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 the 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 the 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 the 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 a 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 the 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 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.