The Calculations, Synthesis And Antibacterial Evaluation Of Novel Imidazo[1,5-A] Pyridine Derivatives

19new imidazo[1,5-a]pyridine compounds screening from about110designedcompounds were selected based on the preliminary docking studies, including71,3,4-oxadiazole derivatives and12hydrazone derivatives.All the newly synthesized compounds were characterized by IR,1HNMR,13CNMRand HRMS. Absorption and fluorescence spectra were measured in dichloromethane; anintense absorption maxima was noted at290nm and emission maxima was noted at470nm. The newly synthesized compounds were screened for their antibacterial activity basedon the promising preliminary antibacterial screening results. The mode of action of theseactive compounds was carried out by docking of receptor Streptococcus pneumoniaehyaluronidase SpnHL (PDB ID:2BRP) with newly synthesized candidate ligands. Thesecompounds exhibited well established bonds with one or more amino acids in the receptoractive pocket. From the docking studies, compound8g was considered to be the bestinhibitor. The preliminary in vitro-antibacterial screening results indicated that thesynthesized compounds have potential of antimicrobial. The compounds of differentconcentrations existed different degrees of inhibition in Chinese hamster ovary cellsproliferation. The measured LD50is2.21-3.39μg/mL.Hyaluronidase, as a virulence factor, can be produced by a number of Gram-positivebacteria, such as Streptococcus pyogenes, Streptococcus pneumonia and Staphylococcusaureus. Bacterial hyaluronan lyases (Hyal) degrade hyaluronan, an important component ofthe extracellular matrix, and are involved in microbial spread. Hyal inhibitors may serve astools to study the role of the enzyme, its substrates and products in the course of bacterialinfections. Moreover, such enzyme inhibitors are potential candidates for antibacterialcombination therapy. Based on crystal structures of Streptococcus pneumoniae Hyal incomplex with a hexasaccharide substrate and with different inhibitors. A series of novel substituted1,3,4-oxadiazole derivatives were synthesized by thereaction of3-butyl-1-chloroimidazo [1,5-a]pyridine-7-carbohydrazide with propionylchloride and substituted benzoic chloride in the presence of phosphorus oxychloride. Thecompounds were characterized using IR,1H NMR,13C NMR and HRMS. Absorption andfluorescence spectra were measured in dichloromethane; an intense absorption maximawas noted at ca.290nm and emission maxima was noted at ca.470nm. The absorptionspectra of the1,3,4-oxadiazole derivatives reveal that a phenyl and an ethyl groupattachedto the1,3,4-oxadiazole ring markedly influenced the maximum absorption. The structuresbased on density function theory (DFT) calculation show planar configurations for thecompounds. The calculated molecular orbital correlates well with their absorption.The substitution pattern of the imidazo[1,5-a]pyridine-hydrazone derivatives wascarefully selected to confer different electronic environment to the molecules. Thus,electron donating groups to aromatic ring, such as methyl, methoxy, hydroxyl anddimethylamine and electron withdrawing groups from aromatic ring, such as halogens,nitro and trifluoromethyl were chosen as substituents on the chemical structure of the targetcompounds. Furthermore, heterocyclic thiophen was also selected. Either electrondonating groups or electron withdrawing groups, imidazo[1,5-a]pyridine-hydrazonederivatives showed good antibacterial activity for all the tested bacteria with minimalinhibitory concentration (MIC) anging between0.78and2.85μg/mL.