Novel saccharin analogs as promising antibacterial and anticancer agents: synthesis, DFT, POM analysis, molecular docking, molecular dynamic simulations, and cell-based assay

Magda H Abdellattif; Ahmed Elkamhawy; Mohamed Hagar; Taibi Ben Hadda; Wesam S Shehab; Wael Mansy; Amany Belal; M M H Arief; Mostafa A Hussien

doi:10.3389/fphar.2022.958379

Novel saccharin analogs as promising antibacterial and anticancer agents: synthesis, DFT, POM analysis, molecular docking, molecular dynamic simulations, and cell-based assay

Front Pharmacol. 2022 Oct 4:13:958379. doi: 10.3389/fphar.2022.958379. eCollection 2022.

Authors

Magda H Abdellattif¹, Ahmed Elkamhawy^{2

3}, Mohamed Hagar⁴, Taibi Ben Hadda^{5

6}, Wesam S Shehab⁷, Wael Mansy⁸, Amany Belal⁹, M M H Arief¹⁰, Mostafa A Hussien^{11

12}

Affiliations

¹ Department of Chemistry, College of Science, Taif University, Taif, Saudi Arabia.
² College of Pharmacy, Dongguk University-Seoul, Goyang, South Korea.
³ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
⁴ Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
⁵ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
⁶ Laboratory of Applied Chemistry and Environment, Faculty of Sciences, Mohammed Premier University, Oujda, Morocco.
⁷ Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt.
⁸ Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
⁹ Department of Pharmaceutical Chemistry, College of Pharmacy Taif University, Taif, Saudi Arabia.
¹⁰ Department of Chemistry, Faculty of Science, Benha University, Benha, Egypt.
¹¹ Department of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
¹² Department of Chemistry, Faculty of Science, Port Said University, Port Said, Egypt.

Abstract

Saccharine is a pharmacologically significant active scaffold for various biological activities, including antibacterial and anticancer activities. Herein, saccharinyl hydrazide (1) was synthesized and converted into 2-[(2Z)-2-(1,1-dioxo-1,2-dihydro-3H-1λ⁶,2- benzothiazole-3-ylidene) hydrazinyl] acetohydrazide (5), which was employed as a key precursor for synthesizing a novel series of small molecules bearing different moieties of monosaccharides, aldehydes, and anhydrides. Potent biological activities were found against Staphylococcus and Escherichia coli , and the results indicated that compounds 6c and 10a were the most active analogs with an inhibition zone diameter of 30-35 mm . In cell-based anticancer assay over Ovcar-3 and M-14 cell lines, compound 10a was the most potent analog with IC₅₀ values of 7.64 ± 0.01 and 8.66 ± 0.01 µM, respectively. The Petra Orisis Molinspiration (POM) theoretical method was used to calculate the drug score of tested compounds and compare them with their experimental screening data. Theoretical DFT calculations were carried out in a gas phase in a set of B3LYP 6-311G (d,p). Molecular docking studies utilizing the MOE indicated the best binding mode with the highest energy interaction within the binding sites. The molecular docking for Ovcar-3 was carried out on the ovarian cancer protein (3W2S), while the molecular docking for M-14 melanoma was carried out on the melanoma cancer protein (2OPZ). The MD performed about 2ns simulations to validate selected compounds' theoretical studies.

Keywords: DFT; MD; POM analyses; docking; pharmacophore sites; saccharinyl hydrazide.