Design, synthesis, SAR and ADMET analyses of the novel class of synthetic 7-amino[1,2,5]oxadiazolo[3,4-b]pyridine-6-carboxylate derivatives with vasorelaxant activity
A twenty six 7-amino[1,2,5]oxadiazolo[3,4-b]pyridine-6-carboxylate (7-aminofurazano[3,4-b]pyridine-6-carboxylate) derivatives have been synthesized and characterized by IR, 1H NMR, 13C NMR spectroscopy, elemental analysis and LC-MS. The potential vasodilator activity of the synthesized compounds was...
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Elsevier
2025-01-01
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| Series: | Results in Chemistry |
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| author | Anatolii Varenyk Roman Vydzhak Svitlana Panchishin Irina Ivanova Victor Zhirnov Volodymyr Brovarets |
| author_facet | Anatolii Varenyk Roman Vydzhak Svitlana Panchishin Irina Ivanova Victor Zhirnov Volodymyr Brovarets |
| author_sort | Anatolii Varenyk |
| collection | DOAJ |
| description | A twenty six 7-amino[1,2,5]oxadiazolo[3,4-b]pyridine-6-carboxylate (7-aminofurazano[3,4-b]pyridine-6-carboxylate) derivatives have been synthesized and characterized by IR, 1H NMR, 13C NMR spectroscopy, elemental analysis and LC-MS. The potential vasodilator activity of the synthesized compounds was assessed for their ability to induce relaxation of phenylephrine-precontracted isolated rat aortic segments. Eight derivatives showed high vasorelaxant activity, ranging from 73.7 to 87.3 %. Six samples contained an ethyl carboxylate moiety at the 6th position and alkyl or cycloalkyl substituents at the 5th position. Moreover, in the series of compounds with n-alkyl and cycloalkyl substituents, the derivative activity decreased linearly as the number of carbon atoms diminished. ADMET analysis showed that the highly active derivatives met the requirements for drug candidates regarding bioavailability, physicochemical and pharmacokinetic properties. These compounds are also approved by all the filters used, such as druglikeness and leadlikeness. The only problematic property of these highly active vasorelaxants is their in silico predicted very high carcinogenicity, which may be incompatible with their long-term use. Seven derivatives exhibited high virtual similarity to acetylcholinesterase inhibitors, with scores in the range of 0.857 to 0.932. This suggests that they may increase acetylcholine levels, thereby reducing vascular tone. However, this requires experimental confirmation. It should be noted that some 7-aminofurazano[3,4-b]pyridine-6-carboxylate analogs showed a high similarity to inhibitors of adenosine receptors, the non-receptor protein tyrosine kinases JAK2 and JAK3, glycogen synthase kinase-3 beta, prostaglandin E synthase and arachidonate 5-lipoxygenase, providing a basis for direct virtual assessment of their interaction with these targets. The results obtained highlight the considerable potential for further development of this class of compounds as vasoactive agents. |
| format | Article |
| id | doaj-art-125a6932894746cf88408ff145e1208a |
| institution | Kabale University |
| issn | 2211-7156 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
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| series | Results in Chemistry |
| spelling | doaj-art-125a6932894746cf88408ff145e1208a2025-01-29T05:01:02ZengElsevierResults in Chemistry2211-71562025-01-0113102031Design, synthesis, SAR and ADMET analyses of the novel class of synthetic 7-amino[1,2,5]oxadiazolo[3,4-b]pyridine-6-carboxylate derivatives with vasorelaxant activityAnatolii Varenyk0Roman Vydzhak1Svitlana Panchishin2Irina Ivanova3Victor Zhirnov4Volodymyr Brovarets5Department of Chemistry of Bioactive Nitrogen-Containing Heterocyclic Bases, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, 1, Academician Kukhar Str, Kyiv 02094 UkraineDepartment of Chemistry of Bioactive Nitrogen-Containing Heterocyclic Bases, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, 1, Academician Kukhar Str, Kyiv 02094 Ukraine; Corresponding author.Department of Chemistry of Bioactive Nitrogen-Containing Heterocyclic Bases, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, 1, Academician Kukhar Str, Kyiv 02094 UkraineDepartment of Chemistry of Bioactive Nitrogen-Containing Heterocyclic Bases, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, 1, Academician Kukhar Str, Kyiv 02094 Ukraine; Department for Pharmacology of Cellular Signaling Systems and Experimental Therapeutics, SI Institute of Pharmacology and Toxicology of the National Academy of Medical Sciences of Ukraine, 14, Antona Tsedika Str, Kyiv 03057 UkraineDepartment of Chemistry of Bioactive Nitrogen-Containing Heterocyclic Bases, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, 1, Academician Kukhar Str, Kyiv 02094 UkraineDepartment of Chemistry of Bioactive Nitrogen-Containing Heterocyclic Bases, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, 1, Academician Kukhar Str, Kyiv 02094 UkraineA twenty six 7-amino[1,2,5]oxadiazolo[3,4-b]pyridine-6-carboxylate (7-aminofurazano[3,4-b]pyridine-6-carboxylate) derivatives have been synthesized and characterized by IR, 1H NMR, 13C NMR spectroscopy, elemental analysis and LC-MS. The potential vasodilator activity of the synthesized compounds was assessed for their ability to induce relaxation of phenylephrine-precontracted isolated rat aortic segments. Eight derivatives showed high vasorelaxant activity, ranging from 73.7 to 87.3 %. Six samples contained an ethyl carboxylate moiety at the 6th position and alkyl or cycloalkyl substituents at the 5th position. Moreover, in the series of compounds with n-alkyl and cycloalkyl substituents, the derivative activity decreased linearly as the number of carbon atoms diminished. ADMET analysis showed that the highly active derivatives met the requirements for drug candidates regarding bioavailability, physicochemical and pharmacokinetic properties. These compounds are also approved by all the filters used, such as druglikeness and leadlikeness. The only problematic property of these highly active vasorelaxants is their in silico predicted very high carcinogenicity, which may be incompatible with their long-term use. Seven derivatives exhibited high virtual similarity to acetylcholinesterase inhibitors, with scores in the range of 0.857 to 0.932. This suggests that they may increase acetylcholine levels, thereby reducing vascular tone. However, this requires experimental confirmation. It should be noted that some 7-aminofurazano[3,4-b]pyridine-6-carboxylate analogs showed a high similarity to inhibitors of adenosine receptors, the non-receptor protein tyrosine kinases JAK2 and JAK3, glycogen synthase kinase-3 beta, prostaglandin E synthase and arachidonate 5-lipoxygenase, providing a basis for direct virtual assessment of their interaction with these targets. The results obtained highlight the considerable potential for further development of this class of compounds as vasoactive agents.http://www.sciencedirect.com/science/article/pii/S2211715625000141Furazano[3, 4-b]pyridine[1, 2, 5]Oxadiazolo[3, 4-b]pyridineNickel complexes of 1, 3-dicarbonyl compoundsVasorelaxant activitySAR analysisADMET analysis |
| spellingShingle | Anatolii Varenyk Roman Vydzhak Svitlana Panchishin Irina Ivanova Victor Zhirnov Volodymyr Brovarets Design, synthesis, SAR and ADMET analyses of the novel class of synthetic 7-amino[1,2,5]oxadiazolo[3,4-b]pyridine-6-carboxylate derivatives with vasorelaxant activity Results in Chemistry Furazano[3, 4-b]pyridine [1, 2, 5]Oxadiazolo[3, 4-b]pyridine Nickel complexes of 1, 3-dicarbonyl compounds Vasorelaxant activity SAR analysis ADMET analysis |
| title | Design, synthesis, SAR and ADMET analyses of the novel class of synthetic 7-amino[1,2,5]oxadiazolo[3,4-b]pyridine-6-carboxylate derivatives with vasorelaxant activity |
| title_full | Design, synthesis, SAR and ADMET analyses of the novel class of synthetic 7-amino[1,2,5]oxadiazolo[3,4-b]pyridine-6-carboxylate derivatives with vasorelaxant activity |
| title_fullStr | Design, synthesis, SAR and ADMET analyses of the novel class of synthetic 7-amino[1,2,5]oxadiazolo[3,4-b]pyridine-6-carboxylate derivatives with vasorelaxant activity |
| title_full_unstemmed | Design, synthesis, SAR and ADMET analyses of the novel class of synthetic 7-amino[1,2,5]oxadiazolo[3,4-b]pyridine-6-carboxylate derivatives with vasorelaxant activity |
| title_short | Design, synthesis, SAR and ADMET analyses of the novel class of synthetic 7-amino[1,2,5]oxadiazolo[3,4-b]pyridine-6-carboxylate derivatives with vasorelaxant activity |
| title_sort | design synthesis sar and admet analyses of the novel class of synthetic 7 amino 1 2 5 oxadiazolo 3 4 b pyridine 6 carboxylate derivatives with vasorelaxant activity |
| topic | Furazano[3, 4-b]pyridine [1, 2, 5]Oxadiazolo[3, 4-b]pyridine Nickel complexes of 1, 3-dicarbonyl compounds Vasorelaxant activity SAR analysis ADMET analysis |
| url | http://www.sciencedirect.com/science/article/pii/S2211715625000141 |
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