Design, synthesis and cytotoxic evaluation of novel bis-thiazole derivatives as preferential Pim1 kinase inhibitors with in vivo and in silico study

Bis-thiazole derivatives were synthesised conforming to the Pim1 pharmacophore model following Hantzsch condensation. Pim1 has a major role in regulating the G1/S phase which upon inhibition the cell cycle stops at its early stages. Derivatives 3b and 8b showed the best Pim1 IC50 0.32 and 0.24 mu M, respectively relative to staurosporine IC50 0.36 mu M. Further confirmation of 3b and 8b Pim1 inhibition was implemented by hindering the T47D cell cycle at G0/G1 and S phases where 3b showed 66.5% cells accumulation at G0/G1 phase while 8b demonstrated 26.5% cells accumulation at the S phase compared to 53.9% and 14.9% of a control group for both phases, respectively. Additional in vivo cytotoxic evaluation of 3b and 8b revealed strong antitumor activity with up-regulation of caspase-3 and down-regulation of VEGF and TNF alpha immune expression with concomitant elevation of malondialdehyde levels in case of 8b.

Automated summary

Bis-thiazole derivatives were synthesized based on the Pim1 pharmacophore model and showed strong inhibitory effects on Pim1 activity. Derivatives 3b and 8b exhibited the best Pim1 inhibition with IC50 values of 0.32 and 0.24 μM, respectively, compared to staurosporine (IC50 = 0.36 μM). They also effectively arrested the cell cycle at G0/G1 and S phases, as demonstrated by the significant accumulation of cells in these phases. In vivo cytotoxic evaluation confirmed their potent antitumor activity, with 8b showing additional up-regulation of caspase-3 and down-regulation of VEGF and TNF alpha immune expression.