Synthesis, Characterization, DFT, and In Silico Investigation of Two Newly Synthesized β-Diketone Derivatives as Potent COX-2 Inhibitors

Malahat Musrat Kurbanova; Abel Mammadali Maharramov; Arzu Zabit Sadigova; Fidan Zaur Gurbanova; Suraj Narayan Mali; Rashad Al-Salahi; Youness El Bakri; Chin-Hung Lai

doi:10.3390/bioengineering10121361

Synthesis, Characterization, DFT, and In Silico Investigation of Two Newly Synthesized β-Diketone Derivatives as Potent COX-2 Inhibitors

Bioengineering (Basel). 2023 Nov 27;10(12):1361. doi: 10.3390/bioengineering10121361.

Authors

Malahat Musrat Kurbanova¹, Abel Mammadali Maharramov¹, Arzu Zabit Sadigova¹, Fidan Zaur Gurbanova², Suraj Narayan Mali³, Rashad Al-Salahi⁴, Youness El Bakri⁵, Chin-Hung Lai⁶

Affiliations

¹ Organic Chemistry Department, Baku State University, Z. Khalilov 23, Baku 1148, Azerbaijan.
² Department of Pharmacy and Biotechnology, Bioinformatics, University of Bologna, Via Marsala, 49/A, 40126 Bologna, Italy.
³ Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra 835215, India.
⁴ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
⁵ Department of Theoretical and Applied Chemistry, South Ural State University, Lenin Prospect 76, Chelyabinsk 454080, Russia.
⁶ Department of Medical Applied Chemistry, Chung Shan Medical University, Taichung 40241, Taiwan.

Abstract

Despite extensive genetic and biochemical characterization, the molecular genetic basis underlying the biosynthesis of β-diketones remains largely unexplored. β-Diketones and their complexes find broad applications as biologically active compounds. In this study, in silico molecular docking results revealed that two β-diketone derivatives, namely 2-(2-(4-fluorophenyl)hydrazono)-5,5-dimethylcyclohexane-1,3-dione and 5,5-dimethyl-2-(2-(2-(trifluoromethyl)phenyl)hydrazono)cyclohexane-1,3-dione, exhibit anti-COX-2 activities. However, recent docking results indicated that the relative anti-COX-2 activity of these two studied β-diketones was influenced by the employed docking programs. For improved design of COX-2 inhibitors from β-diketones, we conducted molecular dynamics simulations, density functional theory (DFT) calculations, Hirshfeld surface analysis, energy framework, and ADMET studies. The goal was to understand the interaction mechanisms and evaluate the inhibitory characteristics. The results indicate that 5,5-dimethyl-2-(2-(2-(trifluoromethyl)phenyl)hydrazono)cyclohexane-1,3-dione shows greater anti-COX-2 activity compared to 2-(2-(4-fluorophenyl)hydrazono)-5,5-dimethylcyclohexane-1,3-dione.

Keywords: ADME; COX-2; DFT; Hirshfeld surface; β-diketone.

Grants and funding

RSP-2023R353/King Saud University