Design, Synthesis and Evaluation of Aryl‐Tailored Oxadiazole‐thiones as New Urease Inhibitors
The ubiquitous chronic gastric infections that cause major human health disorders like gastritis and ulcers can be treated using drugs targeting the Helicobacter pylori (H. pylori) urease. Targeted eradication therapy is essential given the growing ineffectiveness of current treatment regimens due t...
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description | The ubiquitous chronic gastric infections that cause major human health disorders like gastritis and ulcers can be treated using drugs targeting the Helicobacter pylori (H. pylori) urease. Targeted eradication therapy is essential given the growing ineffectiveness of current treatment regimens due to broad‐spectrum antibiotic resistance, significant side effects, and low compliance. Therefore, we here report the development of a new series of 1,3,4‐oxadiazole‐2‐thiones with various aryl tail groups (compounds 20–27) as effective urease inhibitors. The most promising analog 5‐[(4‐methoxyphenoxy)methyl]‐2,3‐dihydro‐1,3,4‐oxadiazole‐2‐thione (21) inhibited the urease activity with an IC50 value of 26.6 μM. In addition, kinetic studies revealed the competitive inhibition pattern for 21 with a Ki value of 8.72 μM indicating the potent and specific binding interactions with the urease active site. Molecular docking analysis of 21 inside the active pocket of the urease highlighted several important interactions with amino acid residues such as H492, H519 and R439, which pave the way for further development of improved urease inhibitors with potential application as anti‐infective agents.
In this research, a novel series of oxadiazole‐2‐thiones were synthesized and evaluated against Jack bean urease. Kinetic studies revealed the competitive inhibition of urease by 21. Molecular docking analysis of 21 was also performed highlighting several important interactions, which can be used for further development of improved urease inhibitors using this chemotype. |
doi_str_mv | 10.1002/slct.202204449 |
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In this research, a novel series of oxadiazole‐2‐thiones were synthesized and evaluated against Jack bean urease. Kinetic studies revealed the competitive inhibition of urease by 21. Molecular docking analysis of 21 was also performed highlighting several important interactions, which can be used for further development of improved urease inhibitors using this chemotype.</description><identifier>ISSN: 2365-6549</identifier><identifier>EISSN: 2365-6549</identifier><identifier>DOI: 10.1002/slct.202204449</identifier><language>eng</language><subject>arylhydrazones ; medicinal chemistry ; oxadiazolethione ; urease ; urease inhibitors</subject><ispartof>ChemistrySelect (Weinheim), 2023-02, Vol.8 (8), p.n/a</ispartof><rights>2023 Wiley‐VCH GmbH</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c2199-b447d660b6359852e9df349de94f2932c04f26d9da9a6a2f48e4d9fb81ce4d183</citedby><cites>FETCH-LOGICAL-c2199-b447d660b6359852e9df349de94f2932c04f26d9da9a6a2f48e4d9fb81ce4d183</cites><orcidid>0000-0001-8916-2492 ; 0000-0003-2391-5644 ; 0000-0003-4737-1733 ; 0000-0003-0525-1186 ; 0000-0002-9555-1555 ; 0000-0002-2549-1390</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fslct.202204449$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fslct.202204449$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids></links><search><creatorcontrib>Maz, Tugce Gur</creatorcontrib><creatorcontrib>Caliskan, H. Burak</creatorcontrib><creatorcontrib>Capan, Irfan</creatorcontrib><creatorcontrib>Caliskan, Burcu</creatorcontrib><creatorcontrib>Özçelik, Berrin</creatorcontrib><creatorcontrib>Banoglu, Erden</creatorcontrib><title>Design, Synthesis and Evaluation of Aryl‐Tailored Oxadiazole‐thiones as New Urease Inhibitors</title><title>ChemistrySelect (Weinheim)</title><description>The ubiquitous chronic gastric infections that cause major human health disorders like gastritis and ulcers can be treated using drugs targeting the Helicobacter pylori (H. pylori) urease. Targeted eradication therapy is essential given the growing ineffectiveness of current treatment regimens due to broad‐spectrum antibiotic resistance, significant side effects, and low compliance. Therefore, we here report the development of a new series of 1,3,4‐oxadiazole‐2‐thiones with various aryl tail groups (compounds 20–27) as effective urease inhibitors. The most promising analog 5‐[(4‐methoxyphenoxy)methyl]‐2,3‐dihydro‐1,3,4‐oxadiazole‐2‐thione (21) inhibited the urease activity with an IC50 value of 26.6 μM. In addition, kinetic studies revealed the competitive inhibition pattern for 21 with a Ki value of 8.72 μM indicating the potent and specific binding interactions with the urease active site. Molecular docking analysis of 21 inside the active pocket of the urease highlighted several important interactions with amino acid residues such as H492, H519 and R439, which pave the way for further development of improved urease inhibitors with potential application as anti‐infective agents.
In this research, a novel series of oxadiazole‐2‐thiones were synthesized and evaluated against Jack bean urease. Kinetic studies revealed the competitive inhibition of urease by 21. Molecular docking analysis of 21 was also performed highlighting several important interactions, which can be used for further development of improved urease inhibitors using this chemotype.</description><subject>arylhydrazones</subject><subject>medicinal chemistry</subject><subject>oxadiazolethione</subject><subject>urease</subject><subject>urease inhibitors</subject><issn>2365-6549</issn><issn>2365-6549</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNqFkLFOwzAURS0EElXpyuwPIMV2HDdvrEqBShEd2s6RE9vUyCTIDpQw8Ql8I1-CqyJgY7pHT_e84SJ0TsmYEsIug6u7MSOMEc45HKEBS0WWiIzD8R8-RaMQHgghVOSCZZMBklc62PvmAq_6pttGDlg2Cs9fpHuWnW0b3Bo89b37fP9YS-tarxVevkpl5VvrdLx229jSUQv4Tu_wxmsZNF40W1vZrvXhDJ0Y6YIefecQba7n69ltUixvFrNpkdSMAiQV5xMlBKlEmkGeMQ3KpByUBm4YpKwmMYUCJUEKyQzPNVdgqpzWEWieDtH48Lf2bQhem_LJ20fp-5KScr9Rud-o_NkoCnAQdtbp_p92uSpm61_3C2P5bmY</recordid><startdate>20230223</startdate><enddate>20230223</enddate><creator>Maz, Tugce Gur</creator><creator>Caliskan, H. Burak</creator><creator>Capan, Irfan</creator><creator>Caliskan, Burcu</creator><creator>Özçelik, Berrin</creator><creator>Banoglu, Erden</creator><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0001-8916-2492</orcidid><orcidid>https://orcid.org/0000-0003-2391-5644</orcidid><orcidid>https://orcid.org/0000-0003-4737-1733</orcidid><orcidid>https://orcid.org/0000-0003-0525-1186</orcidid><orcidid>https://orcid.org/0000-0002-9555-1555</orcidid><orcidid>https://orcid.org/0000-0002-2549-1390</orcidid></search><sort><creationdate>20230223</creationdate><title>Design, Synthesis and Evaluation of Aryl‐Tailored Oxadiazole‐thiones as New Urease Inhibitors</title><author>Maz, Tugce Gur ; Caliskan, H. Burak ; Capan, Irfan ; Caliskan, Burcu ; Özçelik, Berrin ; Banoglu, Erden</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2199-b447d660b6359852e9df349de94f2932c04f26d9da9a6a2f48e4d9fb81ce4d183</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>arylhydrazones</topic><topic>medicinal chemistry</topic><topic>oxadiazolethione</topic><topic>urease</topic><topic>urease inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Maz, Tugce Gur</creatorcontrib><creatorcontrib>Caliskan, H. Burak</creatorcontrib><creatorcontrib>Capan, Irfan</creatorcontrib><creatorcontrib>Caliskan, Burcu</creatorcontrib><creatorcontrib>Özçelik, Berrin</creatorcontrib><creatorcontrib>Banoglu, Erden</creatorcontrib><collection>CrossRef</collection><jtitle>ChemistrySelect (Weinheim)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Maz, Tugce Gur</au><au>Caliskan, H. Burak</au><au>Capan, Irfan</au><au>Caliskan, Burcu</au><au>Özçelik, Berrin</au><au>Banoglu, Erden</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, Synthesis and Evaluation of Aryl‐Tailored Oxadiazole‐thiones as New Urease Inhibitors</atitle><jtitle>ChemistrySelect (Weinheim)</jtitle><date>2023-02-23</date><risdate>2023</risdate><volume>8</volume><issue>8</issue><epage>n/a</epage><issn>2365-6549</issn><eissn>2365-6549</eissn><abstract>The ubiquitous chronic gastric infections that cause major human health disorders like gastritis and ulcers can be treated using drugs targeting the Helicobacter pylori (H. pylori) urease. Targeted eradication therapy is essential given the growing ineffectiveness of current treatment regimens due to broad‐spectrum antibiotic resistance, significant side effects, and low compliance. Therefore, we here report the development of a new series of 1,3,4‐oxadiazole‐2‐thiones with various aryl tail groups (compounds 20–27) as effective urease inhibitors. The most promising analog 5‐[(4‐methoxyphenoxy)methyl]‐2,3‐dihydro‐1,3,4‐oxadiazole‐2‐thione (21) inhibited the urease activity with an IC50 value of 26.6 μM. In addition, kinetic studies revealed the competitive inhibition pattern for 21 with a Ki value of 8.72 μM indicating the potent and specific binding interactions with the urease active site. Molecular docking analysis of 21 inside the active pocket of the urease highlighted several important interactions with amino acid residues such as H492, H519 and R439, which pave the way for further development of improved urease inhibitors with potential application as anti‐infective agents.
In this research, a novel series of oxadiazole‐2‐thiones were synthesized and evaluated against Jack bean urease. Kinetic studies revealed the competitive inhibition of urease by 21. Molecular docking analysis of 21 was also performed highlighting several important interactions, which can be used for further development of improved urease inhibitors using this chemotype.</abstract><doi>10.1002/slct.202204449</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0001-8916-2492</orcidid><orcidid>https://orcid.org/0000-0003-2391-5644</orcidid><orcidid>https://orcid.org/0000-0003-4737-1733</orcidid><orcidid>https://orcid.org/0000-0003-0525-1186</orcidid><orcidid>https://orcid.org/0000-0002-9555-1555</orcidid><orcidid>https://orcid.org/0000-0002-2549-1390</orcidid></addata></record> |
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subjects | arylhydrazones medicinal chemistry oxadiazolethione urease urease inhibitors |
title | Design, Synthesis and Evaluation of Aryl‐Tailored Oxadiazole‐thiones as New Urease Inhibitors |
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