Biphenyl Backbone-Based (Bis)Urea and (Bis)Thiourea Derivatives as Antimicrobial and Antioxidant Agents and Evaluation of Docking Studies and ADME Properties

Abstract

In the present study, a new series of (bis)ureas 11(a–f) and (bis)thioureas 13(a–f) of 3,3'-dimethoxy-[1,1'-biphenyl]-4,4'-diamine dihydrochloride (9) has been synthesized. This precursor intermediate 9 in high yields was preparedfrom the commercial starting material, 4,4'-dinitro-[1,1'-biphenyl]-3,3'-diol (7) by following the chemical transformations such as methylation of hydroxyl groups and reduction of nitro to an amine functionality. Antimicrobial and antioxidant activities of the synthesized compounds were evaluated to screen for their biological significance. Antimicrobial activity screening results against four bacteria and two fungi unveiled that a few compounds, 11 b/13b, 11e/13e, and 11d (MIC 3.125 − 6.25 µg/ml) against all the tested bacterial strains and compound 11d against Cladosporium species (MIC 3.125 µg/ml) having potential activity. Especially, (bis)urea compounds 11a, 11 b, and 11e, and (bis)thiourea compounds 13a, 13d, and 13f (MIC 3.125 µg/ml) are proved the comparable activity with standard, cefixime (MIC 3.125 µg/ml) against P. aeruginosa. On the other hand, a few compounds 11c/13c, 13d, and 11e/13e were found, by using DPPH and FRAP methods, to exhibit a good antioxidant activity (IC₅₀ range 25.0–32.5 µg/ml). The synthesized compounds were docked well in the active site of an enzyme, DNA Gyrase A, and the predictions of in silico-ADME and pharmacokinetic parameters suggest that the compounds have good oral bioavailability. The results demonstrate that this class of compounds has an expedient scope to use as antibacterial and antioxidant agents upon further development.

Keywords:

• Biphenyl (bis)ureas and (bis)thioureas
• antimicrobial activity
• antioxidant activity
• molecular docking
• ADME calculations
• DNA Gyrase A

Acknowledgments

The authors thank Micro Labs Limited (ML-27), API Division for providing raw materials and unlimited access to use instrument facilities.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was in part supported by the 985 Project of National Key Universities, Tianjin University, the National Natural Science Foundation of China (NSFC) through Grant-in-Aid numbers: [41651001, 91644103 and 41775120], and the Foreign Youth Talent Introduction Programme [WQ20180020], China.