Novel Quinoline- and Naphthalene-Incorporated Hydrazineylidene–Propenamide Analogues as Antidiabetic Agents: Design, Synthesis, and Computational Studies
<b>Background:</b> Type 2 diabetes has become a significant global health challenge. Numerous drugs have been developed to treat the condition, either as standalone therapies or in combination when glycemic control cannot be achieved with a single medication. As existing treatments often...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-12-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/17/12/1692 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850037377208156160 |
|---|---|
| author | Osama Alharbi Wael H. Alsaedi Mosa Alsehli Saif H. Althagafi Hussam Y. Alharbi Yazeed M. Asiri Ramith Ramu Mohammed Al-Ghorbani |
| author_facet | Osama Alharbi Wael H. Alsaedi Mosa Alsehli Saif H. Althagafi Hussam Y. Alharbi Yazeed M. Asiri Ramith Ramu Mohammed Al-Ghorbani |
| author_sort | Osama Alharbi |
| collection | DOAJ |
| description | <b>Background:</b> Type 2 diabetes has become a significant global health challenge. Numerous drugs have been developed to treat the condition, either as standalone therapies or in combination when glycemic control cannot be achieved with a single medication. As existing treatments often come with limitations, there is an increasing focus on creating novel therapeutic agents that offer greater efficacy and fewer side effects to better address this widespread issue. <b>Methods</b>: The methylene derivatives <b>3a</b>,<b>b</b> were coupled with phenyl/ethyl isothiocyanate in the basic medium, and dimethyl sulfate was subsequently added. Further, <b>5a</b>–<b>d</b> were reacted with the quinoline/naphthalene hydrazides <b>6a</b>,<b>b</b>. The target compounds <b>7a</b>–<b>g</b> were subjected to the in vitro enzyme inhibition studies on α-glucosidase, α-amylase, and aldose reductase. <b>Results</b>: <b>7g</b> exerted remarkable inhibitory effects on α-glycosidase [Inhibitory Concentration (IC<sub>50</sub>): 20.23 ± 1.10 µg/mL] and α-amylase (17.15 ± 0.30 µg/mL), outperforming acarbose (28.12 ± 0.20 µg/mL for α-glycosidase and 25.42 ± 0.10 µg/mL for α-amylase), and exhibited a strong inhibition action on aldose reductase (12.15 ± 0.24 µg/mL), surpassing quercetin (15.45 ± 0.32 µg/mL) and the other tested compounds. In a computational study, <b>7g</b> demonstrated promising binding affinities (−8.80, −8.91 kcal/mol) with α-glycosidase and α-amylase, compared to acarbose (−10.87, −10.38 kcal/mol) for α-glycosidase and α-amylase. Additionally, <b>7g</b> had strong binding with aldose reductase (−9.20 kcal/mol) in comparison to quercetin (−9.95 kcal/mol). Molecular dynamics (MDs) simulations demonstrated that <b>7g</b> remained stable over a 100 ns simulation period, and the binding free energy estimates remained consistent throughout this time. <b>Conclusions</b>: We reported the modification of quinoline and naphthalene rings to hydrazineylidene–propenamides <b>7a</b>–<b>g</b> using various synthetic approaches. <b>7g</b> emerged as a leading candidate, exhibiting greater inhibition of α-glycosidase, α-amylase, and aldose reductase. These findings underscore their potential as essential molecules for the development of innovative antidiabetic treatments. |
| format | Article |
| id | doaj-art-e19137df4f424a129d355c8e7d59101a |
| institution | DOAJ |
| issn | 1424-8247 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj-art-e19137df4f424a129d355c8e7d59101a2025-08-20T02:56:54ZengMDPI AGPharmaceuticals1424-82472024-12-011712169210.3390/ph17121692Novel Quinoline- and Naphthalene-Incorporated Hydrazineylidene–Propenamide Analogues as Antidiabetic Agents: Design, Synthesis, and Computational StudiesOsama Alharbi0Wael H. Alsaedi1Mosa Alsehli2Saif H. Althagafi3Hussam Y. Alharbi4Yazeed M. Asiri5Ramith Ramu6Mohammed Al-Ghorbani7Department of Chemistry, Faculty of Science, Taibah University, Madinah 42353, Saudi ArabiaDepartment of Chemistry, Faculty of Science, Taibah University, Madinah 42353, Saudi ArabiaDepartment of Chemistry, Faculty of Science, Taibah University, Madinah 42353, Saudi ArabiaDepartment of Chemistry, Faculty of Science, Al-Baha University, P.O. Box 1988, Al Baha 65431, Saudi ArabiaDepartment of Chemistry, Faculty of Science, Taibah University, Yanbu 46421, Saudi ArabiaDepartment of Chemistry, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi ArabiaDepartment of Biotechnology and Bioinformatics, JSS Academy of Higher Education and Research, Mysuru 570015, IndiaDepartment of Chemistry, Faculty of Science, Taibah University, Madinah 42353, Saudi Arabia<b>Background:</b> Type 2 diabetes has become a significant global health challenge. Numerous drugs have been developed to treat the condition, either as standalone therapies or in combination when glycemic control cannot be achieved with a single medication. As existing treatments often come with limitations, there is an increasing focus on creating novel therapeutic agents that offer greater efficacy and fewer side effects to better address this widespread issue. <b>Methods</b>: The methylene derivatives <b>3a</b>,<b>b</b> were coupled with phenyl/ethyl isothiocyanate in the basic medium, and dimethyl sulfate was subsequently added. Further, <b>5a</b>–<b>d</b> were reacted with the quinoline/naphthalene hydrazides <b>6a</b>,<b>b</b>. The target compounds <b>7a</b>–<b>g</b> were subjected to the in vitro enzyme inhibition studies on α-glucosidase, α-amylase, and aldose reductase. <b>Results</b>: <b>7g</b> exerted remarkable inhibitory effects on α-glycosidase [Inhibitory Concentration (IC<sub>50</sub>): 20.23 ± 1.10 µg/mL] and α-amylase (17.15 ± 0.30 µg/mL), outperforming acarbose (28.12 ± 0.20 µg/mL for α-glycosidase and 25.42 ± 0.10 µg/mL for α-amylase), and exhibited a strong inhibition action on aldose reductase (12.15 ± 0.24 µg/mL), surpassing quercetin (15.45 ± 0.32 µg/mL) and the other tested compounds. In a computational study, <b>7g</b> demonstrated promising binding affinities (−8.80, −8.91 kcal/mol) with α-glycosidase and α-amylase, compared to acarbose (−10.87, −10.38 kcal/mol) for α-glycosidase and α-amylase. Additionally, <b>7g</b> had strong binding with aldose reductase (−9.20 kcal/mol) in comparison to quercetin (−9.95 kcal/mol). Molecular dynamics (MDs) simulations demonstrated that <b>7g</b> remained stable over a 100 ns simulation period, and the binding free energy estimates remained consistent throughout this time. <b>Conclusions</b>: We reported the modification of quinoline and naphthalene rings to hydrazineylidene–propenamides <b>7a</b>–<b>g</b> using various synthetic approaches. <b>7g</b> emerged as a leading candidate, exhibiting greater inhibition of α-glycosidase, α-amylase, and aldose reductase. These findings underscore their potential as essential molecules for the development of innovative antidiabetic treatments.https://www.mdpi.com/1424-8247/17/12/1692quinolinenaphthaleneα-glycosidaseα-amylase and aldose reductase enzyme inhibitionsmolecular docking simulationmolecular dynamics simulation |
| spellingShingle | Osama Alharbi Wael H. Alsaedi Mosa Alsehli Saif H. Althagafi Hussam Y. Alharbi Yazeed M. Asiri Ramith Ramu Mohammed Al-Ghorbani Novel Quinoline- and Naphthalene-Incorporated Hydrazineylidene–Propenamide Analogues as Antidiabetic Agents: Design, Synthesis, and Computational Studies Pharmaceuticals quinoline naphthalene α-glycosidase α-amylase and aldose reductase enzyme inhibitions molecular docking simulation molecular dynamics simulation |
| title | Novel Quinoline- and Naphthalene-Incorporated Hydrazineylidene–Propenamide Analogues as Antidiabetic Agents: Design, Synthesis, and Computational Studies |
| title_full | Novel Quinoline- and Naphthalene-Incorporated Hydrazineylidene–Propenamide Analogues as Antidiabetic Agents: Design, Synthesis, and Computational Studies |
| title_fullStr | Novel Quinoline- and Naphthalene-Incorporated Hydrazineylidene–Propenamide Analogues as Antidiabetic Agents: Design, Synthesis, and Computational Studies |
| title_full_unstemmed | Novel Quinoline- and Naphthalene-Incorporated Hydrazineylidene–Propenamide Analogues as Antidiabetic Agents: Design, Synthesis, and Computational Studies |
| title_short | Novel Quinoline- and Naphthalene-Incorporated Hydrazineylidene–Propenamide Analogues as Antidiabetic Agents: Design, Synthesis, and Computational Studies |
| title_sort | novel quinoline and naphthalene incorporated hydrazineylidene propenamide analogues as antidiabetic agents design synthesis and computational studies |
| topic | quinoline naphthalene α-glycosidase α-amylase and aldose reductase enzyme inhibitions molecular docking simulation molecular dynamics simulation |
| url | https://www.mdpi.com/1424-8247/17/12/1692 |
| work_keys_str_mv | AT osamaalharbi novelquinolineandnaphthaleneincorporatedhydrazineylidenepropenamideanaloguesasantidiabeticagentsdesignsynthesisandcomputationalstudies AT waelhalsaedi novelquinolineandnaphthaleneincorporatedhydrazineylidenepropenamideanaloguesasantidiabeticagentsdesignsynthesisandcomputationalstudies AT mosaalsehli novelquinolineandnaphthaleneincorporatedhydrazineylidenepropenamideanaloguesasantidiabeticagentsdesignsynthesisandcomputationalstudies AT saifhalthagafi novelquinolineandnaphthaleneincorporatedhydrazineylidenepropenamideanaloguesasantidiabeticagentsdesignsynthesisandcomputationalstudies AT hussamyalharbi novelquinolineandnaphthaleneincorporatedhydrazineylidenepropenamideanaloguesasantidiabeticagentsdesignsynthesisandcomputationalstudies AT yazeedmasiri novelquinolineandnaphthaleneincorporatedhydrazineylidenepropenamideanaloguesasantidiabeticagentsdesignsynthesisandcomputationalstudies AT ramithramu novelquinolineandnaphthaleneincorporatedhydrazineylidenepropenamideanaloguesasantidiabeticagentsdesignsynthesisandcomputationalstudies AT mohammedalghorbani novelquinolineandnaphthaleneincorporatedhydrazineylidenepropenamideanaloguesasantidiabeticagentsdesignsynthesisandcomputationalstudies |