1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview

1,2,3-Triazole-containing hybrids as potential anticancer agents: Current developments, action mechanisms and structure-activity relationships.

Therapeutic evolution of benzimidazole derivatives in the last quinquennial period.

Benzotriazole: An overview on its versatile biological behavior

Cancer, also known as malignant neoplasm, is a dreadful disease which involves abnormal cell growth having the potential to invade or spread to other parts of the body Benzimidazole is an organic compound that is heterocyclic and aromatic in nature It is a bicyclic compound formed by the fusion of the benzene and imidazole ring systems It is an important pharmacophore and a privileged structure in medicinal chemistry According to the World Health Organisation (2015 survey), one in six deaths is due to cancer around the globe, accounting for 88 million deaths of which 70% of the cases were from low- and middle-income countries In the efforts to develop suitable anticancer drugs, medicinal chemists have focussed on benzimidazole derivatives This review article covers the current development of benzimidazole-based anticancer agents along with the synthetic approaches and structure-activity relationships (SAR)

Benzimidazole Scaffold as Anticancer Agent: Synthetic Approaches and Structure–Activity Relationship

Synthesis of novel polybrominated benzimidazole derivatives-potential CK2 inhibitors with anticancer and proapoptotic activity.

Synthesis of novel proxyphylline derivatives with dual Anti-Candida albicans and anticancer activity.

Synthesis of novel chiral TBBt derivatives with hydroxyl moiety. Studies on inhibition of human protein kinase CK2α and cytotoxicity properties

A series of new polybrominated benzimidazoles and benzotriazoles has been synthesized and their influence on the activity of protein kinase CK2 was evaluated. It was revealed that the most active inhibitors are those with methyl or ethyl substituent at benzene ring, namely 5,6,7-tribromo-4-methyl-1H-benzotriazole (38, IC50 0.51 μM) and 5,6,7-tribromo-4-ethyl-1H-benzotriazole (40, IC50 0.16 μM). The derivatives with large aromatic or heterocyclic substituents connected to benzimidazole or benzotriazole scaffold appeared to be less potent inhibitors.

Design and synthesis of CK2 inhibitors

To further clarify the role of the individual bromine atoms of 4,5,6,7-tetrabromotriazole (TBBt), a relatively selective inhibitor of protein kinase CK2, we have examined the inhibition (IC50) of human CK2α by the two mono-, the four di-, and the two tri- bromobenzotriazoles relative to that of TBBt. Halogenation of the central vicinal C(5)/C(6) atoms proved to be a key factor in enhancing inhibitory activity, in that 5,6-di-Br2Bt and 4,5,6-Br3Bt were almost as effective inhibitors as TBBt, notwithstanding their marked differences in pKa for dissociation of the triazole proton. The decrease in pKa on halogenation of the peripheral C(4)/C(7) atoms virtually nullifies the gain due to hydrophobic interactions, and does not lead to a decrease in IC50. Molecular modeling of structures of complexes of the ligands with the enzyme, as well as QSAR analysis, pointed to a balance of hydrophobic and electrostatic interactions as a discriminator of inhibitory activity. The role of halogen bonding remains debatable, as originally noted for the crystal structure of TBBt with CK2α (pdb1j91). Finally we direct attention to the promising applicability of our series of well-defined halogenated benzotriazoles to studies on inhibition of kinases other than CK2.

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Patrycja Wińska

Papers

Synthesis of novel polybrominated benzimidazole derivatives-potential CK2 inhibitors with anticancer and proapoptotic activity.

Synthesis of novel proxyphylline derivatives with dual Anti-Candida albicans and anticancer activity.

Synthesis of novel chiral TBBt derivatives with hydroxyl moiety. Studies on inhibition of human protein kinase CK2α and cytotoxicity properties

Design and synthesis of CK2 inhibitors

Isomeric Mono-, Di-, and Tri-Bromobenzo-1H-Triazoles as Inhibitors of Human Protein Kinase CK2α