Muti-target rationale design of novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates as telomerase/JAK1/STAT3/TLR4 inhibitors: In vitro and in vivo investigations

[Display omitted] •The new candidate 4l with improved telomerase and growth inhibition suggesting its potential use as a successful “multitarget-directed drug”.•Compound 4l was further selected to evaluate its additional JAK1/STAT3/TLR4 inhibitory potentials.•Compound 4l represented a very promising...

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Veröffentlicht in:Bioorganic chemistry 2024-12, Vol.153, p.107843, Article 107843
Hauptverfasser: Shaldam, Moataz A., Mousa, Mai H.A., Tawfik, Haytham O., El-Dessouki, Ahmed M., Sharaky, Marwa, Saleh, Mohamed M., Alzahrani, Abdullah Yahya Abdullah, Moussa, Sana Ben, Al-Karmalawy, Ahmed A.
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container_start_page 107843
container_title Bioorganic chemistry
container_volume 153
creator Shaldam, Moataz A.
Mousa, Mai H.A.
Tawfik, Haytham O.
El-Dessouki, Ahmed M.
Sharaky, Marwa
Saleh, Mohamed M.
Alzahrani, Abdullah Yahya Abdullah
Moussa, Sana Ben
Al-Karmalawy, Ahmed A.
description [Display omitted] •The new candidate 4l with improved telomerase and growth inhibition suggesting its potential use as a successful “multitarget-directed drug”.•Compound 4l was further selected to evaluate its additional JAK1/STAT3/TLR4 inhibitory potentials.•Compound 4l represented a very promising JAK1 inhibitory potential, a superior STAT3-inhibitory potential, and downregulated TLR4 protein expression effectively.•Molecular docking and in vivo studies were performed. In this work, additional effort was applied to design new BIBR1532-based analogues with potential inhibitory activity against telomerase and acting as multitarget antitumor candidates to overcome the resistance problem. Therefore, novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates (4a-n) were synthesized. Applying the lead optimization strategy of the previously designed compound 8e; compound 4l showed an improved telomerase inhibition of 64.95 % and a superior growth inhibition of 79 % suggesting its potential use as a successful “multitarget-directed drug” for cancer therapy. Accordingly, compound 4l was further selected to evaluate its additional JAK1/STAT3/TLR4 inhibitory potentials. Compound 4l represented a very promising JAK1 inhibitory potential with a 0.46-fold change, compared to that of pacritinib reference standard (0.33-fold change). Besides, it showed a superior STAT3-inhibitory potential with a 0.22-fold change compared to sorafenib (0.33-fold change). Additionally, compound 4l downregulated TLR4 protein expression by 0.81-fold change compared to that of resatorvid (0.29-fold change). Also, molecular docking was performed to investigate the binding mode and affinity of the superior candidate 4l towards the four target receptors (telomerase, JAK1, STAT3, and TLR4). Furthermore, the therapeutic potential of compound 4l as an antitumor agent was additionally explored through in vivo studies involving female mice implanted with Solid Ehrlich Carcinoma (SEC). Remarkably, compound 4l led to prominent reductions in tumor size and mass. Concurrent enhancements in biochemical, hematologic, histopathologic, and immunohistochemical parameters further confirmed the suppression of angiogenesis and inflammation, elucidating additional mechanisms by which compound 4l exerts its anticancer effects.
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In this work, additional effort was applied to design new BIBR1532-based analogues with potential inhibitory activity against telomerase and acting as multitarget antitumor candidates to overcome the resistance problem. Therefore, novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates (4a-n) were synthesized. Applying the lead optimization strategy of the previously designed compound 8e; compound 4l showed an improved telomerase inhibition of 64.95 % and a superior growth inhibition of 79 % suggesting its potential use as a successful “multitarget-directed drug” for cancer therapy. Accordingly, compound 4l was further selected to evaluate its additional JAK1/STAT3/TLR4 inhibitory potentials. Compound 4l represented a very promising JAK1 inhibitory potential with a 0.46-fold change, compared to that of pacritinib reference standard (0.33-fold change). Besides, it showed a superior STAT3-inhibitory potential with a 0.22-fold change compared to sorafenib (0.33-fold change). Additionally, compound 4l downregulated TLR4 protein expression by 0.81-fold change compared to that of resatorvid (0.29-fold change). Also, molecular docking was performed to investigate the binding mode and affinity of the superior candidate 4l towards the four target receptors (telomerase, JAK1, STAT3, and TLR4). Furthermore, the therapeutic potential of compound 4l as an antitumor agent was additionally explored through in vivo studies involving female mice implanted with Solid Ehrlich Carcinoma (SEC). Remarkably, compound 4l led to prominent reductions in tumor size and mass. 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All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c241t-9951b9703cd63f647cd4ade8b95684fcbb68077a11b805b7d3c0906f043415553</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S004520682400748X$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39332072$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shaldam, Moataz A.</creatorcontrib><creatorcontrib>Mousa, Mai H.A.</creatorcontrib><creatorcontrib>Tawfik, Haytham O.</creatorcontrib><creatorcontrib>El-Dessouki, Ahmed M.</creatorcontrib><creatorcontrib>Sharaky, Marwa</creatorcontrib><creatorcontrib>Saleh, Mohamed M.</creatorcontrib><creatorcontrib>Alzahrani, Abdullah Yahya Abdullah</creatorcontrib><creatorcontrib>Moussa, Sana Ben</creatorcontrib><creatorcontrib>Al-Karmalawy, Ahmed A.</creatorcontrib><title>Muti-target rationale design of novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates as telomerase/JAK1/STAT3/TLR4 inhibitors: In vitro and in vivo investigations</title><title>Bioorganic chemistry</title><addtitle>Bioorg Chem</addtitle><description>[Display omitted] •The new candidate 4l with improved telomerase and growth inhibition suggesting its potential use as a successful “multitarget-directed drug”.•Compound 4l was further selected to evaluate its additional JAK1/STAT3/TLR4 inhibitory potentials.•Compound 4l represented a very promising JAK1 inhibitory potential, a superior STAT3-inhibitory potential, and downregulated TLR4 protein expression effectively.•Molecular docking and in vivo studies were performed. In this work, additional effort was applied to design new BIBR1532-based analogues with potential inhibitory activity against telomerase and acting as multitarget antitumor candidates to overcome the resistance problem. Therefore, novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates (4a-n) were synthesized. Applying the lead optimization strategy of the previously designed compound 8e; compound 4l showed an improved telomerase inhibition of 64.95 % and a superior growth inhibition of 79 % suggesting its potential use as a successful “multitarget-directed drug” for cancer therapy. Accordingly, compound 4l was further selected to evaluate its additional JAK1/STAT3/TLR4 inhibitory potentials. Compound 4l represented a very promising JAK1 inhibitory potential with a 0.46-fold change, compared to that of pacritinib reference standard (0.33-fold change). Besides, it showed a superior STAT3-inhibitory potential with a 0.22-fold change compared to sorafenib (0.33-fold change). Additionally, compound 4l downregulated TLR4 protein expression by 0.81-fold change compared to that of resatorvid (0.29-fold change). Also, molecular docking was performed to investigate the binding mode and affinity of the superior candidate 4l towards the four target receptors (telomerase, JAK1, STAT3, and TLR4). Furthermore, the therapeutic potential of compound 4l as an antitumor agent was additionally explored through in vivo studies involving female mice implanted with Solid Ehrlich Carcinoma (SEC). Remarkably, compound 4l led to prominent reductions in tumor size and mass. 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inhibitors</subject><subject>Janus Kinase 1 - metabolism</subject><subject>Mice</subject><subject>Molecular Docking Simulation</subject><subject>Molecular Structure</subject><subject>Multitarget-directed design</subject><subject>Preclinical</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Pyridazines - chemical synthesis</subject><subject>Pyridazines - chemistry</subject><subject>Pyridazines - pharmacology</subject><subject>STAT3 Transcription Factor - antagonists &amp; inhibitors</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Telomerase</subject><subject>Telomerase - antagonists &amp; inhibitors</subject><subject>Telomerase - metabolism</subject><subject>Toll-Like Receptor 4 - antagonists &amp; inhibitors</subject><subject>Toll-Like Receptor 4 - metabolism</subject><issn>0045-2068</issn><issn>1090-2120</issn><issn>1090-2120</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UcuOEzEQHCEQGxb-ACEfswcnfs2LA1K04rEQQIJwtjx2T-JoZpy1PSOFf-Pf8DKBI6dWd1d1V3dl2UtKVpTQYn1cNdY5v18xwkQqlZXgj7IFJTXBjDLyOFsQInLMSFFdZc9COBJCqSiLp9kVrzlnpGSL7NfnMVocld9DRF5F6wbVATIQ7H5ArkWDm6BDYWxCtHGMYNAXfDrAcO4ww8tlcUlOZ2-N-mkHzPG5u4kH626Uhqh6awBpNZjUjhCQCihC53rwKsD64-YTXX_fbXZ8vdt-E8gOB9vY6Hx4je4GNNnoHUrk1EjJ5FKcICnZ_1EanmdPWtUFeHGJ19mPd293tx_w9uv7u9vNFmsmaMR1ndOmLgnXpuBtIUpthDJQNXVeVKLVTVNUpCwVpU1F8qY0XKcvFi0RXNA8z_l1tpznnry7H5MA2dugoevUAG4MktP0f1aXvEpQMUO1dyF4aOXJ2175s6REPhgnj3I2Tj4YJ2fjEu3VZcPY9GD-kf46lQBvZgCkOycLXgZtYdBgrAcdpXH2_xt-A8qKrQs</recordid><startdate>202412</startdate><enddate>202412</enddate><creator>Shaldam, Moataz A.</creator><creator>Mousa, Mai H.A.</creator><creator>Tawfik, Haytham O.</creator><creator>El-Dessouki, Ahmed M.</creator><creator>Sharaky, Marwa</creator><creator>Saleh, Mohamed M.</creator><creator>Alzahrani, Abdullah Yahya Abdullah</creator><creator>Moussa, Sana Ben</creator><creator>Al-Karmalawy, Ahmed A.</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>202412</creationdate><title>Muti-target rationale design of novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates as telomerase/JAK1/STAT3/TLR4 inhibitors: In vitro and in vivo investigations</title><author>Shaldam, Moataz A. ; Mousa, Mai H.A. ; Tawfik, Haytham O. ; El-Dessouki, Ahmed M. ; Sharaky, Marwa ; Saleh, Mohamed M. ; Alzahrani, Abdullah Yahya Abdullah ; Moussa, Sana Ben ; Al-Karmalawy, Ahmed A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c241t-9951b9703cd63f647cd4ade8b95684fcbb68077a11b805b7d3c0906f043415553</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Acetamides - chemical synthesis</topic><topic>Acetamides - chemistry</topic><topic>Acetamides - pharmacology</topic><topic>Animals</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Carcinoma, Ehrlich Tumor - drug therapy</topic><topic>Carcinoma, Ehrlich Tumor - metabolism</topic><topic>Carcinoma, Ehrlich Tumor - pathology</topic><topic>Cell Proliferation - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Design</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Humans</topic><topic>JAK1/STAT3/TLR4</topic><topic>Janus Kinase 1 - antagonists &amp; inhibitors</topic><topic>Janus Kinase 1 - metabolism</topic><topic>Mice</topic><topic>Molecular Docking Simulation</topic><topic>Molecular Structure</topic><topic>Multitarget-directed design</topic><topic>Preclinical</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Pyridazines - chemical synthesis</topic><topic>Pyridazines - chemistry</topic><topic>Pyridazines - pharmacology</topic><topic>STAT3 Transcription Factor - antagonists &amp; inhibitors</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Telomerase</topic><topic>Telomerase - antagonists &amp; inhibitors</topic><topic>Telomerase - metabolism</topic><topic>Toll-Like Receptor 4 - antagonists &amp; inhibitors</topic><topic>Toll-Like Receptor 4 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shaldam, Moataz A.</creatorcontrib><creatorcontrib>Mousa, Mai H.A.</creatorcontrib><creatorcontrib>Tawfik, Haytham O.</creatorcontrib><creatorcontrib>El-Dessouki, Ahmed M.</creatorcontrib><creatorcontrib>Sharaky, Marwa</creatorcontrib><creatorcontrib>Saleh, Mohamed M.</creatorcontrib><creatorcontrib>Alzahrani, Abdullah Yahya Abdullah</creatorcontrib><creatorcontrib>Moussa, Sana Ben</creatorcontrib><creatorcontrib>Al-Karmalawy, Ahmed A.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shaldam, Moataz A.</au><au>Mousa, Mai H.A.</au><au>Tawfik, Haytham O.</au><au>El-Dessouki, Ahmed M.</au><au>Sharaky, Marwa</au><au>Saleh, Mohamed M.</au><au>Alzahrani, Abdullah Yahya Abdullah</au><au>Moussa, Sana Ben</au><au>Al-Karmalawy, Ahmed A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Muti-target rationale design of novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates as telomerase/JAK1/STAT3/TLR4 inhibitors: In vitro and in vivo investigations</atitle><jtitle>Bioorganic chemistry</jtitle><addtitle>Bioorg Chem</addtitle><date>2024-12</date><risdate>2024</risdate><volume>153</volume><spage>107843</spage><pages>107843-</pages><artnum>107843</artnum><issn>0045-2068</issn><issn>1090-2120</issn><eissn>1090-2120</eissn><abstract>[Display omitted] •The new candidate 4l with improved telomerase and growth inhibition suggesting its potential use as a successful “multitarget-directed drug”.•Compound 4l was further selected to evaluate its additional JAK1/STAT3/TLR4 inhibitory potentials.•Compound 4l represented a very promising JAK1 inhibitory potential, a superior STAT3-inhibitory potential, and downregulated TLR4 protein expression effectively.•Molecular docking and in vivo studies were performed. In this work, additional effort was applied to design new BIBR1532-based analogues with potential inhibitory activity against telomerase and acting as multitarget antitumor candidates to overcome the resistance problem. Therefore, novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates (4a-n) were synthesized. Applying the lead optimization strategy of the previously designed compound 8e; compound 4l showed an improved telomerase inhibition of 64.95 % and a superior growth inhibition of 79 % suggesting its potential use as a successful “multitarget-directed drug” for cancer therapy. Accordingly, compound 4l was further selected to evaluate its additional JAK1/STAT3/TLR4 inhibitory potentials. Compound 4l represented a very promising JAK1 inhibitory potential with a 0.46-fold change, compared to that of pacritinib reference standard (0.33-fold change). Besides, it showed a superior STAT3-inhibitory potential with a 0.22-fold change compared to sorafenib (0.33-fold change). Additionally, compound 4l downregulated TLR4 protein expression by 0.81-fold change compared to that of resatorvid (0.29-fold change). Also, molecular docking was performed to investigate the binding mode and affinity of the superior candidate 4l towards the four target receptors (telomerase, JAK1, STAT3, and TLR4). Furthermore, the therapeutic potential of compound 4l as an antitumor agent was additionally explored through in vivo studies involving female mice implanted with Solid Ehrlich Carcinoma (SEC). Remarkably, compound 4l led to prominent reductions in tumor size and mass. Concurrent enhancements in biochemical, hematologic, histopathologic, and immunohistochemical parameters further confirmed the suppression of angiogenesis and inflammation, elucidating additional mechanisms by which compound 4l exerts its anticancer effects.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>39332072</pmid><doi>10.1016/j.bioorg.2024.107843</doi></addata></record>
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subjects Acetamides - chemical synthesis
Acetamides - chemistry
Acetamides - pharmacology
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Carcinoma, Ehrlich Tumor - drug therapy
Carcinoma, Ehrlich Tumor - metabolism
Carcinoma, Ehrlich Tumor - pathology
Cell Proliferation - drug effects
Dose-Response Relationship, Drug
Drug Design
Drug Screening Assays, Antitumor
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
JAK1/STAT3/TLR4
Janus Kinase 1 - antagonists & inhibitors
Janus Kinase 1 - metabolism
Mice
Molecular Docking Simulation
Molecular Structure
Multitarget-directed design
Preclinical
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Pyridazines - chemical synthesis
Pyridazines - chemistry
Pyridazines - pharmacology
STAT3 Transcription Factor - antagonists & inhibitors
STAT3 Transcription Factor - metabolism
Structure-Activity Relationship
Telomerase
Telomerase - antagonists & inhibitors
Telomerase - metabolism
Toll-Like Receptor 4 - antagonists & inhibitors
Toll-Like Receptor 4 - metabolism
title Muti-target rationale design of novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates as telomerase/JAK1/STAT3/TLR4 inhibitors: In vitro and in vivo investigations
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