Design, synthesis, biological assessment and molecular modeling studies of novel imidazothiazole-thiazolidinone hybrids as potential anticancer and anti-inflammatory agents
A new series of imidazothiazole derivatives bearing thiazolidinone moiety ( 4a - g and 5a - d ) were designed, synthesized and evaluated for potential epidermal growth factor receptor (EGFR) kinase inhibition, anticancer and anti-inflammatory activity, cardiomyopathy toxicity and hepatotoxicity. Com...
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Veröffentlicht in: | Scientific reports 2024-04, Vol.14 (1), p.8457-8457, Article 8457 |
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Sprache: | eng |
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Zusammenfassung: | A new series of imidazothiazole derivatives bearing thiazolidinone moiety (
4a
-
g
and
5a
-
d
) were designed, synthesized and evaluated for potential epidermal growth factor receptor (EGFR) kinase inhibition, anticancer and anti-inflammatory activity, cardiomyopathy toxicity and hepatotoxicity. Compound
4c
inhibited EGFR kinase at a concentration of 18.35 ± 1.25 µM, whereas standard drug erlotinib showed IC
50
value of 06.12 ± 0.92 µM. The molecular docking, dynamics simulation and MM-GBSA binding energy calculations revealed strong interaction of compound
4c
with binding site of EGFR. The synthesized compounds were evaluated for their anticancer activity by MTT assay against three human cancer cell lines A549 (Lung), MCF-7 (Breast), HCT116 (Colon), one normal human embryonic kidney cell line HEK293 and also for their EGFR kinase inhibitory activity. Few compounds of the series (
4a
,
4b
,
4c
) showed promising growth inhibition against all the tested cancer cell lines and against EGFR kinase. Among these, compound
4c
was found to be most active and displayed IC
50
value of 10.74 ± 0.40, 18.73 ± 0.88 against cancer cell lines A549 and MCF7 respectively whereas it showed an IC
50
value of 96.38 ± 1.79 against HEK293 cell line indicating lesser cytotoxicity for healthy cell. Compounds
4a
,
4b
and
4c
were also examined for their apoptosis inducing potential through AO/EB dual staining assay and it was observed that their antiproliferative activity against A549 cells is mediated via induction of apoptosis. Cardiomyopathy studies showed normal cardiomyocytes with no marked sign of pyknotic nucleus of compounds
4b
and
4c
. Hepatotoxicity studies of compounds
4b
and
4c
also showed normal architecture of hepatocytes. Compounds
4a
-
g
and
5a
-
d
were also evaluated for their
in-vitro
anti-inflammatory activity by protein albumin denaturation assay. Among the tested compounds
4a
-
d
and
5a
-
b
showed promising activity and were selected for
in-vivo
inflammatory activity against carrageenan rat paw edema test. Among these compounds,
4b
was found to be most active in the series showing 84.94% inhibition, whereas the standard drug diclofenac sodium showed 84.57% inhibition. Compound
4b
also showed low ulcerogenic potential and lipid peroxidation. Thus, compounds
4c
and
4b
could be a promising lead compounds for developing anticancer and anti-inflammatory agents with low toxicity and selectivity. |
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ISSN: | 2045-2322 2045-2322 |
DOI: | 10.1038/s41598-024-59063-x |