Design, synthesis, crystal structure, in vitro cytotoxicity evaluation, density functional theory calculations and docking studies of 2-(benzamido) benzohydrazide derivatives as potent AChE and BChE inhibitors

Naghmana Kausar; Shahzad Murtaza; Muhammad Nadeem Arshad; Rahman Shah Zaib Saleem; Abdullah M Asiri; Samia Kausar; Ataf Ali Altaf; Adina Tatheer; Ashraf Y Elnaggar; Salah M El-Bahy

doi:10.1039/d1ra07221h

Design, synthesis, crystal structure, in vitro cytotoxicity evaluation, density functional theory calculations and docking studies of 2-(benzamido) benzohydrazide derivatives as potent AChE and BChE inhibitors

RSC Adv. 2021 Dec 24;12(1):154-167. doi: 10.1039/d1ra07221h. eCollection 2021 Dec 20.

Authors

Naghmana Kausar¹, Shahzad Murtaza¹, Muhammad Nadeem Arshad^{2

3}, Rahman Shah Zaib Saleem⁴, Abdullah M Asiri^{2

3}, Samia Kausar^{1

5}, Ataf Ali Altaf⁶, Adina Tatheer¹, Ashraf Y Elnaggar⁷, Salah M El-Bahy⁸

Affiliations

¹ Department of Chemistry, University of Gujrat Gujrat 50700 Pakistan naghmana.kousar@uog.edu.pk.
² Chemistry Department, Faculty of Science, King Abdulaziz University P. O. Box 80203 Jeddah 21589 Saudi Arabia.
³ Center of Excellence for Advanced Materials Research (CEAMR), King Abdulaziz University P. O. Box 80203 Jeddah 21589 Saudi Arabia.
⁴ Lahore University of Management Sciences (LUMS) Lahore Pakistan.
⁵ Catalysis Research Center, Department of Chemistry, Technical University of Munich Lichtenbergstrasse 4 85747 Garching Germany.
⁶ Department of Chemistry, University of Okara Okara 56300 Pakistan.
⁷ Department of Food Nutrition Science, College of Science, Taif University P. O. Box 11099 Taif 21944 Saudi Arabia.
⁸ Department of Chemistry, Turabah University College, Taif University P.O. Box 11099 Taif 21944 Saudi Arabia.

Abstract

A series of hydrazone derivatives of 2-(benzamido) benzohydrazide was designed, synthesized, and characterized utilizing FTIR, NMR and UV spectroscopic techniques along with mass spectrometry. Compound 10 was also characterized through X-ray crystallography. These synthesized compounds were assessed for their potential as anti-Alzheimer's agents by checking their AChE and BChE inhibition properties by in vitro analysis. The synthesized derivatives were also evaluated for their antioxidant potential along with cytotoxicity studies. The results clearly indicated that dual inhibition of both the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) was achieved by most of the compounds (03-13), showing varying IC₅₀values. Remarkably, compound 06 (IC₅₀ = 0.09 ± 0.05 for AChE and 0.14 ± 0.05 for BChE) and compound 13 (IC₅₀ = 0.11 ± 0.03 for AChE and 0.10 ± 0.06 for BChE) from the series showed IC₅₀ values comparable to the standard donepezil (IC₅₀ = 0.10 ± 0.02 for AChE and 0.14 ± 0.03 for BChE). Moreover, the derivative 11 also exhibited selective inhibition against BChE with IC₅₀ = 0.12 ± 0.09. Meanwhile, compounds 04 and 10 exhibited good anti-oxidant activities, showing % scavenging of 95.06% and 82.55%, respectively. Cytotoxicity studies showed that the synthesized compounds showed cell viability greater than 80%; thus, these compounds can be safely used as drugs. DFT and molecular docking studies also supported the experimental findings.