Introduction The global emergence of resistance to antimicro

Introduction The global emergence of resistance to antimicrobial agents is increasingly limiting the effectiveness of current drugs, especially in immuno compromised patients. Drug resistance, especially by bacteria and fungi, is one of the major concerns to public health and scientific communities’ worldwide [1,2]. To overcome the microbial resistance, there is an urgent need for developing new antimicrobial agents which will be more selective, potent and less toxic compared to the existing drugs in clinical treatment. Glucosamine-6-phosphate synthase (GlcN-6-P synthase) is reported to be one of the unique targets for developing new antimicrobial agents [3]. GlcN-6-P synthase is the trivial name of glutamine fructose-6-phosphate amidotransferase, which catalyses the formation of glucosamine-6-phosphate from glutamine via fructosamine-6-phosphate. Inhibition of the enzyme GlcN-6-P synthase leads to check the formation of glucosamine-6-phosphate which has indispensable role in the cell wall assembly for microorganism as well as for human cell. Short-time inactivation of GlcN-6-P synthase in fungal R406 is lethal for the pathogen (it induces morphological changes, agglutination and lysis), while in mammals depletion of the amino-sugar pool for a short time is not lethal, because of the much longer lifespan of mammalian cells, long half life of GlcN-6-P synthase and rapid expression of the mammalian gene encoding the enzyme. Despite numerous attempts to developed new structural prototype in the search for more effective antimicrobial agents; 1,2,4-triazole still remains as one of the most versatile class of antimicrobial agents [4,5] and therefore, medicinal chemists use this triazole moiety as potential substructures for further molecular exploration. Several compounds possessing 1,2,4-triazole nucleus are clinically used as antifungal agents (E.g.: posaconazole, fluconazole, itraconazole and terconazole). More over literature survey revealed that 3,4-derivative of 1,2,4-triazoles have high potential for antibacterial [6] antifungal [7,8], antitubercular [9] and antiviral [10] activities. The reported 1,2,4 triazole compounds A, B & C (Fig. 1) showed significant antimicrobial activity at 16 μg/mL (against fungi), <1.956 μg/mL (against bacteria) and 0.39–1.59 μg/mL (against bacteria) concentration level, respectively. With past experience in azoles [11,12] and in view of the facts mentioned above, we designed common structure 1,2,4-triazole nucleus D (Fig. 1) carrying various substituted aromatic moieties at 3rd & 4th position, oxygen or sulphur at 5th position. Herein, we docked designed triazoles with GlcN-6-P synthase (PDB-1JXA) and selected best twelve compounds having good glide score. The selected triazoles were synthesized and evaluated for in-vitro antibacterial and antifungal activity.
Results and discussion
Conclusion To verify docking scores in practice, the designed compounds were synthesized and its antimicrobial properties were checked. Docking scores and predicted antimicrobial activity of synthesized compounds were well correlated. Antibacterial study and docking study reveals that the high affinity of synthesized derivatives (B4b, B4g and B4j) within the binding pocket of GluN-6-P synthase strongly enhanced the determined activities of these derivatives as potent antimicrobial agents, particularly as antifungal agents. A detailed analysis of the interaction pattern for this complex leads us to the conclusion that minor changes in the structure of the inhibitor should enhance the interactions and improve the inhibitory properties of the molecule. Ligand interactions with Ser347, Thr352, Val399, and Glh488 amino acid residues are essential for increasing binding affinity and orientation at the active site of the receptor as antimicrobial activity. ADMET properties shows all the synthesized compounds were fit for further development studies. So further enzyme inhibition study is essential to predict the exact antimicrobial mechanism and also modification need to improve antimicrobial activity of the synthesized compounds.