Synthesis, in vitro and in silico evaluation of halogenated xanthone and benzophenone derivatives as antibacterial agents against acne-causing bacteria

Acne which is caused by Cutibacterium acnes and Staphylococcus aureus bacteria is the most common skin problem among adolescents and young adults. Topical antibiotics like tetracycline are commonly used to treat acne but their effectiveness has declined as bacteria develop antibiotic resistance. Thus, this research emphasizes the antibacterial properties of new synthetic derivatives of halogenated xanthone and benzophenone (1a-1f), (2a-2d), (3a-3i), and (4a-4j) via in vitro antibacterial assay with tetracycline, erythromycin, and salicylic acid as reference standards. Based on the well diffusion assay (WDA), compound 1 f revealed the most potent antibacterial properties by inhibiting the acne-causing bacteria strains with a recorded inhibition zone of 15.67 ± 0.58 mm (C. acnes; ATCC 6919), 16.00 ± 0.00 mm (C. acnes; ATCC 11827), 15.00 ± 0.00 mm (S. aureus; ATCC 6538), and 30.00 ± 0.00 mm (S. aureus; ATCC 10832). These findings were further supported by the MIC and MBC values of compound 1 f, which ranged from 0.02 to 0.50 mg/mL. Next, the structure-activity relationship study revealed the attachment of different substituents at different positions that were responsible for the potent activity of compound 1 f. Compound 1 f reveals good binding affinity values towards C. acnes and S. aureus and better interaction with the protein active site. In silico study of drug-likeness and therapeutic effectiveness properties, including Lipinski's ‘rule of five’, Veber's rule, and ADME properties, projected that the compound 1 f would be toxicity-free, non-carcinogenic, and risk-free, which could be used as a better therapeutic agent for acne formulation with a guarantee for healthy skin.

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