An Efficient Synthesis of Novel Aminothiazolylacetamido-Substituted 3,5-Bis(arylidene)-4-piperidone Derivatives and Their Cytotoxicity Studies

Abstract

The expansion of 3,5-bis(arylidene)-4-piperidone derivatives with heterocyclic compounds such as 1,3-thiazole should take into account this correlation. The synthesized aminothiazolylacetamido-substituted 3,5-bis(arylidene)-4-piperidone derivatives 3a-j were found to have GI₅₀ values in the range of 0.15-0.28 μM against HeLa and HCT116 cancer cell lines. In silico docking studies confirmed that the proteasome inhibition mechanism involves a nucleophilic attack from the N-terminal threonine residue of the β-subunits to the C=O group of compounds. A C=O group of amide was able to interact with the NH group of the alanine residue and the 5g NH group of amino thiazole, along with an OH group of the serine residue. These results strongly suggest that the synthesized compounds could be a potential candidate inhibitor of the 20S proteasome. These molecules have the potential to be developed as cytotoxic and anticancer agents, as revealed by this study.

Figure 1

Modification of curcumin β-diketone to mono carbonyl moiety.

Figure 2

ORTEP of compound 5c.

Scheme 1. Synthesis of 5(a–k)

Reagents and conditions: Step-1: arylaldehydes, dry HCl, acetic acid, RT, 30 min; Step-2: (2-amino-thiazol-4-yl)-acetyl chloride hydrochloride, triethylamine (TEA), dichloro methane, 0–5 °C.

Figure 3

Model of predicted binding modes of compound 5f and 5g.

Figure 4

GI₅₀ values of the thiophene and phenyl-substituted 1,5-diaryl-3-oxo-1,4-pentadienyl group.