Synthesis and evaluation of monocarbonyl analogues of curcumin as potential agents against tuberculosis

Author(s)

Gabriela Miranda Ayusso

• Document type: Master's Dissertation
• Press: São José do Rio Preto. 2019-02-26.
• Institution: Universidade Estadual Paulista (Unesp). Instituto de Biociências Letras e Ciências Exatas. São José do Rio Preto
• Defense date: 2019-02-13
• Advisor: Luis Octávio Regasini; Fernando Rogério Pavan

Abstract

Tuberculosis (TB) is the tenth leading cause of death in the world. The peculiar morphophysiological features of Mycobacterium tuberculosis, the main etiological agent of TB, and the emergence of drug resistant strains represent major challenges in the development of drugs against TB. Natural products play an important role in the discovery of new drugs. Curcumin is present in the turmeric rhizomes and demonstrates several bioactivities, including antibacterial. This compound has limitations that prevent its use as therapeutical agent, mainly related to the β-diketone moiety of its structure. The aim of present study was to synthesize and evaluate the anti-TB activity, the toxicity and the in silico pharmacokinetic properties of monocarbonyl analogues of curcumin. Two series of curcumin analogues with the β-diketone moiety replaced by a monocarbonyl group were synthesized. The curcumin and its analogues were evaluated against M. tuberculosis H37Rv. The replacement of β-diketone moiety by a monocarbonyl group and the presence of heteroatoms and the nitro group improved the antimycobacterial effect. The compounds which demonstrated minimum inhibitory concentration for 90% (MIC90) < 85 μM were subjected to toxicity tests against human lung fibroblasts MRC-5 and murine macrophages J774A.1 to determine the inhibitory concentration for 50% (IC50) and the selectivity index (SI). In general, the analogues displayed lower toxicity and higher selectivity for macrophages than lung fibroblasts. The compounds with SI ≥ 10 were analysed against clinical isolates of M. tuberculosis with resistance to different anti-TB drugs. The activity of analogues 7, 8, 13, 15–17, 27 and 28 against three clinical isolates suggested that these compounds probably have a differentiated action mechanism. In addition to demonstrate highest anti-TB activity against M. tuberculosis H37Rv, the analogue 28 was the most selective for lung fibroblasts and macrophages. This compound did not present antagonism with rifampicin and moxifloxacin and did not demonstrate significant in vivo toxicity in Galleria mellonella, indicating its potential safe use in the clinical setting. In silico studies indicated that bioactive analogues are potential drugs candidates by oral administration. Therefore, our study established preliminary structureactivity relationship data, besides to identify monocarbonyl analogues of curcumin as promising drugs candidates against TB. (AU)

• FAPESP's process: 17/08383-7 - Preparation and Biological Evaluation of Dehydrozingerone Derivatives as Potential Agents agianst Tuberculosis
• Grantee: Gabriela Miranda Ayusso
• Support Opportunities: Scholarships in Brazil - Master