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Glycyrrhetinic acid and its analogs: A new class of antifilarial agents
Although a number of chemicals have been isolated from Glycyrrhiza glabra, only a few have been evaluated for their biological significance. As part of our drug discovery program for antifilarial agents from Indian medicinal plants, the roots of G. glabra were chemically investigated, which resulted...
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| Published in: | Bioorganic & medicinal chemistry letters 2013-05, Vol.23 (9), p.2566-2570 |
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| creator | Kalani, Komal Kushwaha, Vikas Verma, Richa Murthy, P. Kalpana Srivastava, S.K. |
| description | Although a number of chemicals have been isolated from Glycyrrhiza glabra, only a few have been evaluated for their biological significance. As part of our drug discovery program for antifilarial agents from Indian medicinal plants, the roots of G. glabra were chemically investigated, which resulted in the isolation and characterization of an antifilarial agent, glycyrrhetinic acid (GA, 1a) effective against microfilariae (mf) in vitro (LC100: 12.5μM; IC50: 1.20μM), but was inactive against adult worms. Further, GA (1a) was converted into six analogs (2a–7a) and their antifilarial potential was evaluated by studying in vitro motility and MTT reduction assays employing mf and adult worms of Brugia malayi. The results showed that out of six GA analogs, the benzyl amide analog (6a) killed adults and mf at 25 and 50μM concentration, respectively, and inhibited 49% MTT reduction potential of the adult parasites. The IC50 values were found to be 8.8 and 2.2μM for adults and mf, respectively. The SI of the compound was >60. On the other hand the octylamide analog (7a) required much higher concentration to adversely affect the parasites. Finally, both active amide analogs (6a and 7a) were in vivo evaluated using B. malayi-jird model, which showed that analog 6a possesses promising macrofilaricidal activity at 100mg/kg, s.c. ×5days and around 40% of the treated animals showed calcified masses of worm fragments in peritoneal cavity of the animals. To the best of our knowledge this is the first ever report on the antifilarial potential of GA analogs. Further work on optimization of the antifilarial lead is under progress. |
| doi_str_mv | 10.1016/j.bmcl.2013.02.115 |
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Kalpana ; Srivastava, S.K.</creator><creatorcontrib>Kalani, Komal ; Kushwaha, Vikas ; Verma, Richa ; Murthy, P. Kalpana ; Srivastava, S.K.</creatorcontrib><description>Although a number of chemicals have been isolated from Glycyrrhiza glabra, only a few have been evaluated for their biological significance. As part of our drug discovery program for antifilarial agents from Indian medicinal plants, the roots of G. glabra were chemically investigated, which resulted in the isolation and characterization of an antifilarial agent, glycyrrhetinic acid (GA, 1a) effective against microfilariae (mf) in vitro (LC100: 12.5μM; IC50: 1.20μM), but was inactive against adult worms. Further, GA (1a) was converted into six analogs (2a–7a) and their antifilarial potential was evaluated by studying in vitro motility and MTT reduction assays employing mf and adult worms of Brugia malayi. The results showed that out of six GA analogs, the benzyl amide analog (6a) killed adults and mf at 25 and 50μM concentration, respectively, and inhibited 49% MTT reduction potential of the adult parasites. The IC50 values were found to be 8.8 and 2.2μM for adults and mf, respectively. The SI of the compound was >60. On the other hand the octylamide analog (7a) required much higher concentration to adversely affect the parasites. Finally, both active amide analogs (6a and 7a) were in vivo evaluated using B. malayi-jird model, which showed that analog 6a possesses promising macrofilaricidal activity at 100mg/kg, s.c. ×5days and around 40% of the treated animals showed calcified masses of worm fragments in peritoneal cavity of the animals. To the best of our knowledge this is the first ever report on the antifilarial potential of GA analogs. Further work on optimization of the antifilarial lead is under progress.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2013.02.115</identifier><identifier>PMID: 23541646</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>adults ; Animals ; Antifilarial activity ; Brugia malayi ; Brugia malayi - drug effects ; chemistry ; drugs ; Female ; Filaricides - chemistry ; Filaricides - isolation & purification ; Filaricides - pharmacology ; Glycyrrhetinic Acid - analogs & derivatives ; Glycyrrhetinic Acid - isolation & purification ; Glycyrrhetinic Acid - pharmacology ; Glycyrrhetinic acid-analogs ; Glycyrrhiza - chemistry ; Glycyrrhiza glabra ; inhibitory concentration 50 ; medicinal plants ; microfilariae ; Microfilariae - drug effects ; nematicides ; parasites ; Plant Roots - chemistry ; roots</subject><ispartof>Bioorganic & medicinal chemistry letters, 2013-05, Vol.23 (9), p.2566-2570</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-c380t-b625d74a3a2802f167e49f6d0affdb752d819a72ab2ac678e92b67ff2d1bdc553</citedby><cites>FETCH-LOGICAL-c380t-b625d74a3a2802f167e49f6d0affdb752d819a72ab2ac678e92b67ff2d1bdc553</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23541646$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kalani, Komal</creatorcontrib><creatorcontrib>Kushwaha, Vikas</creatorcontrib><creatorcontrib>Verma, Richa</creatorcontrib><creatorcontrib>Murthy, P. Kalpana</creatorcontrib><creatorcontrib>Srivastava, S.K.</creatorcontrib><title>Glycyrrhetinic acid and its analogs: A new class of antifilarial agents</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Although a number of chemicals have been isolated from Glycyrrhiza glabra, only a few have been evaluated for their biological significance. As part of our drug discovery program for antifilarial agents from Indian medicinal plants, the roots of G. glabra were chemically investigated, which resulted in the isolation and characterization of an antifilarial agent, glycyrrhetinic acid (GA, 1a) effective against microfilariae (mf) in vitro (LC100: 12.5μM; IC50: 1.20μM), but was inactive against adult worms. Further, GA (1a) was converted into six analogs (2a–7a) and their antifilarial potential was evaluated by studying in vitro motility and MTT reduction assays employing mf and adult worms of Brugia malayi. The results showed that out of six GA analogs, the benzyl amide analog (6a) killed adults and mf at 25 and 50μM concentration, respectively, and inhibited 49% MTT reduction potential of the adult parasites. The IC50 values were found to be 8.8 and 2.2μM for adults and mf, respectively. The SI of the compound was >60. On the other hand the octylamide analog (7a) required much higher concentration to adversely affect the parasites. Finally, both active amide analogs (6a and 7a) were in vivo evaluated using B. malayi-jird model, which showed that analog 6a possesses promising macrofilaricidal activity at 100mg/kg, s.c. ×5days and around 40% of the treated animals showed calcified masses of worm fragments in peritoneal cavity of the animals. To the best of our knowledge this is the first ever report on the antifilarial potential of GA analogs. Further work on optimization of the antifilarial lead is under progress.</description><subject>adults</subject><subject>Animals</subject><subject>Antifilarial activity</subject><subject>Brugia malayi</subject><subject>Brugia malayi - drug effects</subject><subject>chemistry</subject><subject>drugs</subject><subject>Female</subject><subject>Filaricides - chemistry</subject><subject>Filaricides - isolation & purification</subject><subject>Filaricides - pharmacology</subject><subject>Glycyrrhetinic Acid - analogs & derivatives</subject><subject>Glycyrrhetinic Acid - isolation & purification</subject><subject>Glycyrrhetinic Acid - pharmacology</subject><subject>Glycyrrhetinic acid-analogs</subject><subject>Glycyrrhiza - chemistry</subject><subject>Glycyrrhiza glabra</subject><subject>inhibitory concentration 50</subject><subject>medicinal plants</subject><subject>microfilariae</subject><subject>Microfilariae - drug effects</subject><subject>nematicides</subject><subject>parasites</subject><subject>Plant Roots - chemistry</subject><subject>roots</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNp9kE1LAzEQhoMotlb_gAfdo5ddk2w2uyteStEqFDxowVuYzUdNSXdrslX6701p9SgMDAzPvDM8CF0SnBFM-O0ya1bSZRSTPMM0I6Q4QkPCOEtzhotjNMQ1x2lVs_cBOgthiTFhmLFTNKB5wQhnfIimU7eVW-8_dG9bKxOQViXQqsT2IXZw3SLcJeOk1d-JdBBC0pk4762xDrwFl8BCt304RycGXNAXhz5C88eHt8lTOnuZPk_Gs1TmFe7ThtNClQxyoBWmhvBSs9pwhcEY1ZQFVRWpoaTQUJC8rHRNG14aQxVplCyKfIRu9rlr331udOjFygapnYNWd5sgSE7LMhahEaV7VPouBK-NWHu7Ar8VBIudQLEUO4FiJ1BgKqLAuHR1yN80K63-Vn6NReB6DxjoBCy8DWL-GhOKaDcnNdvdvd8TOnr4stqLIK1upVbWa9kL1dn_PvgBU5CKUg</recordid><startdate>20130501</startdate><enddate>20130501</enddate><creator>Kalani, Komal</creator><creator>Kushwaha, Vikas</creator><creator>Verma, Richa</creator><creator>Murthy, P. 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Kalpana ; Srivastava, S.K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c380t-b625d74a3a2802f167e49f6d0affdb752d819a72ab2ac678e92b67ff2d1bdc553</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>adults</topic><topic>Animals</topic><topic>Antifilarial activity</topic><topic>Brugia malayi</topic><topic>Brugia malayi - drug effects</topic><topic>chemistry</topic><topic>drugs</topic><topic>Female</topic><topic>Filaricides - chemistry</topic><topic>Filaricides - isolation & purification</topic><topic>Filaricides - pharmacology</topic><topic>Glycyrrhetinic Acid - analogs & derivatives</topic><topic>Glycyrrhetinic Acid - isolation & purification</topic><topic>Glycyrrhetinic Acid - pharmacology</topic><topic>Glycyrrhetinic acid-analogs</topic><topic>Glycyrrhiza - chemistry</topic><topic>Glycyrrhiza glabra</topic><topic>inhibitory concentration 50</topic><topic>medicinal plants</topic><topic>microfilariae</topic><topic>Microfilariae - drug effects</topic><topic>nematicides</topic><topic>parasites</topic><topic>Plant Roots - chemistry</topic><topic>roots</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kalani, Komal</creatorcontrib><creatorcontrib>Kushwaha, Vikas</creatorcontrib><creatorcontrib>Verma, Richa</creatorcontrib><creatorcontrib>Murthy, P. 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Kalpana</au><au>Srivastava, S.K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Glycyrrhetinic acid and its analogs: A new class of antifilarial agents</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2013-05-01</date><risdate>2013</risdate><volume>23</volume><issue>9</issue><spage>2566</spage><epage>2570</epage><pages>2566-2570</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><notes>http://dx.doi.org/10.1016/j.bmcl.2013.02.115</notes><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Although a number of chemicals have been isolated from Glycyrrhiza glabra, only a few have been evaluated for their biological significance. As part of our drug discovery program for antifilarial agents from Indian medicinal plants, the roots of G. glabra were chemically investigated, which resulted in the isolation and characterization of an antifilarial agent, glycyrrhetinic acid (GA, 1a) effective against microfilariae (mf) in vitro (LC100: 12.5μM; IC50: 1.20μM), but was inactive against adult worms. Further, GA (1a) was converted into six analogs (2a–7a) and their antifilarial potential was evaluated by studying in vitro motility and MTT reduction assays employing mf and adult worms of Brugia malayi. The results showed that out of six GA analogs, the benzyl amide analog (6a) killed adults and mf at 25 and 50μM concentration, respectively, and inhibited 49% MTT reduction potential of the adult parasites. The IC50 values were found to be 8.8 and 2.2μM for adults and mf, respectively. The SI of the compound was >60. On the other hand the octylamide analog (7a) required much higher concentration to adversely affect the parasites. Finally, both active amide analogs (6a and 7a) were in vivo evaluated using B. malayi-jird model, which showed that analog 6a possesses promising macrofilaricidal activity at 100mg/kg, s.c. ×5days and around 40% of the treated animals showed calcified masses of worm fragments in peritoneal cavity of the animals. To the best of our knowledge this is the first ever report on the antifilarial potential of GA analogs. Further work on optimization of the antifilarial lead is under progress.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>23541646</pmid><doi>10.1016/j.bmcl.2013.02.115</doi><tpages>5</tpages></addata></record> |
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| subjects | adults Animals Antifilarial activity Brugia malayi Brugia malayi - drug effects chemistry drugs Female Filaricides - chemistry Filaricides - isolation & purification Filaricides - pharmacology Glycyrrhetinic Acid - analogs & derivatives Glycyrrhetinic Acid - isolation & purification Glycyrrhetinic Acid - pharmacology Glycyrrhetinic acid-analogs Glycyrrhiza - chemistry Glycyrrhiza glabra inhibitory concentration 50 medicinal plants microfilariae Microfilariae - drug effects nematicides parasites Plant Roots - chemistry roots |
| title | Glycyrrhetinic acid and its analogs: A new class of antifilarial agents |
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