QSAR Studies Of Bioactivity Of Quinoline And Isothiazolone Derivatives

The relationship between structures and antibacterial activities of quinoline and isothiazolone was used by using both density functional theory (DFT) at the B3LYP/6-31G (d, p) basis set and multiple linear regression analysis (MLR) method. The quinolines included two classes: 15 2,3,6,8-substituted-quinolines and 36 4-alkoxy, 4-aminoalkyl and 4-alkylthioquinoline derivatives. The quantum chemical study of 69 compounds mentioned above was carried out at equilibrium geometries, distribution of mulliken charges and the frontier molecular orbital compositions. Rregression analysis was used to determine the main independent factors which affected the activity of the compounds and a QSAR model was established. Statistical test and evaluation for the obtained models were performed with LOO cross-validation and variation inflation factors(VIF). The results indicated that all of these models had good correlation and stability. 4 new 2,3,6,8-substituted-quinoline molecules were designed and their predicted antibacterial activities were obtained based on the QSAR model. The main investigative results are as follows:(1) 2,3,6,8-substituted-quinolines: C(5) atom is the active site. On replacement of methyl group to cyano at C(8), increased antibacterial activity against S. aureus. Moreover, the benzene ring mainly accept the electronics. The obtained QSAR model demonstrates that the nucleophilic frontier electron density of C(5) atom ( f_C(5)^N) and the bond order of C(9)-N(1) ( B_C(9)-N(1)) are the predominant factors affecting the antibacterial activity against S. aureus. Moreover, 4 new molecules designed show high antibacterial activity which calculate using the obtained QSAR model.(2) 4-alkoxy, 4-aminoalkyl and 4-alkylthioquinoline derivatives: C(7) and C(8) atoms are the active sites. LUMO orbital is important for the antibacterial activity of quinolines. The obtained QSAR model demonstrates that octanol-water partition coefficient ( LogP ), the numbe of hydrogen bond's donor, the net charges of C(2) and C(7) atom ( q_C(2) and q_C(7)) are found to be the predominant ones affecting the antibacterial activity against E.coli.(3) Isothiazolone derivatives: S(1) and N(2) atoms are the active sites. The bond order of S(1)-N(2) favors the activity and decreasing moderately can enhance the antibacterial activity. Moreover, 5-chloro derivatives are more active against E.coli than unsubstituted analogues. The obtained QSAR model demonstrates that the nucleophilic frontier electron density of C(5) atom ( f_C(5)^N) and the net charge of S(1) ( q_S(1)) play the predominant role in antibacterial activity against E.coli.