Anticancer Activity and In Silico ADMET Properties of 2,4,5-Trisubstitutedthiazole Derivatives

Abstract

Background: Recently, a series of 15 compounds with 2,4,5-trisubstitutedthiazole scaffold having 2- amino/amido/ureido functional groups attached with 5-aryl and 4-carboxylic acid/ester groups (1-15) were reported from our research group as novel potential inhibitors of carbonic anhydrase III (CA III) enzyme. Several research studies revealed the potential role of CA inhibitors as anticancer agents, giving us the impetus to further explore these compounds for their potential as anticancer agents. Objectives: The objective of this study is to investigate the potential of 2,4,5-trisubstitutedthiazole derivatives (1-15) for their possible cytotoxic activity (in vitro) and to calculate (in silico) the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties to evaluate the drug-likeness of these compounds. Methods: Cytotoxic activity (in vitro) was carried out on two breast cancer cell lines (MCF7 and MDA231), and lymphoblastoid human erythroleukemia cell line (K562) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Doxorubicin was used as a positive control. ADMET properties were calculated (in silico) using QikProp module of Schrodinger. Results: Compounds 6 and 9 with a phenylureido group at 2-position, and a methyl-carboxylate moiety at 4-position having para-tolyl and benzyl moiety, respectively at the 5-position of the thiazole ring showed significant cytotoxicity against all the three cell lines. In particular, compound 6 with para-tolyl group at 5-position, exhibited most potent inhibitory effect on the viability of MCF7, MDA231 and K562 cells, with IC50 values of 22, 26 and 11 µM, respectively. Notably, all the highly active compounds possess phenyluriedo group at 2-position with a methyl ester group at 4-position, indicating the probable role of these substituents in the target interaction and inducing cytotoxicity. Interestingly, compounds 1-4 and 10-13 with a free amino group at 2-position did not show any cytotoxic effect on K562 cell line, while exhibiting mild to moderate cytotoxicity against the MCF7 and MDA231 cell lines. However, none of the tested compounds showed any activity against normal human dermal fibroblast cells indicating the safety/tolerability of the examined concentrations. Furthermore, these compounds also exhibited satisfactory ADMET properties (in silico), without violating the Lipinski’s rule of five. Conclusion: The most active compounds 6 and 9 predicted to have good oral absorption and low human serum protein binding, exhibiting no reactive functional group and probable CNS activity compared with 95% of the known oral drugs as predicted (in silico) by QikProp. Thus, compounds 6 and 9 can be considered as lead molecules for further modification and discovery of novel anticancer agents with nanomolar potency.

Influence of Open Chain and Cyclic Structure of Peptidomimetics on Antibacterial Activity in E. coli Strains

“…The obtained MIC values, as well as our previous studies with various types of the analyzed compounds [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ], indicate that derivatives of diketopiperazines also show a strong toxic effect of the analyzed model strains of bacteria. The three compounds analyzed were selected for further analysis by modifying their DNA.…”

“…The bacterial tests used, and MIC and MBC were accurately described in detail in the previous work [ 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. An MTT test to assess the metabolic activity of cells was performed on the basis of [ 27 , 28 , 29 , 30 ], with THLE-5b as the control and the caco-2 cell line derived from human adenocarcinoma.…”

Quinoline analogue as a potential inhibitor of SARS-CoV-2 main protease: ADMET prediction, molecular docking and dynamics simulation analysis

“…Furthermore, the MD studies performed in this study for the highly potent drug candidate Q9 also proved that the binding conformational stability with SARS-CoV-2 M pro (PDB ID 6LU7) does not change its nature. The results of our ADMET analysis are also useful in providing insights into the structural criteria for synthesizing a new potential drug molecule with a better inhibitory activity against COVID-19 [60,61]. Overall, the present work should lead to the identification of novel, less toxic, and highly efficient quinoline derivatives for chemical interventions to manage COVID-19 infections.…”

Antitubercular, Cytotoxicity, and Computational Target Validation of Dihydroquinazolinone Derivatives

“…Finally, the binding mode and binding stability of a virtual complex of compound 3m with its putative target were simulated using Amber 12 relative to the native co-crystallized inhibitor. Moreover, a range of pharmacokinetic and toxicity descriptors for the tested compounds ( 3a – 3m ) was calculated using the ADMET Descriptors protocol and the Toxicity Prediction (TOPKAT) protocol in DS [ 85 ].…”