Structure-based drug design and characterization of novel pyrazine hydrazinylidene derivatives with a benzenesulfonate scaffold as noncovalent inhibitors of DprE1 tor tuberculosis treatment
In this study, we present a novel series of ( E )-4-((2-(pyrazine-2-carbonyl) hydrazineylidene)methyl)phenyl benzenesulfonate (T1-T8) and 4-(( E )-((( Z )-amino(pyrazin-2-yl)methylene)hydrazineylidene)methyl)phenyl benzenesulfonate (T9-T16) derivatives which exert their inhibitory effects on decapre...
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| Veröffentlicht in: | Molecular diversity 2024-12, Vol.28 (6), p.4221-4239 |
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| creator | Shivakumar Dinesha, P. Udayakumar, D. |
| description | In this study, we present a novel series of (
E
)-4-((2-(pyrazine-2-carbonyl) hydrazineylidene)methyl)phenyl benzenesulfonate (T1-T8) and 4-((
E
)-(((
Z
)-amino(pyrazin-2-yl)methylene)hydrazineylidene)methyl)phenyl benzenesulfonate (T9-T16) derivatives which exert their inhibitory effects on decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) through the formation of hydrogen bonds with the pivotal active site Cys387 residue. Their effectiveness against the
M. tuberculosis
H37Rv strain was examined and notably, three compounds (namely T4, T7, and T12) exhibited promising antitubercular activity, with a minimum inhibitory concentration (MIC) of 1.56 µg/mL. The target compounds were screened for their antibacterial activity against a range of bacterial strains, encompassing
S. aureus
,
B. subtilis
,
S. mutans
,
E. coli
,
S. typhi
, and
K. pneumoniae
. Additionally, their antifungal efficacy against
A. fumigatus
and
A. niger
also was scrutinized. Compounds T6 and T12 demonstrated significant antibacterial activity, while compound T6 exhibited substantial antifungal activity. Importantly, all of these active compounds demonstrated exceedingly low toxicity without any adverse effects on normal cells. To deepen our understanding of these compounds, we have undertaken an in silico analysis encompassing Absorption, Distribution, Metabolism, and Excretion (ADME) considerations. Furthermore, molecular docking analyses against the DprE1 enzyme was conducted and Density-Functional Theory (DFT) studies were employed to elucidate the electronic properties of the compounds, thereby enhancing our understanding of their pharmacological potential.
Graphical abstract |
| doi_str_mv | 10.1007/s11030-024-10812-0 |
| format | Article |
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E
)-4-((2-(pyrazine-2-carbonyl) hydrazineylidene)methyl)phenyl benzenesulfonate (T1-T8) and 4-((
E
)-(((
Z
)-amino(pyrazin-2-yl)methylene)hydrazineylidene)methyl)phenyl benzenesulfonate (T9-T16) derivatives which exert their inhibitory effects on decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) through the formation of hydrogen bonds with the pivotal active site Cys387 residue. Their effectiveness against the
M. tuberculosis
H37Rv strain was examined and notably, three compounds (namely T4, T7, and T12) exhibited promising antitubercular activity, with a minimum inhibitory concentration (MIC) of 1.56 µg/mL. The target compounds were screened for their antibacterial activity against a range of bacterial strains, encompassing
S. aureus
,
B. subtilis
,
S. mutans
,
E. coli
,
S. typhi
, and
K. pneumoniae
. Additionally, their antifungal efficacy against
A. fumigatus
and
A. niger
also was scrutinized. Compounds T6 and T12 demonstrated significant antibacterial activity, while compound T6 exhibited substantial antifungal activity. Importantly, all of these active compounds demonstrated exceedingly low toxicity without any adverse effects on normal cells. To deepen our understanding of these compounds, we have undertaken an in silico analysis encompassing Absorption, Distribution, Metabolism, and Excretion (ADME) considerations. Furthermore, molecular docking analyses against the DprE1 enzyme was conducted and Density-Functional Theory (DFT) studies were employed to elucidate the electronic properties of the compounds, thereby enhancing our understanding of their pharmacological potential.
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E
)-4-((2-(pyrazine-2-carbonyl) hydrazineylidene)methyl)phenyl benzenesulfonate (T1-T8) and 4-((
E
)-(((
Z
)-amino(pyrazin-2-yl)methylene)hydrazineylidene)methyl)phenyl benzenesulfonate (T9-T16) derivatives which exert their inhibitory effects on decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) through the formation of hydrogen bonds with the pivotal active site Cys387 residue. Their effectiveness against the
M. tuberculosis
H37Rv strain was examined and notably, three compounds (namely T4, T7, and T12) exhibited promising antitubercular activity, with a minimum inhibitory concentration (MIC) of 1.56 µg/mL. The target compounds were screened for their antibacterial activity against a range of bacterial strains, encompassing
S. aureus
,
B. subtilis
,
S. mutans
,
E. coli
,
S. typhi
, and
K. pneumoniae
. Additionally, their antifungal efficacy against
A. fumigatus
and
A. niger
also was scrutinized. Compounds T6 and T12 demonstrated significant antibacterial activity, while compound T6 exhibited substantial antifungal activity. Importantly, all of these active compounds demonstrated exceedingly low toxicity without any adverse effects on normal cells. To deepen our understanding of these compounds, we have undertaken an in silico analysis encompassing Absorption, Distribution, Metabolism, and Excretion (ADME) considerations. Furthermore, molecular docking analyses against the DprE1 enzyme was conducted and Density-Functional Theory (DFT) studies were employed to elucidate the electronic properties of the compounds, thereby enhancing our understanding of their pharmacological potential.
Graphical abstract</description><subject>Alcohol Oxidoreductases</subject><subject>Antitubercular Agents - chemistry</subject><subject>Antitubercular Agents - pharmacology</subject><subject>Bacterial Proteins - antagonists & inhibitors</subject><subject>Bacterial Proteins - chemistry</subject><subject>Benzenesulfonates</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Drug Design</subject><subject>Life Sciences</subject><subject>Microbial Sensitivity Tests</subject><subject>Molecular Docking Simulation</subject><subject>Mycobacterium tuberculosis - drug effects</subject><subject>Mycobacterium tuberculosis - enzymology</subject><subject>Organic Chemistry</subject><subject>Original Article</subject><subject>Pharmacy</subject><subject>Polymer Sciences</subject><subject>Pyrazines - chemistry</subject><subject>Pyrazines - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Tuberculosis</subject><subject>Tuberculosis - drug therapy</subject><issn>1381-1991</issn><issn>1573-501X</issn><issn>1573-501X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kctuFDEQRVsIRELgB1ggS2zYNLhsj7t7iZLwkCKxACR2lh_VGUc99uDHoJl_499wMgEkFqyqSnXurZJu1z0H-hooHd5kAMppT5nogY7AevqgO4XVwPsVhW8PW89H6GGa4KR7kvMNpU0G_HF3wkchxgGm0-7n55KqLTVhb3RGR1yq18Rh9teB6OCIXeukbcHkD7r4GEicSYg7XMh2n_TBByTrvbvr9ot32GbX4F2Dd5jJD1_WRBOD4dBWuS5zDLogyVbPc1wc0bnZBRt3esFQiA9rb3yJKd8eutimSyBtIqUaTLYuMftMSkJdNg1_2j2a9ZLx2X09676-u_xy_qG_-vT-4_nbq95yJksvpGGMo3BaaznYyYFjAIMcjWDcjIOwwoHkowSB02QMUDYIKXEEK5BOEz_rXh19tyl-r5iL2vhscVl0wFizYpNgMK4krBr68h_0JtYU2neKgxgaKQfRKHakbIo5J5zVNvmNTnsFVN2Gq47hqhauugtX0SZ6cW9dzQbdH8nvNBvAj0Buq3CN6e_t_9j-AjustC0</recordid><startdate>20241201</startdate><enddate>20241201</enddate><creator>Shivakumar</creator><creator>Dinesha, P.</creator><creator>Udayakumar, D.</creator><general>Springer International Publishing</general><general>Springer Nature B.V</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>K9.</scope><scope>7X8</scope></search><sort><creationdate>20241201</creationdate><title>Structure-based drug design and characterization of novel pyrazine hydrazinylidene derivatives with a benzenesulfonate scaffold as noncovalent inhibitors of DprE1 tor tuberculosis treatment</title><author>Shivakumar ; Dinesha, P. ; Udayakumar, D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c326t-46b223e4daaa67c9d1d211768b423b874c4d1638614e99bb1027466e81c4e0993</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Alcohol Oxidoreductases</topic><topic>Antitubercular Agents - chemistry</topic><topic>Antitubercular Agents - pharmacology</topic><topic>Bacterial Proteins - antagonists & inhibitors</topic><topic>Bacterial Proteins - chemistry</topic><topic>Benzenesulfonates</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Drug Design</topic><topic>Life Sciences</topic><topic>Microbial Sensitivity Tests</topic><topic>Molecular Docking Simulation</topic><topic>Mycobacterium tuberculosis - drug effects</topic><topic>Mycobacterium tuberculosis - enzymology</topic><topic>Organic Chemistry</topic><topic>Original Article</topic><topic>Pharmacy</topic><topic>Polymer Sciences</topic><topic>Pyrazines - chemistry</topic><topic>Pyrazines - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Tuberculosis</topic><topic>Tuberculosis - drug therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shivakumar</creatorcontrib><creatorcontrib>Dinesha, P.</creatorcontrib><creatorcontrib>Udayakumar, D.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular diversity</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shivakumar</au><au>Dinesha, P.</au><au>Udayakumar, D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-based drug design and characterization of novel pyrazine hydrazinylidene derivatives with a benzenesulfonate scaffold as noncovalent inhibitors of DprE1 tor tuberculosis treatment</atitle><jtitle>Molecular diversity</jtitle><stitle>Mol Divers</stitle><addtitle>Mol Divers</addtitle><date>2024-12-01</date><risdate>2024</risdate><volume>28</volume><issue>6</issue><spage>4221</spage><epage>4239</epage><pages>4221-4239</pages><issn>1381-1991</issn><issn>1573-501X</issn><eissn>1573-501X</eissn><abstract>In this study, we present a novel series of (
E
)-4-((2-(pyrazine-2-carbonyl) hydrazineylidene)methyl)phenyl benzenesulfonate (T1-T8) and 4-((
E
)-(((
Z
)-amino(pyrazin-2-yl)methylene)hydrazineylidene)methyl)phenyl benzenesulfonate (T9-T16) derivatives which exert their inhibitory effects on decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) through the formation of hydrogen bonds with the pivotal active site Cys387 residue. Their effectiveness against the
M. tuberculosis
H37Rv strain was examined and notably, three compounds (namely T4, T7, and T12) exhibited promising antitubercular activity, with a minimum inhibitory concentration (MIC) of 1.56 µg/mL. The target compounds were screened for their antibacterial activity against a range of bacterial strains, encompassing
S. aureus
,
B. subtilis
,
S. mutans
,
E. coli
,
S. typhi
, and
K. pneumoniae
. Additionally, their antifungal efficacy against
A. fumigatus
and
A. niger
also was scrutinized. Compounds T6 and T12 demonstrated significant antibacterial activity, while compound T6 exhibited substantial antifungal activity. Importantly, all of these active compounds demonstrated exceedingly low toxicity without any adverse effects on normal cells. To deepen our understanding of these compounds, we have undertaken an in silico analysis encompassing Absorption, Distribution, Metabolism, and Excretion (ADME) considerations. Furthermore, molecular docking analyses against the DprE1 enzyme was conducted and Density-Functional Theory (DFT) studies were employed to elucidate the electronic properties of the compounds, thereby enhancing our understanding of their pharmacological potential.
Graphical abstract</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>38448719</pmid><doi>10.1007/s11030-024-10812-0</doi><tpages>19</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1381-1991 |
| ispartof | Molecular diversity, 2024-12, Vol.28 (6), p.4221-4239 |
| issn | 1381-1991 1573-501X 1573-501X |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2942185615 |
| source | MEDLINE; Springer Online Journals |
| subjects | Alcohol Oxidoreductases Antitubercular Agents - chemistry Antitubercular Agents - pharmacology Bacterial Proteins - antagonists & inhibitors Bacterial Proteins - chemistry Benzenesulfonates Biochemistry Biomedical and Life Sciences Drug Design Life Sciences Microbial Sensitivity Tests Molecular Docking Simulation Mycobacterium tuberculosis - drug effects Mycobacterium tuberculosis - enzymology Organic Chemistry Original Article Pharmacy Polymer Sciences Pyrazines - chemistry Pyrazines - pharmacology Structure-Activity Relationship Tuberculosis Tuberculosis - drug therapy |
| title | Structure-based drug design and characterization of novel pyrazine hydrazinylidene derivatives with a benzenesulfonate scaffold as noncovalent inhibitors of DprE1 tor tuberculosis treatment |
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