Uracil as a Zn-Binding Bioisostere of the Allergic Benzenesulfonamide in the Design of Quinoline–Uracil Hybrids as Anticancer Carbonic Anhydrase Inhibitors
A series of quinoline–uracil hybrids (<b>10a–l</b>) has been rationalized and synthesized. The inhibitory activity against hCA isoforms I, II, IX, and XII was explored. Compounds <b>10a–l</b> demonstrated powerful inhibitory activity against all tested hCA isoforms. Compound...
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MDPI AG
2022-04-01
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| Online Access: | https://www.mdpi.com/1424-8247/15/5/494 |
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| author | Samar A. El-Kalyoubi Ehab S. Taher Tarek S. Ibrahim Mohammed Farrag El-Behairy Amany M. M. Al-Mahmoudy |
| author_facet | Samar A. El-Kalyoubi Ehab S. Taher Tarek S. Ibrahim Mohammed Farrag El-Behairy Amany M. M. Al-Mahmoudy |
| author_sort | Samar A. El-Kalyoubi |
| collection | DOAJ |
| description | A series of quinoline–uracil hybrids (<b>10a–l</b>) has been rationalized and synthesized. The inhibitory activity against hCA isoforms I, II, IX, and XII was explored. Compounds <b>10a–l</b> demonstrated powerful inhibitory activity against all tested hCA isoforms. Compound <b>10h</b> displayed the best selectivity profile with good activity. Compound 10d displayed the best activity profile with minimal selectivity. Compound <b>10l</b> emerged as the best congener considering both activity (IC<sub>50</sub> = 140 and 190 nM for hCA IX and hCA XII, respectively) and selectivity (S.I. = 13.20 and 9.75 for II/IX, and II/XII, respectively). The most active hybrids were assayed for antiproliferative and pro-apoptotic activities against MCF-7 and A549. In silico studies, molecular docking, physicochemical parameters, and ADMET analysis were performed to explain the acquired CA inhibitory action of all hybrids. A study of the structure–activity relationship revealed that bulky substituents at uracil <i>N</i>-1 were unfavored for activity while substituted quinoline and thiouracil were effective for selectivity. |
| first_indexed | 2024-03-10T03:11:45Z |
| format | Article |
| id | doaj.art-ba1011e7b67d4fe2bed1d304b66199bf |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T03:11:45Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-ba1011e7b67d4fe2bed1d304b66199bf2023-11-23T12:33:25ZengMDPI AGPharmaceuticals1424-82472022-04-0115549410.3390/ph15050494Uracil as a Zn-Binding Bioisostere of the Allergic Benzenesulfonamide in the Design of Quinoline–Uracil Hybrids as Anticancer Carbonic Anhydrase InhibitorsSamar A. El-Kalyoubi0Ehab S. Taher1Tarek S. Ibrahim2Mohammed Farrag El-Behairy3Amany M. M. Al-Mahmoudy4Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo 11651, EgyptDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, EgyptDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Menoufiya 32897, EgyptDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, EgyptA series of quinoline–uracil hybrids (<b>10a–l</b>) has been rationalized and synthesized. The inhibitory activity against hCA isoforms I, II, IX, and XII was explored. Compounds <b>10a–l</b> demonstrated powerful inhibitory activity against all tested hCA isoforms. Compound <b>10h</b> displayed the best selectivity profile with good activity. Compound 10d displayed the best activity profile with minimal selectivity. Compound <b>10l</b> emerged as the best congener considering both activity (IC<sub>50</sub> = 140 and 190 nM for hCA IX and hCA XII, respectively) and selectivity (S.I. = 13.20 and 9.75 for II/IX, and II/XII, respectively). The most active hybrids were assayed for antiproliferative and pro-apoptotic activities against MCF-7 and A549. In silico studies, molecular docking, physicochemical parameters, and ADMET analysis were performed to explain the acquired CA inhibitory action of all hybrids. A study of the structure–activity relationship revealed that bulky substituents at uracil <i>N</i>-1 were unfavored for activity while substituted quinoline and thiouracil were effective for selectivity.https://www.mdpi.com/1424-8247/15/5/494uracilquinolinecarbonic anhydraseanticancerzinc-binding group |
| spellingShingle | Samar A. El-Kalyoubi Ehab S. Taher Tarek S. Ibrahim Mohammed Farrag El-Behairy Amany M. M. Al-Mahmoudy Uracil as a Zn-Binding Bioisostere of the Allergic Benzenesulfonamide in the Design of Quinoline–Uracil Hybrids as Anticancer Carbonic Anhydrase Inhibitors Pharmaceuticals uracil quinoline carbonic anhydrase anticancer zinc-binding group |
| title | Uracil as a Zn-Binding Bioisostere of the Allergic Benzenesulfonamide in the Design of Quinoline–Uracil Hybrids as Anticancer Carbonic Anhydrase Inhibitors |
| title_full | Uracil as a Zn-Binding Bioisostere of the Allergic Benzenesulfonamide in the Design of Quinoline–Uracil Hybrids as Anticancer Carbonic Anhydrase Inhibitors |
| title_fullStr | Uracil as a Zn-Binding Bioisostere of the Allergic Benzenesulfonamide in the Design of Quinoline–Uracil Hybrids as Anticancer Carbonic Anhydrase Inhibitors |
| title_full_unstemmed | Uracil as a Zn-Binding Bioisostere of the Allergic Benzenesulfonamide in the Design of Quinoline–Uracil Hybrids as Anticancer Carbonic Anhydrase Inhibitors |
| title_short | Uracil as a Zn-Binding Bioisostere of the Allergic Benzenesulfonamide in the Design of Quinoline–Uracil Hybrids as Anticancer Carbonic Anhydrase Inhibitors |
| title_sort | uracil as a zn binding bioisostere of the allergic benzenesulfonamide in the design of quinoline uracil hybrids as anticancer carbonic anhydrase inhibitors |
| topic | uracil quinoline carbonic anhydrase anticancer zinc-binding group |
| url | https://www.mdpi.com/1424-8247/15/5/494 |
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