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Aryl-n-hexanamide linked enaminones of usnic acid as promising antimicrobial agents

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Abstract

Lichen secondary metabolites are well explored medicinal agents with diverse pharmacological properties. One of the important antibiotic lichen secondary metabolites is usnic acid. Its diverse medicinal profiles prompted us to explore it as a potential antitubercular molecule. Towards this direction, continuing our efforts on the discovery and development of new analogs with potent antitubercular properties we designed, synthesized, and evaluated a set of 37 usnic acid enaminone-coupled aryl-n-hexanamides (3–39). The study yielded a 3,4-dimethoxyphenyl compound (13, 5.3 µM) as the most active anti-TB molecule. The docking studies were performed on 7 different enzymes to better understand the binding modes, where it was observed that compound 13 bound strongly with glucose dehydrogenase (Gscore: − 9.03). Further antibacterial investigations revealed compound 2 with potent inhibition on Salmonella typhi and Bacillus subtilis (MIC 3 µM) and MIC values of 7 and 14 µM on Streptococcus mutans and Escherichia coli respectively. Compound 19 (3-F-5-CF3-phenyl) displayed encouraging antibacterial profiles against E. coli, S. typhi and S. mutans with MIC values of 10 µM respectively. Interestingly, compound 20 (2,6-difluorophenyl) also displayed good antibacterial activity against E. coli with an MIC value of 6 µM. These encouraging pharmacological results will help for better designing and developing usnic acid-based semi-synthetic derivatives as potential antimicrobial agents.

Graphical abstract

A set of 37 new usnic acid enaminone-coupled aryl-n-hexanamides were synthesized and evaluated as potential antimicrobial agents. Compound 13 was identified as the most active antitubercular molecule. 13 was further docked against 7 different enzymes of tuberculosis. The molecule displayed maximum binding energy with the enzyme Glucose dehydrogenase (Gscore: − 9.03), indicating that these hexanamides possibly act by inhibiting the glucose metabolic pathway of the bacterium. Surprisingly, the intermediate hexanoic acid 2 was identified as potent antibacterial agent, acting on both gram-positive and gram-negative bacterial strains (3–14 μM). The active compounds may be subjected to structural iterations to develop further leads.

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The supplementary information provides copies 1H, 13C-NMR and HRMS spectra of the final molecules.

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Acknowledgements

The Authors thank SERB, Department of Science and Technology, India for financial assistance (EMR/2017/002946). PKB, RKP and ANP are thankful to the Department of Science and Technology, INSPIRE component for research fellowships. CSIR-IICT communication number: IICT/Pubs./2021/283.

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Author notes

  1. Pavan Kumar Bangalore

    Present address: Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, 14850, USA

  2. Ravi Kumar Pedapati and Abburi Naga Pranathi have contributed equally.

Authors and Affiliations

  1. Fluoro and Agrochemicals Division, CSIR- Indian Institute of Chemical Technology, Hyderabad, Telangana, 500007, India

    Pavan Kumar Bangalore, Ravi Kumar Pedapati, Abburi Naga Pranathi & Srinivas Kantevari

  2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201002, India

    Pavan Kumar Bangalore, Ravi Kumar Pedapati, Abburi Naga Pranathi & Srinivas Kantevari

  3. Applied Biology Division, CSIR- Indian Institute of Chemical Technology, Hyderabad, Telangana, 500007, India

    Uma Rajeswari Batchu & Sunil Misra

  4. Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad, Telangana, 500078, India

    Madhurekha Estharala & Dharmarajan Sriram

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Bangalore, P.K., Pedapati, R.K., Pranathi, A.N. et al. Aryl-n-hexanamide linked enaminones of usnic acid as promising antimicrobial agents. Mol Divers 27, 811–836 (2023). https://doi.org/10.1007/s11030-022-10456-y

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