Insights on Cancer Cell Inhibition, Subcellular Activities, and Kinase Profile of Phenylacetamides Pending 1 H-Imidazol-5-One Variants

Maan T Khayat; Abdelsattar M Omar; Farid Ahmed; Mohammad I Khan; Sara M Ibrahim; Yosra A Muhammad; Azizah M Malebari; Thikryat Neamatallah; Moustafa E El-Araby

doi:10.3389/fphar.2021.794325

Insights on Cancer Cell Inhibition, Subcellular Activities, and Kinase Profile of Phenylacetamides Pending 1 H-Imidazol-5-One Variants

Front Pharmacol. 2022 Jan 5:12:794325. doi: 10.3389/fphar.2021.794325. eCollection 2021.

Authors

Maan T Khayat¹, Abdelsattar M Omar^{1

2

3}, Farid Ahmed^{4

5}, Mohammad I Khan^{3

6}, Sara M Ibrahim⁶, Yosra A Muhammad^{1

3}, Azizah M Malebari¹, Thikryat Neamatallah⁷, Moustafa E El-Araby^{1

3}

Affiliations

¹ Faculty of Pharmacy, Department of Pharmaceutical Chemistry, King Abdulaziz University, Jeddah, Saudi Arabia.
² Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Al-Azhar University, Nasr City, Egypt.
³ Center for Artificial Intelligence in Precision Medicines, King Abdulaziz University, Jeddah, Saudi Arabia.
⁴ Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
⁵ Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
⁶ Faculty of Science, Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia.
⁷ Faculty of Pharmacy, Department of Pharmacology and Toxicology, King Abdulaziz University, Jeddah, Saudi Arabia.

Abstract

Structural changes of small-molecule drugs may bring interesting biological properties, especially in the field of kinase inhibitors. We sought to study tirbanibulin, a first-in-class dual Src kinase (non-ATP competitive)/tubulin inhibitor because there was not enough reporting about its structure-activity relationships (SARs). In particular, the present research is based on the replacement of the outer ring of the biphenyl system of 2-[(1,1'-biphenyl)-4-yl]-N-benzylacetamide, the identified pharmacophore of KX chemotype, with a heterocyclic ring. The newly synthesized compounds showed a range of activities in cell-based anticancer assays, agreeing with a clear SAR profile. The most potent compound, (Z)-N-benzyl-4-[4-(4-methoxybenzylidene)-2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl]phenylacetamide (KIM-161), demonstrated cytotoxic IC₅₀ values at 294 and 362 nM against HCT116 colon cancer and HL60 leukemia cell lines, respectively. Profiling of this compound (aqueous solubility, liver microsomal stability, cytochrome P450 inhibition, reactivity with reduced glutathione, and plasma protein binding) confirmed its adequate drug-like properties. Mechanistic studies revealed that this compound does not depend on tubulin or Src kinase inhibition as a factor in forcing HL60 to exit its cell cycle and undergo apoptosis. Instead, KIM-161 downregulated several other kinases such as members of BRK, FLT, and JAK families. It also strongly suppresses signals of ERK1/2, GSK-3α/β, HSP27, and STAT2, while it downregulated AMPKα1 phosphorylation within the HL60 cells. Collectively, these results suggest that phenylacetamide-1H-imidazol-5-one (KIM-161) could be a promising lead compound for further clinical anticancer drug development.

Keywords: imidazolone; leukemia; multi-kinase downregulation; phosphokinase profiling; scaffold hopping; src kinase; structure–properties relationship; tirbanibulin.