Synthesis and characterization of thymol-derived phenoxy acetamide derivatives using DFT, molecular docking, and parasitological investigations

AHMED Ramadan Rabee^1*Saied M. Soliman¹Hamida Abdel-Hamid¹Esraa A. Moneer²Sara H. Akl²Yahya H. Shahin³Aliaa A. Masoud⁴Doaa A Ghareeb⁴Mariusz Jaremko⁵Abdul-Hamid Emwas⁶Mazen Sherif¹Mohamed Hagar^1*

• ¹Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
• ²2 Department of Medical Laboratory Technology, Faculty of Applied Health Sciences Technology, Pharos University in Alexandria, Alexandria, Egypt, Alexandria, Egypt
• ³3 Department of Medical Laboratory Technology, Faculty of Health and Medical Techniques, Almaaqal University, Basrah, Iraq., Basrah, Iraq
• ⁴4 Bio-Screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt, Alexandria, Egypt
• ⁵5 Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Makkah, 23955-6900, Saudi Arabia., Thuwal, Saudi Arabia
• ⁶6 KAUST Core Laboratories, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Kingdom of Saudi Arabia, Thuwal, Saudi Arabia

Novel phenoxy acetamide derivatives based on a thymol moiety were synthesized for target parasitological investigation. The newly synthesized compounds, 5a, 5b, 7a, 7b, and 9, were synthesized as phenoxy acetamide derivatives containing a phthalimide or naphthalimide ring through a condensation reaction with various acid anhydrides. Their structures were confirmed based on spectral data derived through Fourier-transform infrared, proton and carbon-13 nuclear magnetic resonance, and elemental analyses. The parasitological, biochemical, and immunological activities of the compounds were measured. The screened compounds were subjected to molecular docking in the active site of CpCDPK1, in addition to analyses based on Lipinski's rule and SwissADME. The results showed that compounds 5a, 5b, and 7b demonstrated promising antiparasitic activity, characterized by high gastrointestinal absorption and favorable drug-likeness profiles. Furthermore, 5a and 7b exhibited higher binding affinities than that of the reference drug. In practical assessments, compound 7b exhibited the highest percentage reduction in oocyst counts (67%). Density functional theory calculations were performed to assess the thermodynamic stability, molecular geometry, frontier molecular orbital energy gaps, and molecular electrostatic potentials of compounds 5a, 5b, 7a, 7b, and 9.Phenoxy acetamide derivatives based on a thymol moiety were synthesized through condensation reactions with a series of acid anhydrides. As shown in Scheme 1, 2-(2-isopropyl-5methylphenoxy)acetohydrazide (3) was reacted with different acid anhydrides, including phthalic anhydride (4a), 1,2,4-benzene tricarboxylic acid anhydride (4b), 1,8-naphthalic anhydride (6a), 4amino-1,8-naphthalic anhydride (6b), and pyromellitic dianhydride (8) in dimethylformamide (DMF) and glacial acetic acid under reflux conditions for 4-6 h to afford compounds 5a, 5b, 7a, 7b, and 9, respectively.The structures of the synthesized compounds 5a, 5b, 7a, 7b, and 9 were confirmed using spectroscopic data. The proton nuclear magnetic resonance ( 1 H-NMR) spectrum showed characteristic singlet peaks for NH (10.08-10.90 ppm) and aliphatic CH3 (1.13-2.27 ppm). The infrared (IR) spectra of all synthesized compounds showed two sharp bands of C=O (conjugated anhydride) at ν = 1792 cm -1 and 1744 cm -1 .