Title:New Approaches for the Synthesis of Heterocyclic Compounds Corporating Benzo[d]imidazole as Anticancer Agents, Tyrosine, Pim-1 Kinases Inhibitions and their PAINS Evaluations
VOLUME: 21 ISSUE: 3
Author(s):Rafat M. Mohareb*, Yara R. Milad, Bahaa M. Mostafa and Reem A. El-Ansary
Affiliation:Department of Chemistry, Faculty of Science, Cairo University, Giza, Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Department of Chemistry, Faculty of Science, Cairo University, Giza, Department of Chemistry, Faculty of Science, Cairo University, Giza
Keywords:Benzo[d]midazole, thiophene, quinoline, cytotoxicity, tyrosine kinases, PAINS alert.
Abstract:
Background: Benzo[d]imidazoles are highly biologically active, in addition, they are considered as a
class of heterocyclic compounds with many pharmaceutical applications.
Objective: We are aiming in this work to synthesize target molecules that possess not only anti-tumor activities
but also kinase inhibitors. The target molecules were obtained starting from the benzo[d]imidazole derivatives
followed by their heterocyclization reactions to produce anticancer target molecules.
Methods: The 1-(1H-benzo[d]imidazol-2-yl)propan-2-one (3) and the ethyl 2-(1H-benzo[d]imidazol-2-
yl)acetate (16) were used as the key starting material which reacted with salicylaldehyde to give the corresponding
benzo[4,5]imidazo[1,2-a]quinoline derivatives. On the other hand, both of them were reacted with different
reagents to give thiophene, pyran and benzo[4,5]imidazo[1,2-c]pyrimidine derivatives. The synthesized compounds
were evaluated against the six cancer cell lines A549, HT-29, MKN-45, U87MG, SMMC-7721, and
H460 together with inhibitions toward tyrosine kinases, c-Met kinase and prostate cancer cell line PC-3 using
the standard MTT assay in vitro, with foretinib as the positive control.
Results: Most of the synthesized compounds exhibited high inhibitions toward the tested cancer cell lines. In
addition, tyrosine and Pim-1 kinases inhibitions were performed for the most active compounds where the variation
of substituent through the aryl ring and heterocyclic ring afforded compounds with high activities. Our
analysis showed that there is a strong correlation between the structure of the compound and the substituents of
target molecules.
Conclusion: Our present research proved that the synthesized heterocyclic compounds with varieties of substituents
have a strong impact on the activity of compounds. The evaluations through different cell lines and
tyrosine kinases indicated that the compounds were the excellent candidates as anticancer agents. This could
encourage doing further research within this field for the building of compounds with high inhibitions.
