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

Mohammad M Al-Sanea; Tamer M Nasr; Samir Bondock; Aya Y Gawish; Nada M Mohamed

doi:10.1080/14756366.2023.2166936

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

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2166936. doi: 10.1080/14756366.2023.2166936.

Authors

Mohammad M Al-Sanea¹, Tamer M Nasr^{2

3}, Samir Bondock^{4

5}, Aya Y Gawish⁶, Nada M Mohamed²

Affiliations

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Modern University for Technology and Information (MTI) University, Cairo, Egypt.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Helwan, Egypt.
⁴ Chemistry Department, Faculty of Science, King Khalid University, Abha, Saudi Arabia.
⁵ Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt.
⁶ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information (MTI) University, Cairo, Egypt.

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.

MeSH terms

Antineoplastic Agents* / pharmacology
Cell Cycle
Cell Proliferation
Drug Screening Assays, Antitumor
Staurosporine / pharmacology
Structure-Activity Relationship
Thiazoles* / pharmacology
Up-Regulation

Substances

Thiazoles
Antineoplastic Agents
Staurosporine

Grants and 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].