Synthesis, biological activity and structure-activity relationship of novel diphenylurea derivatives containing tetrahydroquinoline as carbonic anhydrase I and II inhibitors

Abstract

A series of novel tetrahydroquinoline derivatives containing urea moiety was synthesized and their invitro inhibitory effects on the human carbonic anhydrase isoenzymes (hCA-I and hCA-II) were evaluated by using the CO2 hydration method. All the synthesized compounds exhibited inhibitory activity against both hCA I and hCA II with 1-(4-fluorophenyl)-3-(4-(4-p-tolyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)urea (7k, IC50 value of 5.28M and 5.51M, against hCA I and hCA II, respectively) as the strongest inhibitor in this study. Structure-activity relationships were also investigated. The results showed that most of synthesized compounds have a higher inhibitory activity against hCA I than hCA II. Also the substituents, containing two or more pairs of non-bonding electrons, generally increased the hCA I and II inhibitory activity. Furthermore, some electronic parameters such as the highest occupied molecular orbital and the lowest unoccupied molecular orbital (HOMO-LUMO) energy levels, electron affinity, total energy and dipole moments of the best inhibitors (7b, 7h and 7k) in this study were also calculated by using Gaussian software. The results revealed that HOMO-LUMO energy differences, total energy, chemical hardness and dipole moment of 7b, 7h and 7k showed a linear relationship with increasing inhibitory activity.