Synthesis and Structural Activity Relationship Study of Ursolic Acid Derivatives as Antitubercular Agent

Sadhna Vishwakarma; Santosh Kumar Srivastava; Naveen K Khare; Shiwa Chaubey; Vinita Chaturvedi; Priyanka Trivedi; Sana Khan; Feroz Khan

doi:10.2174/0115734064256660231027042758

Synthesis and Structural Activity Relationship Study of Ursolic Acid Derivatives as Antitubercular Agent

Med Chem. 2023 Nov 7. doi: 10.2174/0115734064256660231027042758. Online ahead of print.

Authors

Sadhna Vishwakarma¹, Santosh Kumar Srivastava¹, Naveen K Khare², Shiwa Chaubey², Vinita Chaturvedi³, Priyanka Trivedi³, Sana Khan⁴, Feroz Khan⁴

Affiliations

¹ Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants (CIMAP), Lucknow 226015, India.
² Department of Chemistry, University of Lucknow, Lucknow-226007, India.
³ Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow-226031, India.
⁴ Metabolic and structural biology department, CSIR-Central Institute of Medicinal and Aromatic Plants (CIMAP), Lucknow-226015, India.

PMID: 37946341
DOI: 10.2174/0115734064256660231027042758

Abstract

Objective: The chemical transformation of ursolic acid (UA) into novel C-3 aryl ester derivatives and in vitro and silico assessment of their antitubercular potential.

Background: UA is a natural pentacyclic triterpenoid with many pharmacological properties. Semisynthetic UA analogs have demonstrated enhanced anticancer, antimalarial, and antifilarial properties in our previous studies.

Method: The C-30 carboxylic group of previously isolated UA was protected, and various C-3 aryl ester derivatives were semi-synthesized. The agar dilution method was used to evaluate the in vitro antitubercular efficacy of Mycobacterium tuberculosis (Mtb) H37Ra. In silico docking studies of the active derivative were carried out against Mtb targets, catalase peroxidase (PDB: 1SJ2), dihydrofolate reductase (PDB: 4M2X), enoyl-ACP reductase (PDB: 4TRO), and cytochrome bc1 oxidase (PDB: 7E1V).

Results: The derivative 3-O-(2-amino,3-methyl benzoic acid)-ethyl ursolate (UA-1H) was the most active among the eight derivatives (MIC1 2.5 µg/mL) against Mtb H37Ra. Also, UA-1H demonstrated significant binding affinity in the range of 10.8-11.4 kcal/mol against the antiTb target proteins, which was far better than the positive control Isoniazid, Ethambutol, and co-crystallized ligand (HEM). Moreover, the predicted hit UA-1H showed no inhibition of Cytochrome P450 2D6 (CYP2D6), suggesting its potential for favorable metabolism in Phase I clinical studies.

Conclusion: The ursolic acid derivative UA-1H possesses significant in vitro antitubercular potential with favorable in silico pharmacokinetics. Hence, further in vivo assessments are suggested for UA-1H for its possible development into a secure and efficient antitubercular drug.

Keywords: Eucalyptus tereticornis; Ursolic acid; anti-tubercular activity; in silico docking.; in vitro; triterpenoid.