title: Synthesis of arylpyrazole linked benzimidazole conjugates as potential microtubule disruptors.
abstract: In an attempt to develop potent and selective anticancer agents, a series of twenty arylpyrazole linked benzimidazole conjugates (10a-t) were designed and synthesized as microtubule destabilizing agents. The joining of arylpyrazole to the benzimidazole moiety resulted in a four ring (A, B, C and D) molecular scaffold that comprises of polar heterocyclic rings in the middle associated with rotatable single bonds and substituted aryl rings placed in the opposite directions. These conjugates were evaluated for their ability to inhibit the growth of sixty cancer cell line panel of the NCI. Among these some conjugates like 10a, 10b, 10d, 10e, 10p and 10r exhibited significant growth inhibitory activity against most of the cell lines ranging from 0.3 to 13μM. Interestingly, the conjugate 10b with methoxy group on D-ring expressed appreciable cytotoxic potential. A549 cells treated with some of the potent conjugates like 10a, 10b and 10d arrested cells at G2/M phase apart from activating cyclin-B1 protein levels and disrupting microtubule network. Moreover, these conjugates effectively inhibited tubulin polymerization with IC50 values of 1.3-3.8μM. Whereas, the caspase assay revealed that they activate the casepase-3 leading to apoptosis. Particularly 10b having methoxy substituent induced activity almost 3 folds higher than CA-4. Furthermore, a competitive colchicine binding assay and molecular modeling analysis suggests that these conjugates bind to the tubulin successfully at the colchicine binding site. These investigations reveal that such conjugates having pyrazole and benzimidazole moieties have the potential in the development of newer chemotherapeutic agents.
authors: Medicinal Chemistry and Pharmacology, Hyderabad 500007, India. Electronic address: ahmedkamal@iict.res.in.
authors: Ahmed
authors: A
authors: Kamal
authors: Medicinal Chemistry and Pharmacology, Hyderabad 500007, India.
authors: Anver Basha
authors: AB
authors: Shaik
authors: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors: Sowjanya
authors: S
authors: Polepalli
authors: Medicinal Chemistry and Pharmacology, Hyderabad 500007, India.
authors: G Bharath
authors: GB
authors: Kumar
authors: Medicinal Chemistry and Pharmacology, Hyderabad 500007, India.
authors: Vangala Santhosh
authors: VS
authors: Reddy
authors: Medicinal Chemistry and Pharmacology, Hyderabad 500007, India.
authors: Rasala
authors: R
authors: Mahesh
authors: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors: Srujana
authors: S
authors: Garimella
authors: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors: Nishant
authors: N
authors: Jain
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008870:Microtubules / Q000187:drug effects*; D008958:Models, Molecular; D058105:Polymerization; D011720:Pyrazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry
chemical_list: D001562:Benzimidazoles; D011720:Pyrazoles; D014404:Tubulin
keywords: Anticancer; Caspase-3; Molecular modeling; Pyrazole–benzimidazole conjugates; Tubulin polymerization