Synthesis of novel monocarbonyl curcuminoids, evaluation of their efficacy against MRSA, including ex vivo infection model and their mechanistic studies

• Published in: European journal of medicinal chemistry Vol. 195; pp. 112276 - 112291
• Main Authors: Gagandeep, Kumar, Prince, Kandi, Shamseer Kulangara, Mukhopadhyay, Kasturi, Rawat, Diwan S.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.06.2020; Elsevier
• Subjects: 3T3 Cells; Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Curcumin; Curcuminoids; Diarylheptanoids - chemical synthesis; Diarylheptanoids - chemistry; Diarylheptanoids - pharmacology; Life Sciences & Biomedicine; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - physiology; Mice; Microbial Viability - drug effects; MRSA; Pharmacology & Pharmacy; S. aureus; Science & Technology; Curcumin; Antibacterial; S. aureus; Curcuminoids; MRSA; ANTIBIOTICS; ANALOGS; STABILITY; DISCOVERY; S. aureus; PANTON-VALENTINE LEUKOCIDIN; DEGRADATION; STAPHYLOCOCCUS-AUREUS; ASSOCIATION; DERIVATIVES; ANTIMICROBIAL ACTIVITY
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112276

In continuation of our effort to improve the physiological stability and the antibacterial activity of curcuminoids against drug-resistant bacteria, a series of novel monocarbonyl curcuminoids were synthesized and screened for antibacterial activity against S. aureus and E. coli strains. These curcuminoids showed potent antibacterial activity against both methicillin-sensitive and methicillin-resistant strains of S. aureus with MIC values 2–8 and 4–16 μg/mL, respectively. They also exhibited moderate potency against E. coli strains. The four most active curcuminoids (7d, 7i, 7m, and 7p) were on further investigation found to be very stable under physiological conditions, non-hemolytic, and non-toxic toward mammalian cells up to 150 μg/mL concentration. Mechanistic studies revealed that these curcuminoids displayed potent bactericidal activity by targeting cell membranes. Further, in an ex vivo mammalian co-culture infection model study, remarkably, the curcuminoids 7i and 7p were able to clear the internalized bacteria in mammalian cells and the activity was found to be superior to conventional antibiotics such as vancomycin and linezolid. Therefore, the present study affords us water-soluble, stable, non-toxic curcuminoids that may serve as lead molecules for development as antibacterial agents against MRSA infections. [Display omitted] •A series of novel, water-soluble, and physiologically stable curcuminoids was synthesized.•Curcuminoids were active against both S. aureus and E. coli bacterial strains.•Most active compounds (7d, 7i, 7m, and 7p) were found to be non-hemolytic and non-toxic.•The study revealed that these compounds target bacterial cell membranes.•Exvivo study of 7i and 7p displayed the superior antibiotic activity than conventional drugs.