Semisynthesis, Structure Elucidation and Anti-Mycobacterium marinum Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactones with Interesting Ketal Groups

Yin, Jun-Na; Wang, Cui-Fang; Zhang, Xiu-Li; Cheng, Ya-Jie; Wu, Yan-Wei; Zhang, Qun; Shao, Chang-Lun; Wei, Mei-Yan; Gu, Yu-Cheng

doi:10.3390/md22100431

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Semisynthesis, Structure Elucidation and Anti-Mycobacterium marinum Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactones with Interesting Ketal Groups

by

Jun-Na Yin

^1,†,

Cui-Fang Wang

^1,†,

Xiu-Li Zhang

¹,

Ya-Jie Cheng

¹,

Yan-Wei Wu

¹,

Qun Zhang

¹,

Chang-Lun Shao

^1,2

,

Mei-Yan Wei

^1,2,* and

Yu-Cheng Gu

^3,*

¹

Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China

²

Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, China

³

Syngenta Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Mar. Drugs 2024, 22(10), 431; https://doi.org/10.3390/md22100431

Submission received: 8 September 2024 / Revised: 19 September 2024 / Accepted: 23 September 2024 / Published: 25 September 2024

(This article belongs to the Special Issue Pharmacological Potential of Marine Natural Products, 2nd Edition)

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Abstract

The incidence of Mycobacterium marinum infection is on the rise; however, the existing drug treatment cycle is lengthy and often requires multi-drug combination. Therefore, there is a need to develop new and effective anti-M. marinum drugs. Cochliomycin A, a 14-membered resorcylic acid lactone with an acetonide group at C-5′ and C-6′, exhibits a wide range of antimicrobial, antimalarial, and antifouling activities. To further explore the effect of this structural change at C-5′ and C-6′ on this compound’s activity, we synthesized a series of compounds with a structure similar to that of cochliomycin A, bearing ketal groups at C-5′ and C-6′. The R/S configuration of the diastereoisomer at C-13′ was further determined through an NOE correlation analysis of CH₃ or CH₂ at the derivative C-13′ position and the H-5′ and H-6′ by means of a 1D NOE experiment. Further comparative ¹H NMR analysis of diastereoisomers showed the difference in the chemical shift (δ) value of the diastereoisomers. The synthetic compounds were screened for their anti-microbial activities in vitro. Compounds 15–24 and 28–35 demonstrated promising activity against M. marinum, with MIC₉₀ values ranging from 70 to 90 μM, closely approaching the MIC₉₀ of isoniazid. The preliminary structure–activity relationships showed that the ketal groups with aromatic rings at C-5′ and C-6′ could enhance the inhibition of M. marinum. Further study demonstrated that compounds 23, 24, 29, and 30 had significant inhibitory effects on M. marinum and addictive effects with isoniazid and rifampicin. Its effective properties make it an important clue for future drug development toward combatting M. marinum resistance.

Keywords: 14-membered resorcylic acid lactones; Mycobacterium marinum; anti-Mycobacterium marinum; ketal groups; diastereoisomers

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MDPI and ACS Style

Yin, J.-N.; Wang, C.-F.; Zhang, X.-L.; Cheng, Y.-J.; Wu, Y.-W.; Zhang, Q.; Shao, C.-L.; Wei, M.-Y.; Gu, Y.-C. Semisynthesis, Structure Elucidation and Anti-Mycobacterium marinum Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactones with Interesting Ketal Groups. Mar. Drugs 2024, 22, 431. https://doi.org/10.3390/md22100431

AMA Style

Yin J-N, Wang C-F, Zhang X-L, Cheng Y-J, Wu Y-W, Zhang Q, Shao C-L, Wei M-Y, Gu Y-C. Semisynthesis, Structure Elucidation and Anti-Mycobacterium marinum Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactones with Interesting Ketal Groups. Marine Drugs. 2024; 22(10):431. https://doi.org/10.3390/md22100431

Chicago/Turabian Style

Yin, Jun-Na, Cui-Fang Wang, Xiu-Li Zhang, Ya-Jie Cheng, Yan-Wei Wu, Qun Zhang, Chang-Lun Shao, Mei-Yan Wei, and Yu-Cheng Gu. 2024. "Semisynthesis, Structure Elucidation and Anti-Mycobacterium marinum Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactones with Interesting Ketal Groups" Marine Drugs 22, no. 10: 431. https://doi.org/10.3390/md22100431

APA Style

Yin, J.-N., Wang, C.-F., Zhang, X.-L., Cheng, Y.-J., Wu, Y.-W., Zhang, Q., Shao, C.-L., Wei, M.-Y., & Gu, Y.-C. (2024). Semisynthesis, Structure Elucidation and Anti-Mycobacterium marinum Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactones with Interesting Ketal Groups. Marine Drugs, 22(10), 431. https://doi.org/10.3390/md22100431

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Semisynthesis, Structure Elucidation and Anti-Mycobacterium marinum Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactones with Interesting Ketal Groups

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