochloric acid and sodium acetate as electrophile in the presence of water as solvent to give amine salt and its react with acetyl acetone in low temperature to give diazonium salt as first intermediate, in the second step the coupling diazonium salt (first intermediate) was condensate with various aryl amine derivative to give the second intermediate and cyclization obtained result in the presence of concentrated sulphuric acid to shift water and give the final quinoline derivatives (target compounds). The structures of all synthesized compounds obtained from first and second step (I – XIV) were characterized by thin layer chromatography (TLC), melting point and FT-IR, but the structures of newly synthesized disubstituted quinoline derivatives (XIV-XXII) were established on the basis of TLC, melting point, FT-IR, UV, 1H-NMR and MS spectroscopies analysis. This work achieved by two side study, the first theoretical study achieved on silico by ACD/lab and MOE software programs and the second practical study achieved by the researcher in laboratory for synthesis of the selected compounds.