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Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors - design, synthesis, biological evaluation and molecular modelling
Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against h MAO-A...
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| Published in: | MedChemComm 2020-09, Vol.11 (9), p.163-174 |
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| Main Authors: | , , , , , , |
| Format: | Article |
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| cites | cdi_FETCH-LOGICAL-c454t-83eb5e1b7a1e83031be76c6541518c07f8a38e6fc0814a1b10eae3ca72060cc93 |
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| creator | Sa l k, Begüm Nurpelin Kaya Çavu o lu, Betül Acar Çevik, Ulviye Osmaniye, Derya Levent, Serkan Özkay, Yusuf Kaplanc kl, Zafer As m |
| description | Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against
h
MAO-A than
h
MAO-B. The half maximal inhibitory concentration (IC
50
) values of most of the compounds were lower than that of the common drug moclobemide (IC
50
= 4.664 μM) and compound
6b
was proven to be the most active compound (IC
50
= 0.060 μM). Moreover, it was seen that compound
6b
showed a similar inhibition profile to that of clorgyline (IC
50
= 0.048 μM). The inhibition profile was found to be reversible and competitive for compound
6b
with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound
6b
and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.
Compound
6b
is a reversible and competitive
h
MAO-A inhibitor. |
| doi_str_mv | 10.1039/d0md00150c |
| format | article |
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h
MAO-A than
h
MAO-B. The half maximal inhibitory concentration (IC
50
) values of most of the compounds were lower than that of the common drug moclobemide (IC
50
= 4.664 μM) and compound
6b
was proven to be the most active compound (IC
50
= 0.060 μM). Moreover, it was seen that compound
6b
showed a similar inhibition profile to that of clorgyline (IC
50
= 0.048 μM). The inhibition profile was found to be reversible and competitive for compound
6b
with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound
6b
and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.
Compound
6b
is a reversible and competitive
h
MAO-A inhibitor.</description><identifier>ISSN: 2632-8682</identifier><identifier>ISSN: 2040-2503</identifier><identifier>EISSN: 2632-8682</identifier><identifier>EISSN: 2040-2511</identifier><identifier>DOI: 10.1039/d0md00150c</identifier><identifier>PMID: 33479699</identifier><language>eng</language><publisher>England: Royal Society of Chemistry</publisher><subject>Amine oxidase (flavin-containing) ; Amines ; Chemical synthesis ; Chemistry ; Inhibitors ; Modelling ; Molecular modelling ; Neurological diseases ; Organic compounds ; Pharmacokinetics ; Selectivity ; Therapeutic targets ; Thiadiazoles</subject><ispartof>MedChemComm, 2020-09, Vol.11 (9), p.163-174</ispartof><rights>This journal is © The Royal Society of Chemistry 2020.</rights><rights>Copyright Royal Society of Chemistry 2020</rights><rights>This journal is © The Royal Society of Chemistry 2020 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c454t-83eb5e1b7a1e83031be76c6541518c07f8a38e6fc0814a1b10eae3ca72060cc93</citedby><cites>FETCH-LOGICAL-c454t-83eb5e1b7a1e83031be76c6541518c07f8a38e6fc0814a1b10eae3ca72060cc93</cites><orcidid>0000-0003-1879-1034 ; 0000-0003-2252-0923 ; 0000-0003-3692-163X ; 0000-0001-8270-4949 ; 0000-0001-8815-153X ; 0000-0002-0499-436X ; 0000-0002-0151-6266</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513386/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513386/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27922,27923,53789,53791</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33479699$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sa l k, Begüm Nurpelin</creatorcontrib><creatorcontrib>Kaya Çavu o lu, Betül</creatorcontrib><creatorcontrib>Acar Çevik, Ulviye</creatorcontrib><creatorcontrib>Osmaniye, Derya</creatorcontrib><creatorcontrib>Levent, Serkan</creatorcontrib><creatorcontrib>Özkay, Yusuf</creatorcontrib><creatorcontrib>Kaplanc kl, Zafer As m</creatorcontrib><title>Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors - design, synthesis, biological evaluation and molecular modelling</title><title>MedChemComm</title><addtitle>RSC Med Chem</addtitle><description>Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against
h
MAO-A than
h
MAO-B. The half maximal inhibitory concentration (IC
50
) values of most of the compounds were lower than that of the common drug moclobemide (IC
50
= 4.664 μM) and compound
6b
was proven to be the most active compound (IC
50
= 0.060 μM). Moreover, it was seen that compound
6b
showed a similar inhibition profile to that of clorgyline (IC
50
= 0.048 μM). The inhibition profile was found to be reversible and competitive for compound
6b
with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound
6b
and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.
Compound
6b
is a reversible and competitive
h
MAO-A inhibitor.</description><subject>Amine oxidase (flavin-containing)</subject><subject>Amines</subject><subject>Chemical synthesis</subject><subject>Chemistry</subject><subject>Inhibitors</subject><subject>Modelling</subject><subject>Molecular modelling</subject><subject>Neurological diseases</subject><subject>Organic compounds</subject><subject>Pharmacokinetics</subject><subject>Selectivity</subject><subject>Therapeutic targets</subject><subject>Thiadiazoles</subject><issn>2632-8682</issn><issn>2040-2503</issn><issn>2632-8682</issn><issn>2040-2511</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9ks1v1DAQxS0EotXSC3eQEReENjCOE8e5IK22fEktvcDZcmxn15Vjp3ayUjn2L6_LlqVw4OQnzc9P8_QGoecE3hGg7XsNgwYgNahH6LhktCw44-XjB_oInaR0CQBlTQir26foiNKqaVnbHqObb2FnHCZLuqyKaWultvJncAarMIxh9jphmfAYJuMnKx0-X10UK2z91nZ2CjHhAmuT7MYvcbr20zbrtMSdDS5srMofzE66WU42eCy9xkP2VrOTMSttnLN-8ww96aVL5uT-XaAfnz5-X38pzi4-f12vzgpV1dVUcGq62pCukcRwCpR0pmGK1RWpCVfQ9FxSblivgJNKko6AkYYq2ZTAQKmWLtCHve84d4PRKieK0okx2kHGaxGkFX9PvN2KTdiJpiaUcpYN3twbxHA1mzSJwSaVQ0hvwpxEWXEoGYfcywK9_ge9DHP0OV6mqoozaPkd9XZPqRhSiqY_LENA3LUrTuH89Fe76wy_fLj-Af3dZQZe7YGY1GH65zzEqPvMvPgfQ28BRBq1tA</recordid><startdate>20200901</startdate><enddate>20200901</enddate><creator>Sa l k, Begüm Nurpelin</creator><creator>Kaya Çavu o lu, Betül</creator><creator>Acar Çevik, Ulviye</creator><creator>Osmaniye, Derya</creator><creator>Levent, Serkan</creator><creator>Özkay, Yusuf</creator><creator>Kaplanc kl, Zafer As m</creator><general>Royal Society of Chemistry</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QO</scope><scope>7T5</scope><scope>7T7</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1879-1034</orcidid><orcidid>https://orcid.org/0000-0003-2252-0923</orcidid><orcidid>https://orcid.org/0000-0003-3692-163X</orcidid><orcidid>https://orcid.org/0000-0001-8270-4949</orcidid><orcidid>https://orcid.org/0000-0001-8815-153X</orcidid><orcidid>https://orcid.org/0000-0002-0499-436X</orcidid><orcidid>https://orcid.org/0000-0002-0151-6266</orcidid></search><sort><creationdate>20200901</creationdate><title>Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors - design, synthesis, biological evaluation and molecular modelling</title><author>Sa l k, Begüm Nurpelin ; Kaya Çavu o lu, Betül ; Acar Çevik, Ulviye ; Osmaniye, Derya ; Levent, Serkan ; Özkay, Yusuf ; Kaplanc kl, Zafer As m</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c454t-83eb5e1b7a1e83031be76c6541518c07f8a38e6fc0814a1b10eae3ca72060cc93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Amine oxidase (flavin-containing)</topic><topic>Amines</topic><topic>Chemical synthesis</topic><topic>Chemistry</topic><topic>Inhibitors</topic><topic>Modelling</topic><topic>Molecular modelling</topic><topic>Neurological diseases</topic><topic>Organic compounds</topic><topic>Pharmacokinetics</topic><topic>Selectivity</topic><topic>Therapeutic targets</topic><topic>Thiadiazoles</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sa l k, Begüm Nurpelin</creatorcontrib><creatorcontrib>Kaya Çavu o lu, Betül</creatorcontrib><creatorcontrib>Acar Çevik, Ulviye</creatorcontrib><creatorcontrib>Osmaniye, Derya</creatorcontrib><creatorcontrib>Levent, Serkan</creatorcontrib><creatorcontrib>Özkay, Yusuf</creatorcontrib><creatorcontrib>Kaplanc kl, Zafer As m</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>MedChemComm</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sa l k, Begüm Nurpelin</au><au>Kaya Çavu o lu, Betül</au><au>Acar Çevik, Ulviye</au><au>Osmaniye, Derya</au><au>Levent, Serkan</au><au>Özkay, Yusuf</au><au>Kaplanc kl, Zafer As m</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors - design, synthesis, biological evaluation and molecular modelling</atitle><jtitle>MedChemComm</jtitle><addtitle>RSC Med Chem</addtitle><date>2020-09-01</date><risdate>2020</risdate><volume>11</volume><issue>9</issue><spage>163</spage><epage>174</epage><pages>163-174</pages><issn>2632-8682</issn><issn>2040-2503</issn><eissn>2632-8682</eissn><eissn>2040-2511</eissn><abstract>Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against
h
MAO-A than
h
MAO-B. The half maximal inhibitory concentration (IC
50
) values of most of the compounds were lower than that of the common drug moclobemide (IC
50
= 4.664 μM) and compound
6b
was proven to be the most active compound (IC
50
= 0.060 μM). Moreover, it was seen that compound
6b
showed a similar inhibition profile to that of clorgyline (IC
50
= 0.048 μM). The inhibition profile was found to be reversible and competitive for compound
6b
with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound
6b
and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.
Compound
6b
is a reversible and competitive
h
MAO-A inhibitor.</abstract><cop>England</cop><pub>Royal Society of Chemistry</pub><pmid>33479699</pmid><doi>10.1039/d0md00150c</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-1879-1034</orcidid><orcidid>https://orcid.org/0000-0003-2252-0923</orcidid><orcidid>https://orcid.org/0000-0003-3692-163X</orcidid><orcidid>https://orcid.org/0000-0001-8270-4949</orcidid><orcidid>https://orcid.org/0000-0001-8815-153X</orcidid><orcidid>https://orcid.org/0000-0002-0499-436X</orcidid><orcidid>https://orcid.org/0000-0002-0151-6266</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | MedChemComm, 2020-09, Vol.11 (9), p.163-174 |
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| language | eng |
| recordid | cdi_pubmed_primary_33479699 |
| source | Open Access: PubMed Central; Royal Society of Chemistry |
| subjects | Amine oxidase (flavin-containing) Amines Chemical synthesis Chemistry Inhibitors Modelling Molecular modelling Neurological diseases Organic compounds Pharmacokinetics Selectivity Therapeutic targets Thiadiazoles |
| title | Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors - design, synthesis, biological evaluation and molecular modelling |
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