Novel 2-arylbenzothiazole DNA gyrase inhibitors: Synthesis, antimicrobial evaluation, QSAR and molecular docking studies

• Published in: Bioorganic chemistry 2019-12, Vol.93, p.103373-103373, Article 103373
• Main Authors: Ghannam, Iman A.Y., Abd El-Meguid, Eman A., Ali, Islam H., Sheir, Donia H., El Kerdawy, Ahmed M.
• Format: Article
• Language: English
• Subjects: 2-Arylbenzothiazoles; Antimicrobial agents; DNA gyrase inhibitors; Molecular docking; QSAR
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.103373

[Display omitted] •Novel twenty three 2-arylbenzothiazoles were synthesized and evaluated for their antimicrobial activity.•The tested compounds showed stronger inhibitory activity against Gram-negative than against Gram-positive bacteria.•Compounds 4, 5, 6c, 6d, 6g, 6i, 6j, 7b, 7c, 7g and 8a were tested for their E. coli gyrase inhibitory activity.•QSAR study showed high correlation between the experimental and model predicted antimicrobial activity.•Molecular docking study revealed the key interactions with Asp73 and Gly77 of the DNA gyrase B active site. A series of new 2-arylbenzothiazole derivatives (4, 5, 6a-j, 7a-i and 8a,b) was synthesized and tested for their antimicrobial activity against different Gram-positive, Gram-negative bacteria and yeast using ciprofloxacin and fluconazole as positive controls for the antibacterial and antifungal activities, respectively. The target compounds showed stronger inhibitory activity against Gram-negative than Gram-positive bacteria. The minimum inhibitory concentration (MIC) values were determined for those compounds showed zone of inhibition ≥ 13 mm. Based on the MIC values for the tested compounds against E. coli, compounds (4, 5, 6c, 6d, 6g, 6i, 6j, 7b, 7c, 7g and 8a) were selected and tested for their E. coli gyrase inhibitory activity. The tested compounds showed moderate inhibitory activity against E. coli gyrase. Compounds 5, 6c, 6i, 6j and 7b displayed high inhibitory activity against E. coli gyrase with IC50 values below 10 µM, however, they were less active than ciprofloxacin (E. coli gyrase IC50 = 1.14 µM). The p-hydroxy-m-methoxy benzothiazole analogue 6c was the most active tested compound (E. coli gyrase IC50 = 4.85 µM). Quantitative structure–activity relationship (QSAR) study was also implemented for the newly synthesized compounds. The QSAR study indicated that the structural feature that governs the anti-microbial activity for the newly synthesized benzothiazole derivatives is their structural hydrophilic-lipophilic balance what agrees with the chemical intuition where this balance governs their cellular absorption and so their antimicrobial activity. Molecular docking showed that the newly synthesized compounds possess the required structural feature for E. coli gyrase B inhibition through interaction with the key amino acids Asp73 and Gly77.