Synthesis, Biological Activity and DFT Studies of 1,3,4-oxadiazole Ring in Combination with Pyridinium Salt

Abstract

Aims: In this study, the synthesis and biological activity of new 1,3,4-oxadiazole derivatives will be discussed. Background: Microbial contagion via different bacterial strains discomposes the healthcare system globally. In 2019 E. coli, S. aureus, K. pneumoniae, and S. pneumoniae were reported as the most bacteremia deaths causes. Over time, bacteria develop different ways to overcome antibiotic activity, causing multidrug resistant bacteria (MDR). The MDR is considered one of the biggest concerns to scientists worldwide due to its direct effect on patients' lives. As a result, developing new drugs has become imperative for scientists to protect human life. Objective: Developing new water soluble antibacterial drugs from cheap and commercially available materials. Methods: Microdilution Assay Antimicrobial potential was performed based on the reported experimental procedure with slight modifications. Briefly, chemical preparations were serially diluted (2-fold) ten times with Muller Hinton broth. Well number eleven was considered a negative control of bacterial growth, while well number twelve contained nutrient broth only and was used as a positive control for bacterial growth. The achieved ten concentrations of the chemical solutions were from 10 mg/mL to 9 μg/mL. A serial two-fold dilution of DMSO with Muller Hinton broth was prepared to ensure that the antimicrobial potential was not from DMSO. Moreover, the blank or the background was a two-fold dilution for each chemical with broth. The final bacterial concentration in each well (except positive control) was adjusted to 0.75 × 106 CFU/ml. After the inoculation of bacteria, the plates were covered and incubated overnight at 37oC for 24 hours. The plates were then scanned with an enzyme-linked immunosorbent assay (ELISA) reader at 600 Nano moles to examine the bacterial density. The lowest concentration of the chemical that did not allow any visible microbial growth in the test broth was considered the minimal inhibitory concentration (MIC), which was then further confirmed by culturing each (MIC) well on Muller Henton agar and incubating overnight at 37oC for twenty-four hours. The molecular geometries of compounds 4a, 4e, 4j, and 4p were optimized at the B3LYP/6-311+G(d,p) level of theory using DFT calculations. Results: The antimicrobial examination results show that compound 4j has an interesting activity against E. faecium with MIC value of 9 μg/mL. However, it was found to have low activity against E.coli and K. pneumoniae with an MIC value of 625 μg/mL. On the other hand, compound 4e showed very good activity against E.coli with an MIC value of 78 μg/mL and good activity against K. pneumoniae with an MIC value of 312 μg/mL. The structural properties were further investigated by density functional theory (DFT) calculations. The most biologically active compounds 4e and 4j were optimized in the gas phase using B3LYP method and 6-31+G(d,p) as a bases set. The resulting ground-state structures take a V shape as the two conjugated system are connected by methylene group. The molecular electrostatic potential map (MEP) of 4e and 4j was calculated and the results indicate that, the most intense blue region with the largest positive potential is distributed over the pyridinium ring, which indicates its binding with the chloride ion.