Synthesis and biological evaluation of a novel series of aryl S,N-ketene acetals as antileishmanial agents
A series of aryl S N ketene acetals 7(a–f) was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. ·A series of trimethoxy aryl S,N-ketene acetals has been synthesized.·Compounds were evaluated against extracellular promastigotes and intrace...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2013-07, Vol.23 (13), p.3979-3982 |
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| creator | Suryawanshi, S.N. Kumar, Santosh Tiwari, Avinash Shivahare, Rahul Chhonker, Yashpal Singh Pandey, Susmita Shakya, Nishi Bhatta, Rabi Sankar Gupta, Suman |
| description | A series of aryl S N ketene acetals 7(a–f) was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani.
·A series of trimethoxy aryl S,N-ketene acetals has been synthesized.·Compounds were evaluated against extracellular promastigotes and intracellular amastigotes of Leishmania donovani.·Of the six screened compounds, 7a and 7b have shown interesting antiamastigote activity with IC50s of 1.2 and 2.1μM and selectivity indices of 34 and 30, respectively.·Compounds 7a and 7b showed significant inhibition of parasite multiplication, 72% and 83%, respectively, against L. donovani/hamster model.·Compound 7b exhibited moderate metabolic stability with three metabolites (M1, M2 and M3) formed by CYP enzyme.
A series of aryl S,N-ketene acetals 7(a–f) was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. All the 6 compounds exhibited significant in vitro activity against intracellular amastigotes of L. donovani with IC50 values ranging from 1.2 to 3.5μM and were found promising as compared with reference drugs, sodium stibogluconate (SSG) and paromomycin. On the basis of good selectivity indices (SI), they were further tested for their in vivo potential against L. donovani/hamster model. Two compounds 7a and 7b showed significant inhibition of parasite multiplication, 72% and 83%, respectively. These compounds were comparable with SSG and superior to paromomycin. Preliminary in vitro metabolic investigations were also performed to assess the metabolic stability and in vitro hepatic intrinsic clearance (Clint) of compound 7b in hamster liver microsomes. |
| doi_str_mv | 10.1016/j.bmcl.2013.04.025 |
| format | Article |
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·A series of trimethoxy aryl S,N-ketene acetals has been synthesized.·Compounds were evaluated against extracellular promastigotes and intracellular amastigotes of Leishmania donovani.·Of the six screened compounds, 7a and 7b have shown interesting antiamastigote activity with IC50s of 1.2 and 2.1μM and selectivity indices of 34 and 30, respectively.·Compounds 7a and 7b showed significant inhibition of parasite multiplication, 72% and 83%, respectively, against L. donovani/hamster model.·Compound 7b exhibited moderate metabolic stability with three metabolites (M1, M2 and M3) formed by CYP enzyme.
A series of aryl S,N-ketene acetals 7(a–f) was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. All the 6 compounds exhibited significant in vitro activity against intracellular amastigotes of L. donovani with IC50 values ranging from 1.2 to 3.5μM and were found promising as compared with reference drugs, sodium stibogluconate (SSG) and paromomycin. On the basis of good selectivity indices (SI), they were further tested for their in vivo potential against L. donovani/hamster model. Two compounds 7a and 7b showed significant inhibition of parasite multiplication, 72% and 83%, respectively. These compounds were comparable with SSG and superior to paromomycin. Preliminary in vitro metabolic investigations were also performed to assess the metabolic stability and in vitro hepatic intrinsic clearance (Clint) of compound 7b in hamster liver microsomes.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2013.04.025</identifier><identifier>PMID: 23673014</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Acetals - chemical synthesis ; Acetals - chemistry ; Acetals - pharmacology ; amastigotes ; animal models ; Antileishmanial activity ; antileishmanials ; Antiparasitic Agents - chemical synthesis ; Antiparasitic Agents - chemistry ; Antiparasitic Agents - pharmacology ; Aryl S,N-ketene acetal ; chemistry ; Dose-Response Relationship, Drug ; drugs ; Ethylenes - chemical synthesis ; Ethylenes - chemistry ; Ethylenes - pharmacology ; Hamster ; hamsters ; inhibitory concentration 50 ; Ketones - chemical synthesis ; Ketones - chemistry ; Ketones - pharmacology ; Leishmania donovani ; Leishmania donovani - drug effects ; liver microsomes ; Molecular Structure ; parasites ; Parasitic Sensitivity Tests ; Pharmacokinetic studies ; sodium ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2013-07, Vol.23 (13), p.3979-3982</ispartof><rights>2013 Elsevier Ltd</rights><rights>Copyright © 2013 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c413t-8a76351fa70094c38995e1f7f3187fd2eefb52dd5a6611b42bf8b10505a5b01f3</citedby><cites>FETCH-LOGICAL-c413t-8a76351fa70094c38995e1f7f3187fd2eefb52dd5a6611b42bf8b10505a5b01f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2013.04.025$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23673014$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Suryawanshi, S.N.</creatorcontrib><creatorcontrib>Kumar, Santosh</creatorcontrib><creatorcontrib>Tiwari, Avinash</creatorcontrib><creatorcontrib>Shivahare, Rahul</creatorcontrib><creatorcontrib>Chhonker, Yashpal Singh</creatorcontrib><creatorcontrib>Pandey, Susmita</creatorcontrib><creatorcontrib>Shakya, Nishi</creatorcontrib><creatorcontrib>Bhatta, Rabi Sankar</creatorcontrib><creatorcontrib>Gupta, Suman</creatorcontrib><title>Synthesis and biological evaluation of a novel series of aryl S,N-ketene acetals as antileishmanial agents</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A series of aryl S N ketene acetals 7(a–f) was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani.
·A series of trimethoxy aryl S,N-ketene acetals has been synthesized.·Compounds were evaluated against extracellular promastigotes and intracellular amastigotes of Leishmania donovani.·Of the six screened compounds, 7a and 7b have shown interesting antiamastigote activity with IC50s of 1.2 and 2.1μM and selectivity indices of 34 and 30, respectively.·Compounds 7a and 7b showed significant inhibition of parasite multiplication, 72% and 83%, respectively, against L. donovani/hamster model.·Compound 7b exhibited moderate metabolic stability with three metabolites (M1, M2 and M3) formed by CYP enzyme.
A series of aryl S,N-ketene acetals 7(a–f) was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. All the 6 compounds exhibited significant in vitro activity against intracellular amastigotes of L. donovani with IC50 values ranging from 1.2 to 3.5μM and were found promising as compared with reference drugs, sodium stibogluconate (SSG) and paromomycin. On the basis of good selectivity indices (SI), they were further tested for their in vivo potential against L. donovani/hamster model. Two compounds 7a and 7b showed significant inhibition of parasite multiplication, 72% and 83%, respectively. These compounds were comparable with SSG and superior to paromomycin. Preliminary in vitro metabolic investigations were also performed to assess the metabolic stability and in vitro hepatic intrinsic clearance (Clint) of compound 7b in hamster liver microsomes.</description><subject>Acetals - chemical synthesis</subject><subject>Acetals - chemistry</subject><subject>Acetals - pharmacology</subject><subject>amastigotes</subject><subject>animal models</subject><subject>Antileishmanial activity</subject><subject>antileishmanials</subject><subject>Antiparasitic Agents - chemical synthesis</subject><subject>Antiparasitic Agents - chemistry</subject><subject>Antiparasitic Agents - pharmacology</subject><subject>Aryl S,N-ketene acetal</subject><subject>chemistry</subject><subject>Dose-Response Relationship, Drug</subject><subject>drugs</subject><subject>Ethylenes - chemical synthesis</subject><subject>Ethylenes - chemistry</subject><subject>Ethylenes - pharmacology</subject><subject>Hamster</subject><subject>hamsters</subject><subject>inhibitory concentration 50</subject><subject>Ketones - chemical synthesis</subject><subject>Ketones - chemistry</subject><subject>Ketones - pharmacology</subject><subject>Leishmania donovani</subject><subject>Leishmania donovani - drug effects</subject><subject>liver microsomes</subject><subject>Molecular Structure</subject><subject>parasites</subject><subject>Parasitic Sensitivity Tests</subject><subject>Pharmacokinetic studies</subject><subject>sodium</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1v1DAQhi0EotvCH-AAOXJowkz8kUTigiq-pAoOSyVuluOMt16cuMTZlfrvcdjCEU7WWM88Gr0vYy8QKgRUb_ZVP9pQ1YC8AlFBLR-xDQolSi5APmYb6BSUbSe-n7HzlPYAKECIp-ys5qrhedqw_fZ-Wm4p-VSYaSh6H0PceWtCQUcTDmbxcSqiK0wxxSOFItHsKf3-me9Dsb38Uv6ghSYqjKXFhKxZTYsP5NPtaCafVWZH05KesScuA_T84b1gNx_ef7v6VF5__fj56t11aQXypWxNo7hEZxqATljedp0kdI3j2DZuqIlcL-thkEYpxF7UvWt7BAnSyB7Q8Qv2-uS9m-PPA6VFjz5ZCsFMFA9JowRoVCd583-UKyUb1TYrWp9QO8eUZnL6bvZjDkEj6LUOvddrHXqtQ4PQuY689PLBf-hHGv6u_Mk_A69OgDNRm93sk77ZZkM-EXldI2bi7YmgHNnR06yT9TRZGvxMdtFD9P-64BdejqSW</recordid><startdate>20130701</startdate><enddate>20130701</enddate><creator>Suryawanshi, S.N.</creator><creator>Kumar, Santosh</creator><creator>Tiwari, Avinash</creator><creator>Shivahare, Rahul</creator><creator>Chhonker, Yashpal Singh</creator><creator>Pandey, Susmita</creator><creator>Shakya, Nishi</creator><creator>Bhatta, Rabi Sankar</creator><creator>Gupta, Suman</creator><general>Elsevier Ltd</general><scope>FBQ</scope><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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>M7N</scope><scope>P64</scope></search><sort><creationdate>20130701</creationdate><title>Synthesis and biological evaluation of a novel series of aryl S,N-ketene acetals as antileishmanial agents</title><author>Suryawanshi, S.N. ; Kumar, Santosh ; Tiwari, Avinash ; Shivahare, Rahul ; Chhonker, Yashpal Singh ; Pandey, Susmita ; Shakya, Nishi ; Bhatta, Rabi Sankar ; Gupta, Suman</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c413t-8a76351fa70094c38995e1f7f3187fd2eefb52dd5a6611b42bf8b10505a5b01f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Acetals - chemical synthesis</topic><topic>Acetals - chemistry</topic><topic>Acetals - pharmacology</topic><topic>amastigotes</topic><topic>animal models</topic><topic>Antileishmanial activity</topic><topic>antileishmanials</topic><topic>Antiparasitic Agents - chemical synthesis</topic><topic>Antiparasitic Agents - chemistry</topic><topic>Antiparasitic Agents - pharmacology</topic><topic>Aryl S,N-ketene acetal</topic><topic>chemistry</topic><topic>Dose-Response Relationship, Drug</topic><topic>drugs</topic><topic>Ethylenes - chemical synthesis</topic><topic>Ethylenes - chemistry</topic><topic>Ethylenes - pharmacology</topic><topic>Hamster</topic><topic>hamsters</topic><topic>inhibitory concentration 50</topic><topic>Ketones - chemical synthesis</topic><topic>Ketones - chemistry</topic><topic>Ketones - pharmacology</topic><topic>Leishmania donovani</topic><topic>Leishmania donovani - drug effects</topic><topic>liver microsomes</topic><topic>Molecular Structure</topic><topic>parasites</topic><topic>Parasitic Sensitivity Tests</topic><topic>Pharmacokinetic studies</topic><topic>sodium</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Suryawanshi, S.N.</creatorcontrib><creatorcontrib>Kumar, Santosh</creatorcontrib><creatorcontrib>Tiwari, Avinash</creatorcontrib><creatorcontrib>Shivahare, Rahul</creatorcontrib><creatorcontrib>Chhonker, Yashpal Singh</creatorcontrib><creatorcontrib>Pandey, Susmita</creatorcontrib><creatorcontrib>Shakya, Nishi</creatorcontrib><creatorcontrib>Bhatta, Rabi Sankar</creatorcontrib><creatorcontrib>Gupta, Suman</creatorcontrib><collection>AGRIS</collection><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><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Suryawanshi, S.N.</au><au>Kumar, Santosh</au><au>Tiwari, Avinash</au><au>Shivahare, Rahul</au><au>Chhonker, Yashpal Singh</au><au>Pandey, Susmita</au><au>Shakya, Nishi</au><au>Bhatta, Rabi Sankar</au><au>Gupta, Suman</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and biological evaluation of a novel series of aryl S,N-ketene acetals as antileishmanial agents</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2013-07-01</date><risdate>2013</risdate><volume>23</volume><issue>13</issue><spage>3979</spage><epage>3982</epage><pages>3979-3982</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A series of aryl S N ketene acetals 7(a–f) was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani.
·A series of trimethoxy aryl S,N-ketene acetals has been synthesized.·Compounds were evaluated against extracellular promastigotes and intracellular amastigotes of Leishmania donovani.·Of the six screened compounds, 7a and 7b have shown interesting antiamastigote activity with IC50s of 1.2 and 2.1μM and selectivity indices of 34 and 30, respectively.·Compounds 7a and 7b showed significant inhibition of parasite multiplication, 72% and 83%, respectively, against L. donovani/hamster model.·Compound 7b exhibited moderate metabolic stability with three metabolites (M1, M2 and M3) formed by CYP enzyme.
A series of aryl S,N-ketene acetals 7(a–f) was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. All the 6 compounds exhibited significant in vitro activity against intracellular amastigotes of L. donovani with IC50 values ranging from 1.2 to 3.5μM and were found promising as compared with reference drugs, sodium stibogluconate (SSG) and paromomycin. On the basis of good selectivity indices (SI), they were further tested for their in vivo potential against L. donovani/hamster model. Two compounds 7a and 7b showed significant inhibition of parasite multiplication, 72% and 83%, respectively. These compounds were comparable with SSG and superior to paromomycin. Preliminary in vitro metabolic investigations were also performed to assess the metabolic stability and in vitro hepatic intrinsic clearance (Clint) of compound 7b in hamster liver microsomes.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>23673014</pmid><doi>10.1016/j.bmcl.2013.04.025</doi><tpages>4</tpages></addata></record> |
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| subjects | Acetals - chemical synthesis Acetals - chemistry Acetals - pharmacology amastigotes animal models Antileishmanial activity antileishmanials Antiparasitic Agents - chemical synthesis Antiparasitic Agents - chemistry Antiparasitic Agents - pharmacology Aryl S,N-ketene acetal chemistry Dose-Response Relationship, Drug drugs Ethylenes - chemical synthesis Ethylenes - chemistry Ethylenes - pharmacology Hamster hamsters inhibitory concentration 50 Ketones - chemical synthesis Ketones - chemistry Ketones - pharmacology Leishmania donovani Leishmania donovani - drug effects liver microsomes Molecular Structure parasites Parasitic Sensitivity Tests Pharmacokinetic studies sodium Structure-Activity Relationship |
| title | Synthesis and biological evaluation of a novel series of aryl S,N-ketene acetals as antileishmanial agents |
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