Design and synthesis of benzimidazoles containing substituted oxadiazole, thiadiazole and triazolo-thiadiazines as a source of new anticancer agents
Based on the heterocyclic core of bendamustine, four series (4a–g, 5a–f, 8a–b and 9a–b) of benzimidazole derivatives were designed and synthesized starting from 4-(1H-benzo[d]imidazol-2-yl)-4-oxobutanehydrazide. In the rational design of target molecules, the benzimidazole ring of bendamustine was r...
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doaj-0fa9d75f137744699ad9783189bd31ca2020-11-25T01:08:10ZengElsevierArabian Journal of Chemistry1878-53522019-12-0112832023224Design and synthesis of benzimidazoles containing substituted oxadiazole, thiadiazole and triazolo-thiadiazines as a source of new anticancer agentsMohd Rashid0Asif Husain1Ravinesh Mishra2Shahid Karim3Shamshir Khan4Makhmur Ahmad5Naser Al-wabel6Amjad Husain7Aftab Ahmad8Shah Alam Khan9Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi 110062, India; Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Buraydah Private Colleges, Al-Qassim 31717, Kingdom of Saudi ArabiaDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi 110062, India; Corresponding author. Tel.: +91 11 26059681, 26059688x5647, mobile: +91 9891116086; fax: +91 11 16988874.Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi 110062, IndiaDepartment of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Buraydah Private Colleges, Al-Qassim 31717, Kingdom of Saudi ArabiaDepartment of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Buraydah Private Colleges, Al-Qassim 31717, Kingdom of Saudi ArabiaDepartment of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Buraydah Private Colleges, Al-Qassim 31717, Kingdom of Saudi ArabiaDepartment of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Buraydah Private Colleges, Al-Qassim 31717, Kingdom of Saudi Arabia99, Brookline Avenue, Research North Building, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USAHealth Information Technology Department, Jeddah Community College, King Abdulaziz University, Jeddah 21589, Kingdom of Saudi ArabiaDepartment of Pharmacy, Oman Medical College, Muscat, OmanBased on the heterocyclic core of bendamustine, four series (4a–g, 5a–f, 8a–b and 9a–b) of benzimidazole derivatives were designed and synthesized starting from 4-(1H-benzo[d]imidazol-2-yl)-4-oxobutanehydrazide. In the rational design of target molecules, the benzimidazole ring of bendamustine was retained and the bis-(chloroethyl) amine group (mechlorethamine) was substituted with several biologically active scaffolds such as oxadiazole, thiadiazole, and triazolo-thiadiazines, in the hope of obtaining novel cytotoxic agents with improved efficacy and safety. Cytotoxic activities of the designed analogues were carried out at the National Cancer Institute (NCI), USA, against full NCI 60 human cell lines. Among all the tested compounds, 4f (761982/1) exhibited significant antiproliferative activity and was further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 μM) with GI50 values ranging from 0.09 to 16.2 μM and found superior for CNS cancer cell line SNB-75 (GI50 0.09, TGI 1.39, LC50 >100 and log10GI50 −7.0, log10TGI-5.86, log10LC50 >−4.00). Docking study was also performed to provide an insight about the binding mode into binding sites of topoisomerase enzyme. Hopefully in future, compound 4f could be used as a lead compound for developing new anticancer agents. Keywords: Bendamustine, Benzimidazole, Chlorambucil, Sulforhodamine B, Human cell lineshttp://www.sciencedirect.com/science/article/pii/S1878535215002592 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mohd Rashid Asif Husain Ravinesh Mishra Shahid Karim Shamshir Khan Makhmur Ahmad Naser Al-wabel Amjad Husain Aftab Ahmad Shah Alam Khan |
spellingShingle |
Mohd Rashid Asif Husain Ravinesh Mishra Shahid Karim Shamshir Khan Makhmur Ahmad Naser Al-wabel Amjad Husain Aftab Ahmad Shah Alam Khan Design and synthesis of benzimidazoles containing substituted oxadiazole, thiadiazole and triazolo-thiadiazines as a source of new anticancer agents Arabian Journal of Chemistry |
author_facet |
Mohd Rashid Asif Husain Ravinesh Mishra Shahid Karim Shamshir Khan Makhmur Ahmad Naser Al-wabel Amjad Husain Aftab Ahmad Shah Alam Khan |
author_sort |
Mohd Rashid |
title |
Design and synthesis of benzimidazoles containing substituted oxadiazole, thiadiazole and triazolo-thiadiazines as a source of new anticancer agents |
title_short |
Design and synthesis of benzimidazoles containing substituted oxadiazole, thiadiazole and triazolo-thiadiazines as a source of new anticancer agents |
title_full |
Design and synthesis of benzimidazoles containing substituted oxadiazole, thiadiazole and triazolo-thiadiazines as a source of new anticancer agents |
title_fullStr |
Design and synthesis of benzimidazoles containing substituted oxadiazole, thiadiazole and triazolo-thiadiazines as a source of new anticancer agents |
title_full_unstemmed |
Design and synthesis of benzimidazoles containing substituted oxadiazole, thiadiazole and triazolo-thiadiazines as a source of new anticancer agents |
title_sort |
design and synthesis of benzimidazoles containing substituted oxadiazole, thiadiazole and triazolo-thiadiazines as a source of new anticancer agents |
publisher |
Elsevier |
series |
Arabian Journal of Chemistry |
issn |
1878-5352 |
publishDate |
2019-12-01 |
description |
Based on the heterocyclic core of bendamustine, four series (4a–g, 5a–f, 8a–b and 9a–b) of benzimidazole derivatives were designed and synthesized starting from 4-(1H-benzo[d]imidazol-2-yl)-4-oxobutanehydrazide. In the rational design of target molecules, the benzimidazole ring of bendamustine was retained and the bis-(chloroethyl) amine group (mechlorethamine) was substituted with several biologically active scaffolds such as oxadiazole, thiadiazole, and triazolo-thiadiazines, in the hope of obtaining novel cytotoxic agents with improved efficacy and safety. Cytotoxic activities of the designed analogues were carried out at the National Cancer Institute (NCI), USA, against full NCI 60 human cell lines. Among all the tested compounds, 4f (761982/1) exhibited significant antiproliferative activity and was further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 μM) with GI50 values ranging from 0.09 to 16.2 μM and found superior for CNS cancer cell line SNB-75 (GI50 0.09, TGI 1.39, LC50 >100 and log10GI50 −7.0, log10TGI-5.86, log10LC50 >−4.00). Docking study was also performed to provide an insight about the binding mode into binding sites of topoisomerase enzyme. Hopefully in future, compound 4f could be used as a lead compound for developing new anticancer agents. Keywords: Bendamustine, Benzimidazole, Chlorambucil, Sulforhodamine B, Human cell lines |
url |
http://www.sciencedirect.com/science/article/pii/S1878535215002592 |
work_keys_str_mv |
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