Synthesis and greener pastures biological study of bis-thiadiazoles as potential Covid-19 drug candidates

Musa A Said; Sayed M Riyadh; Nadia S Al-Kaff; A A Nayl; Khaled D Khalil; Stefan Bräse; Sobhi M Gomha

doi:10.1016/j.arabjc.2022.104101

Synthesis and greener pastures biological study of bis-thiadiazoles as potential Covid-19 drug candidates

Arab J Chem. 2022 Sep;15(9):104101. doi: 10.1016/j.arabjc.2022.104101. Epub 2022 Jul 11.

Authors

Musa A Said¹, Sayed M Riyadh², Nadia S Al-Kaff³, A A Nayl⁴, Khaled D Khalil^{2

5}, Stefan Bräse^{6

7}, Sobhi M Gomha^{2

8}

Affiliations

¹ Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia.
² Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt.
³ Department of Biology, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia.
⁴ Department of Chemistry, College of Science, Jouf University, P.O. Box 2014, Sakaka, Aljouf, Saudi Arabia.
⁵ Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Almunawrah, Yanbu 46423, Saudi Arabia.
⁶ Institute of Organic Chemistry (IOC), Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, 76133 Karlsruhe, Germany.
⁷ Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Director Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany.
⁸ Department of Chemistry, Faculty of Science, Islamic University of Madinah, Madinah 42351, Saudi Arabia.

Abstract

A novel series of bis- (Abdelhamid et al., 2017, Banerjee et al., 2018, Bharanidharan et al., 2022)thiadiazoles was synthesized from the reaction of precursor dimethyl 2,2'-(1,2-diphenylethane-1,2-diylidene)-bis(hydrazine-1-carbodithioate) and hydrazonyl chlorides in ethanol under ultrasonic irradiation. Spectral tools (IR. NMR, MS, elemental analyses, molecular dynamic simulation, DFT and LUMO and HOMO) were used to elucidate the structure of the isolated products. Molecular docking for the precursor, 3 and ligands 6a-i to two COVID-19 important proteins M^pro and RdRp was compared with two approved drugs, Remdesivir and Ivermectin. The binding affinity varied between the ligands and the drugs. The highest recorded binding affinity of 6c with M^pro was (-9.2 kcal/mol), followed by 6b and 6a, (-8.9 and -8.5 kcal/mol), respectively. The lowest recorded binding affinity was (-7.0 kcal/mol) for 6 g. In comparison, the approved drugs showed binding affinity (-7.4 and -7.7 kcal/mol), for Remdesivir and Ivermectin, respectively, which are within the range of the binding affinity of our ligands. The binding affinity of the approved drug Ivermectin against RdRp recoded the highest (-8.6 kcal/mol), followed by 6a, 6 h, and 6i are the same have (-8.2 kcal/mol). The lowest reading was found for compound 3 ligand (-6.3 kcal/mol). On the other side, the amino acids also differed between the compounds studied in this project for both the viral proteins. The ligand 6a forms three H-bonds with Thr 319(A), Sr 255(A) and Arg 457(A), whereas Ivermectin forms three H-bonds with His 41(A), Gly143(A) and Gln 18(A) for viral M^pro. The RdRp amino acids residues could be divided into four groups based on the amino acids that interact with hydrogen or hydrophobic interactions. The first group contained 6d, 6b, 6 g, and Remdesivir with 1-4 hydrogen bonds and hydrophobic interactions 1 to 10. Group 2 is 6a and 6f exhibited 1 and 3 hydrogen bonds and 15 and 14 hydrophobic interactions. Group 3 has 6e and Ivermectin shows 4 and 3 hydrogen bonds, respectively and 11 hydrophobic interactions for both compounds. The last group contains ligands 3, 6c, 6 h, and 6i gave 1-3 hydrogen bonds and 6c and 3 recorded the highest number of hydrophobic interactions, 14 for both 6c and 6 h. Pro Tox-II estimated compounds' activities as Hepatoxic, Carcinogenic and Mutagenic, revealing that 6f-h were inactive in all five similar to that found with Remdesivir and Ivermectin. The drug-likeness prediction was carried out by studying physicochemical properties, lipophilicity, size, polarity, insolubility, unsaturation, and flexibility. Generally, some properties of the ligands were comparable to that of the standards used in this study, Remdesivir and Ivermectin.

Keywords: Binding energy; Bis-[1,2,4]thiadiazoles; Drug-likeness prediction; Ivermectin; Molecular docking; Remdesivir.