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

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, <b>3</b> and ligands <b>6a</b>-<b>i</b> 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 <b>6c</b> with M^pro was (-9.2 kcal/mol), followed by <b>6b</b> and <b>6a,</b> (-8.9 and -8.5 kcal/mol), respectively. The lowest recorded binding affinity was (-7.0 kcal/mol) for <b>6 g</b>. 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 <b>6a</b>, <b>6 h</b>, and <b>6i</b> are the same have (-8.2 kcal/mol). The lowest reading was found for compound <b>3</b> 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 <b>6a</b> 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 <b>6d</b>, <b>6b</b>, <b>6 g,</b> and Remdesivir with 1-4 hydrogen bonds and hydrophobic interactions 1 to 10. Group 2 is <b>6a</b> and <b>6f</b> exhibited 1 and 3 hydrogen bonds and 15 and 14 hydrophobic interactions. Group 3 has <b>6e</b> and Ivermectin shows 4 and 3 hydrogen bonds, respectively and 11 hydrophobic interactions for both compounds. The last group contains ligands <b>3</b>, <b>6c</b>, <b>6 h,</b> and <b>6i</b> gave 1-3 hydrogen bonds and <b>6c</b> and <b>3</b> recorded the highest number of hydrophobic interactions, 14 for both <b>6c</b> and <b>6 h</b>. Pro Tox-II estimated compounds' activities as Hepatoxic, Carcinogenic and Mutagenic, revealing that <b>6f-h</b> 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.