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

Abstract

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 µM, respectively relative to staurosporine IC₅₀ 0.36 µM. 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 α immune expression with concomitant elevation of malondialdehyde levels in case of 8b.

Keywords:

• Pim1 inhibitor
• bis-thiazole
• cytotoxicity
• in silico and in vivo study

Acknowledgement

The authors were grateful to the biochemistry and pharmacology team of the National Research Center, National Cancer Institute and NAWAH-Scientific, Egypt for their efforts on kinase, in vivo and cell cycle in vitro analysis. The authors thankfully appreciated the collaboration with the United State Cancer Institute Developmental Therapeutic Program NCI-DTP for the cancerous cell lines screening and Al-Azhar University for the in vivo analysis.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors extend their appreciation to the Deanship of Scientific Research at Jouf University for funding this work through research grant No [DSR-2021–01-03118].