Title:Synthesis and Structural Activity Relationship Study of Ursolic Acid
Derivatives as Antitubercular Agent
Volume: 20
Issue: 6
Author(s): Sadhna Vishwakarma, Santosh K. Srivastava*, Naveen K. Khare*, Shiwa Chaubey, Vinita Chaturvedi, Priyanka Trivedi, Sana Khan and Feroz Khan
Affiliation:
- Department of Medicinal Chemistry, CSIR-Central Institute of Medicinal and Aromatic Plants (CIMAP), Lucknow,
226015, India
- Department of Chemistry, University of Lucknow, Lucknow, 226007, India
Keywords:
Ursolic acid, eucalyptus tereticornis, triterpenoid, antitubercular, in vitro, in silico docking.
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.
Methods: 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.
