Abstract
A simple and efficient method for the synthesis of fifteen novel ketene dithioacetals (2-(6-amino5-cyano-4-aryl-4H-1,3-dithiin-2-ylidene) malononitrile) via a one-pot three-component reaction of activated methylene group malononitrile with carbon disulfide in the presence of arylidene malononitriles were reported. The effects of LiOH.H2O as a base at different concentrations have been investigated and can provide products in good yields at 40-50ºC temperature (54-89%). All the synthesized ketene dithioacetals compounds (MCB1-MCB15) were checked for favorable pharmacokinetic param¬eters along with toxicities which are based on drug-likeness explained by Lipinski’s rule of five by Med chem designer software correlated with that of pkCSM online tool. Explorations of synthesized ketene dithioacetals compounds for the antimicrobial study were found to be effective towards Staphylococcus aureus (MCB5 and MCB13) with a zone of inhibition at 26mm and 22mm which is compared to that of standard ciprofloxacin (26mm). This made our study to explore the inhibition mechanism with the help of molecular docking studies with possible binding energies (-6.4 to -8.9 kJ/mol) by pyrx 0.8 software to represent a good prediction of interactions between the ligand and protein (2XCT). Further evaluation of druggability and ADMET predictions compounds MCB5 and MCB13 were found to be effective. Based on the in-vitro and in-silico studies a series of ketene dithioacetals compounds may be helpful for further studying SAR and designing more potent antimicrobials.
Highlights
Development of organic molecules from one pot reaction has made considerable attention because no necessity for purification of organic intermediates and usage of solvents has been slashed
The changes in binding energies coincided well with the experimental data of antimicrobial studies found that MCB5 and MCB13 found to be effective
With the observations from the biological data and the molecular docking results, might suggest that the antibacterial activities of these compounds are seemingly derived from the interaction between the compounds and the enzyme DNA Gyrase
Summary
Development of organic molecules from one pot reaction has made considerable attention because no necessity for purification of organic intermediates and usage of solvents has been slashed. Heterocyclic chemistry, organosulfur compounds which contain sulfur in their cyclic structure is well known for their pharmacological activities.[1]. 1,3-dithiane substituted with olefin in 2nd position forms compounds ketene dithioacetals, which are useful and convenient reagents for the synthesis of a variety of heterocyclic compounds.[3-8]. These molecule facilitate a nucleophilic character by the olefinic linkage present with the help of electron releasing alkylthio groups.[9-10]. The most suitable method for synthesis of functionalized ketene dithioacetals involves the reaction of an active methylene compound with carbon disulfide in the presence of suitable bases like lithium dialkyl amide,[12] sodium hydride,[13] potassium tbutoxide,[14] KF/Alumina,[15] and triethylamine[16-17] subsequent alkylation with an alkylating agent. With the aim to prepare new α-functionalized ketene dithioacetals from the reaction of αcyano ketene dithioacetals by malononitrile and carbon disulfide, with electrophiles such as arylidene malononitriles derivatives in one component reaction with the help of LiOH.H2O to afford synthesis of 2-(6-amino-5-cyano-4-aryl-4H-1,3-dithiin-2-ylidene) malononitrile as novel compounds
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