Efficient Synthesis with Green Chemistry Approach of Novel Pharmacophores of Imidazole-Based Hybrids for Tumor Treatment: Mechanistic Insights from In Situ to In Silico
Imidazole-based pyrimidine hybrids are considered a remarkable class of compounds in pharmaceutical chemistry. Here, we report the anticancer bioactivities of eleven imidazole-based pyrimidine hybrids (<b>1</b>–<b>11</b>) that specifically target cytosolic carbonic anhydrase...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/20/5079 |
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| author | Majid Khan Syed Raza Shah Faizullah Khan Sobia Ahsan Halim Shaikh Mizanoor Rahman Mohammad Khalid Ajmal Khan Ahmed Al-Harrasi |
| author_facet | Majid Khan Syed Raza Shah Faizullah Khan Sobia Ahsan Halim Shaikh Mizanoor Rahman Mohammad Khalid Ajmal Khan Ahmed Al-Harrasi |
| author_sort | Majid Khan |
| collection | DOAJ |
| description | Imidazole-based pyrimidine hybrids are considered a remarkable class of compounds in pharmaceutical chemistry. Here, we report the anticancer bioactivities of eleven imidazole-based pyrimidine hybrids (<b>1</b>–<b>11</b>) that specifically target cytosolic carbonic anhydrase (CAs) isoenzymes, including human CA-II and human CA-IX (hCA-II, and hCA-IX). A highly eco-friendly aqueous approach was used for the formation of a carbon–carbon bond by reacting aromatic nitro group substitution of nitroimidazoles with carbon nucleophiles. The in vitro results indicate that this new class of compounds (<b>1</b>–<b>11</b>) includes significant inhibitors of hCA IX with IC<sub>50</sub> values in the range of 9.6 ± 0.2–32.2 ± 1.0 µM, while hCA II showed IC<sub>50</sub> values in range of 11.6 ± 0.2–31.1 ± 1.3 µM. Compound <b>2</b> (IC<sub>50</sub> = 12.3 ± 0.1 µM) showed selective inhibition for hCA-II while <b>7</b>, <b>8</b>, and <b>10</b> (IC<sub>50</sub> = 9.6–32.2 µM) were selective for hCA-IX. The mechanism of action was investigated through in vitro kinetics studies that revealed that compounds <b>7</b>, <b>3</b>, <b>11</b>, <b>10</b>, <b>4</b>, and <b>9</b> for CA-IX and <b>1</b>, <b>2</b>, and <b>11</b> for CA-II are competitive inhibitors with dissociation constant (Ki) in the range of 7.32–17.02 µM. Furthermore, the in situ cytotoxicity of these compounds was investigated in the human breast cancer cell line MDA-MB-231 and compared with the normal human breast cell line, MCF-10A. Compound <b>5</b> showed excellent anticancer/cytotoxic activity in MDA-MB-231 with no toxicity to the normal breast cells. In addition, in silico molecular docking was employed to predict the binding mechanism of active compounds with their targets. This in silico observation aligned with our experimental results. Our findings signify that imidazole-based hybrids could be a useful choice to design anticancer agents for breast and lung tumors, or antiglaucoma compounds, by specific inhibition of carbonic anhydrases. |
| first_indexed | 2024-03-09T20:32:08Z |
| format | Article |
| id | doaj.art-81135393a66f4821a838420c32e86627 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T20:32:08Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
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| series | Cancers |
| spelling | doaj.art-81135393a66f4821a838420c32e866272023-11-23T23:21:38ZengMDPI AGCancers2072-66942022-10-011420507910.3390/cancers14205079Efficient Synthesis with Green Chemistry Approach of Novel Pharmacophores of Imidazole-Based Hybrids for Tumor Treatment: Mechanistic Insights from In Situ to In SilicoMajid Khan0Syed Raza Shah1Faizullah Khan2Sobia Ahsan Halim3Shaikh Mizanoor Rahman4Mohammad Khalid5Ajmal Khan6Ahmed Al-Harrasi7Natural and Medical Sciences Research Center, University of Nizwa, 616 Birkat Al Mauz, Nizwa P.O. Box 33, OmanNatural and Medical Sciences Research Center, University of Nizwa, 616 Birkat Al Mauz, Nizwa P.O. Box 33, OmanNatural and Medical Sciences Research Center, University of Nizwa, 616 Birkat Al Mauz, Nizwa P.O. Box 33, OmanNatural and Medical Sciences Research Center, University of Nizwa, 616 Birkat Al Mauz, Nizwa P.O. Box 33, OmanNatural and Medical Sciences Research Center, University of Nizwa, 616 Birkat Al Mauz, Nizwa P.O. Box 33, OmanDepartment of Pharmaceutics, College of Pharmacy, King Khalid University, Abha 62529, Saudi ArabiaNatural and Medical Sciences Research Center, University of Nizwa, 616 Birkat Al Mauz, Nizwa P.O. Box 33, OmanNatural and Medical Sciences Research Center, University of Nizwa, 616 Birkat Al Mauz, Nizwa P.O. Box 33, OmanImidazole-based pyrimidine hybrids are considered a remarkable class of compounds in pharmaceutical chemistry. Here, we report the anticancer bioactivities of eleven imidazole-based pyrimidine hybrids (<b>1</b>–<b>11</b>) that specifically target cytosolic carbonic anhydrase (CAs) isoenzymes, including human CA-II and human CA-IX (hCA-II, and hCA-IX). A highly eco-friendly aqueous approach was used for the formation of a carbon–carbon bond by reacting aromatic nitro group substitution of nitroimidazoles with carbon nucleophiles. The in vitro results indicate that this new class of compounds (<b>1</b>–<b>11</b>) includes significant inhibitors of hCA IX with IC<sub>50</sub> values in the range of 9.6 ± 0.2–32.2 ± 1.0 µM, while hCA II showed IC<sub>50</sub> values in range of 11.6 ± 0.2–31.1 ± 1.3 µM. Compound <b>2</b> (IC<sub>50</sub> = 12.3 ± 0.1 µM) showed selective inhibition for hCA-II while <b>7</b>, <b>8</b>, and <b>10</b> (IC<sub>50</sub> = 9.6–32.2 µM) were selective for hCA-IX. The mechanism of action was investigated through in vitro kinetics studies that revealed that compounds <b>7</b>, <b>3</b>, <b>11</b>, <b>10</b>, <b>4</b>, and <b>9</b> for CA-IX and <b>1</b>, <b>2</b>, and <b>11</b> for CA-II are competitive inhibitors with dissociation constant (Ki) in the range of 7.32–17.02 µM. Furthermore, the in situ cytotoxicity of these compounds was investigated in the human breast cancer cell line MDA-MB-231 and compared with the normal human breast cell line, MCF-10A. Compound <b>5</b> showed excellent anticancer/cytotoxic activity in MDA-MB-231 with no toxicity to the normal breast cells. In addition, in silico molecular docking was employed to predict the binding mechanism of active compounds with their targets. This in silico observation aligned with our experimental results. Our findings signify that imidazole-based hybrids could be a useful choice to design anticancer agents for breast and lung tumors, or antiglaucoma compounds, by specific inhibition of carbonic anhydrases.https://www.mdpi.com/2072-6694/14/20/5079imidazole-based hybrids with hydroxyethyl and pyrimidineanticancermechanistic studiescytotoxicityin silico molecular docking |
| spellingShingle | Majid Khan Syed Raza Shah Faizullah Khan Sobia Ahsan Halim Shaikh Mizanoor Rahman Mohammad Khalid Ajmal Khan Ahmed Al-Harrasi Efficient Synthesis with Green Chemistry Approach of Novel Pharmacophores of Imidazole-Based Hybrids for Tumor Treatment: Mechanistic Insights from In Situ to In Silico Cancers imidazole-based hybrids with hydroxyethyl and pyrimidine anticancer mechanistic studies cytotoxicity in silico molecular docking |
| title | Efficient Synthesis with Green Chemistry Approach of Novel Pharmacophores of Imidazole-Based Hybrids for Tumor Treatment: Mechanistic Insights from In Situ to In Silico |
| title_full | Efficient Synthesis with Green Chemistry Approach of Novel Pharmacophores of Imidazole-Based Hybrids for Tumor Treatment: Mechanistic Insights from In Situ to In Silico |
| title_fullStr | Efficient Synthesis with Green Chemistry Approach of Novel Pharmacophores of Imidazole-Based Hybrids for Tumor Treatment: Mechanistic Insights from In Situ to In Silico |
| title_full_unstemmed | Efficient Synthesis with Green Chemistry Approach of Novel Pharmacophores of Imidazole-Based Hybrids for Tumor Treatment: Mechanistic Insights from In Situ to In Silico |
| title_short | Efficient Synthesis with Green Chemistry Approach of Novel Pharmacophores of Imidazole-Based Hybrids for Tumor Treatment: Mechanistic Insights from In Situ to In Silico |
| title_sort | efficient synthesis with green chemistry approach of novel pharmacophores of imidazole based hybrids for tumor treatment mechanistic insights from in situ to in silico |
| topic | imidazole-based hybrids with hydroxyethyl and pyrimidine anticancer mechanistic studies cytotoxicity in silico molecular docking |
| url | https://www.mdpi.com/2072-6694/14/20/5079 |
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