Synthetic modifications of abietane diterpene acids to potent antimicrobial agents

Abstract

Among abietane type semisynthetic diterpenoids, a series of quinopimaric and maleopimaric acid derivatives modified at the carboxyl and carbonyl groups, and in ring E were synthesised to obtain new compounds with antimicrobial potency against Mycobacterium tuberculosis H₃₇Rv and key ESKAPE pathogens. It was found that compound 8 exhibited low toxicity to human embryonic kidney cell line HEK-293 (> 32 μg/mL) and showed significant bacteriostatic activity against methicillin-resistant Staphylococcus aureus (MRSA) (MIC ≤ 0.25 µg/mL) and excellent antifungal activity against Cryptococcus neoformans var. grubii (MICs ≤0.25 µg/mL) being ≈4 and ≈30 fold more active than vancomycin and fluconazole. It also showed moderate activity against fungus Candida albicans (MIC ≤ 0.25 µg/mL). Compound 9 inhibited M. tuberculosis H₃₇Rv with MIC of 1.25 µg/mL. The docking studies suggest possible interactions of the leading compounds with the molecular targets.

Graphical Abstract

Keywords:

• Dihydroquinopimaric acid
• maleopimaric acid
• antimicrobial activity
• antitubercular activity
• M. tuberculosis H₃₇Rv
• antifungal activity
• docking studies

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Federal program. The authors gratefully acknowledge the staff of the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF), coordinated by the Southern Research Institute (Birmingham, AL) under the direction of the US National Institute of Health and the National Institute of Allergy and Infectious Diseases (Contract No. HHSN266200600011C (N01-AI-60011)). Spectroscopic studies were carried out using equipment available at the “Chemistry” User Facilities Center, Ufa Institute of Chemistry of Russian Academy of Sciences and “Agidel” Collective Usage Center Ufa Federal Research Center, Russian Academy of Sciences.