Bilal A. Al-Jaidi*, Soha Taher Telfah, Sanaa K. Bardaweel, Pran Kishore Deb*, Pobitra Borah, Katharigatta N. Venugopala, Yazan A. Bataineh and Qutaiba Ahmed Al Khames Aga Pages 1 - 5 ( 5 )
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.
Cytotoxicity, 2-amino-5-aryl-thiazole, breast cancer cell lines (MCF7 and MDA231), lymphoblastoid human erythroleukemia (K562) cell line, ADMET, anticancer activity
Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Yarmouk University, P. O. Box - 566, Irbid (21163), Department of Pharmaceutical Sciences, Faculty of Pharmacy, Philadelphia University, P.O BOX (1), Amman (19392), Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Philadelphia University, P.O BOX (1), Amman (19392), Pratiksha Institute of Pharmaceutical Sciences, Chandrapur Road, Panikhaiti, Guwahati781026, Assam, Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Philadelphia University, P.O BOX (1), Amman (19392), Department of Pharmaceutical Sciences, Faculty of Pharmacy, Philadelphia University, P.O BOX (1), Amman (19392)