New Bioactive Fused Triazolothiadiazoles as Bcl-2-Targeted Anticancer Agents

A series of 3-(6-substituted phenyl-[1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazol-3-yl)-1H-indoles (<b>5a</b>–<b>l</b>) were designed, synthesized and evaluated for anti-apoptotic Bcl-2-inhibitory activity. Synthesis of the target compounds was readily accomplished through a rea...

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Autores principales:	Rania Hamdy, Arwyn T. Jones, Mohamed El-Sadek, Alshaimaa M. Hamoda, Sarra B. Shakartalla, Zainab M. AL Shareef, Sameh S. M. Soliman, Andrew D. Westwell
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	triazole thiadiazole indole anticancer Bcl-2 inhibitor pharmacokinetics Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/af2a65ec3d3641878ea076cea3f09a8a
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spelling	oai:doaj.org-article:af2a65ec3d3641878ea076cea3f09a8a2021-11-25T17:54:55ZNew Bioactive Fused Triazolothiadiazoles as Bcl-2-Targeted Anticancer Agents10.3390/ijms2222122721422-00671661-6596https://doaj.org/article/af2a65ec3d3641878ea076cea3f09a8a2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12272https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067A series of 3-(6-substituted phenyl-[1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazol-3-yl)-1H-indoles (<b>5a</b>–<b>l</b>) were designed, synthesized and evaluated for anti-apoptotic Bcl-2-inhibitory activity. Synthesis of the target compounds was readily accomplished through a reaction of acyl hydrazide (<b>1</b>) with carbon disulfide in the presence of alcoholic potassium hydroxide to afford the corresponding intermediate potassium thiocarbamate salt (<b>2</b>), which underwent cyclization reaction in the presence of excess hydrazine hydrate to the corresponding triazole thiol (<b>3</b>). Further cyclisation reaction with substituted benzoyl chloride derivatives in the presence of phosphorous oxychloride afforded the final 6-phenyl-indol-3-yl [1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazole compounds (<b>5a</b>–<b>l</b>). The novel series showed selective sub-micromolar IC<sub>50</sub> growth-inhibitory activity against Bcl-2-expressing human cancer cell lines. The most potent 6-(2,4-dimethoxyphenyl) substituted analogue (<b>5k</b>) showed selective IC<sub>50</sub> values of 0.31–0.7 µM against Bcl-2-expressing cell lines without inhibiting the Bcl-2-negative cell line (Jurkat). ELISA binding affinity assay (interruption of Bcl-2-Bim interaction) showed potent binding affinity for (<b>5k</b>) with an IC<sub>50</sub> value of 0.32 µM. Moreover, it fulfils drug likeness criteria as a promising drug candidate.Rania HamdyArwyn T. JonesMohamed El-SadekAlshaimaa M. HamodaSarra B. ShakartallaZainab M. AL ShareefSameh S. M. SolimanAndrew D. WestwellMDPI AGarticletriazolethiadiazoleindoleanticancerBcl-2 inhibitorpharmacokineticsBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12272, p 12272 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	triazole thiadiazole indole anticancer Bcl-2 inhibitor pharmacokinetics Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	triazole thiadiazole indole anticancer Bcl-2 inhibitor pharmacokinetics Biology (General) QH301-705.5 Chemistry QD1-999 Rania Hamdy Arwyn T. Jones Mohamed El-Sadek Alshaimaa M. Hamoda Sarra B. Shakartalla Zainab M. AL Shareef Sameh S. M. Soliman Andrew D. Westwell New Bioactive Fused Triazolothiadiazoles as Bcl-2-Targeted Anticancer Agents
description	A series of 3-(6-substituted phenyl-[1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazol-3-yl)-1H-indoles (<b>5a</b>–<b>l</b>) were designed, synthesized and evaluated for anti-apoptotic Bcl-2-inhibitory activity. Synthesis of the target compounds was readily accomplished through a reaction of acyl hydrazide (<b>1</b>) with carbon disulfide in the presence of alcoholic potassium hydroxide to afford the corresponding intermediate potassium thiocarbamate salt (<b>2</b>), which underwent cyclization reaction in the presence of excess hydrazine hydrate to the corresponding triazole thiol (<b>3</b>). Further cyclisation reaction with substituted benzoyl chloride derivatives in the presence of phosphorous oxychloride afforded the final 6-phenyl-indol-3-yl [1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazole compounds (<b>5a</b>–<b>l</b>). The novel series showed selective sub-micromolar IC<sub>50</sub> growth-inhibitory activity against Bcl-2-expressing human cancer cell lines. The most potent 6-(2,4-dimethoxyphenyl) substituted analogue (<b>5k</b>) showed selective IC<sub>50</sub> values of 0.31–0.7 µM against Bcl-2-expressing cell lines without inhibiting the Bcl-2-negative cell line (Jurkat). ELISA binding affinity assay (interruption of Bcl-2-Bim interaction) showed potent binding affinity for (<b>5k</b>) with an IC<sub>50</sub> value of 0.32 µM. Moreover, it fulfils drug likeness criteria as a promising drug candidate.
format	article
author	Rania Hamdy Arwyn T. Jones Mohamed El-Sadek Alshaimaa M. Hamoda Sarra B. Shakartalla Zainab M. AL Shareef Sameh S. M. Soliman Andrew D. Westwell
author_facet	Rania Hamdy Arwyn T. Jones Mohamed El-Sadek Alshaimaa M. Hamoda Sarra B. Shakartalla Zainab M. AL Shareef Sameh S. M. Soliman Andrew D. Westwell
author_sort	Rania Hamdy
title	New Bioactive Fused Triazolothiadiazoles as Bcl-2-Targeted Anticancer Agents
title_short	New Bioactive Fused Triazolothiadiazoles as Bcl-2-Targeted Anticancer Agents
title_full	New Bioactive Fused Triazolothiadiazoles as Bcl-2-Targeted Anticancer Agents
title_fullStr	New Bioactive Fused Triazolothiadiazoles as Bcl-2-Targeted Anticancer Agents
title_full_unstemmed	New Bioactive Fused Triazolothiadiazoles as Bcl-2-Targeted Anticancer Agents
title_sort	new bioactive fused triazolothiadiazoles as bcl-2-targeted anticancer agents
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/af2a65ec3d3641878ea076cea3f09a8a
work_keys_str_mv	AT raniahamdy newbioactivefusedtriazolothiadiazolesasbcl2targetedanticanceragents AT arwyntjones newbioactivefusedtriazolothiadiazolesasbcl2targetedanticanceragents AT mohamedelsadek newbioactivefusedtriazolothiadiazolesasbcl2targetedanticanceragents AT alshaimaamhamoda newbioactivefusedtriazolothiadiazolesasbcl2targetedanticanceragents AT sarrabshakartalla newbioactivefusedtriazolothiadiazolesasbcl2targetedanticanceragents AT zainabmalshareef newbioactivefusedtriazolothiadiazolesasbcl2targetedanticanceragents AT samehsmsoliman newbioactivefusedtriazolothiadiazolesasbcl2targetedanticanceragents AT andrewdwestwell newbioactivefusedtriazolothiadiazolesasbcl2targetedanticanceragents
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New Bioactive Fused Triazolothiadiazoles as Bcl-2-Targeted Anticancer Agents

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