Synthesis, Antibacterial Properties and Molecular Modeling Studies of Quinolone-triazole Hybrids

Abstract

Quinolones are one of the most important synthetic antibacterial agents and have been widely used in the treatment of diverse infections including urinary tract, respiratory and bone joint infections as well as sexually transmitted diseases, prostatitis, pneumonia and acute bronchitis. However, quinolone resistance increases in almost all Gram-negative and Gram-positive species as well as tuberculosis. The continued increase in resistance has put enormous pressure on public health systems worldwide, mainly due to the high level of use and to some degree of abuse. The current study deals with bio-conjugation of quinolone antibiotics, including ciprofloxacin, norfloxacin, and pipemidic acid (considering that the pyridopyrimidinyl nucleus is the bio-isosteric form of the quinoline ring), with triazole rings. Interest in the 1,2,3-triazol scaffold for developing novel bio-conjugates is attributed to the pharmacological properties exhibited by 1,2,3-triazole containing-compounds as anti-inflammatory, anti-tumor, and antibacterial agents. Additionally, 1,2,3-triazole possesses favorable properties in the medicinal chemistry field. It has a moderate dipole character, hydrogen bonding capability, rigidity and remarkable metabolic stability. In a previous study, it was found that antibiotic conjugates with amino acids enhance the lipophilic properties of quinolone antibiotics with a retention or increase in antibacterial activity. In the current study, a 1,2,3-triazole nucleus is being introduced into amino acid and antibiotic conjugates to alter their biological properties. Computational chemistry studies including 3D-pharmacophore and 2D-QSAR (quantitative structure-activity relationship) are being used to assist in the understanding of observed biological properties as well as determining the most important structural parameters controlling bio-activity. These studies are also being used to validate observed biological data.