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.
The cytotoxic activity of pine needles ethanolic extract of Pinus merkusii on HeLa cell lines
