An Efficient Synthesis of 1-(1,3-Dioxoisoindolin-2-yl)-3-aryl Urea Analogs as Anticancer and Antioxidant Agents: An Insight into Experimental and <i>In Silico</i> Studies
The present investigation reports the efficient multistep synthesis of 1-(1,3-dioxoisoindolin-2-yl)-3-aryl urea analogs (<b>7a</b>–<b>f</b>) in good yields. All the 1-(1,3-dioxoisoindolin-2-yl)-3-aryl urea analogs (<b>7a</b>–<b>f</b>) were characterize...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-12-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/29/1/67 |
| _version_ | 1797358462711103488 |
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| author | Obaid Afzal Mohamed Jawed Ahsan |
| author_facet | Obaid Afzal Mohamed Jawed Ahsan |
| author_sort | Obaid Afzal |
| collection | DOAJ |
| description | The present investigation reports the efficient multistep synthesis of 1-(1,3-dioxoisoindolin-2-yl)-3-aryl urea analogs (<b>7a</b>–<b>f</b>) in good yields. All the 1-(1,3-dioxoisoindolin-2-yl)-3-aryl urea analogs (<b>7a</b>–<b>f</b>) were characterized by spectroscopic techniques. Five among the six compounds were tested against 56 cancer cell lines at 10 µM as per the standard protocol. 1-(4-Bromophenyl)-3-(1,3-dioxoisoindolin-2-yl)urea (<b>7c</b>) exhibited moderate but significant anticancer activity against EKVX, CAKI-1, UACC-62, MCF7, LOX IMVI, and ACHN with percentage growth inhibitions (PGIs) of 75.46, 78.52, 80.81, 83.48, 84.52, and 89.61, respectively. Compound <b>7c</b> was found to exhibit better anticancer activity than thalidomide against non-small cell lung, CNS, melanoma, renal, prostate, and breast cancer cell lines. It was also found to exhibit superior anticancer activity against melanoma cancer compared to imatinib. Among the tested compounds, the 4-bromosubstitution (<b>7c</b>) on the phenyl ring demonstrated good anticancer activity. Docking scores ranging from −6.363 to −7.565 kcal/mol were observed in the docking studies against the molecular target EGFR. The ligand <b>7c</b> displayed an efficient binding against the EGFR with a docking score of −7.558 kcal/mol and displayed an H-bond interaction with Lys745 and the carbonyl functional group. Compound <b>7c</b> demonstrated a moderate inhibition of EGFR with an IC<sub>50</sub> of 42.91 ± 0.80 nM, in comparison to erlotinib (IC<sub>50</sub> = 26.85 ± 0.72 nM), the standard drug. The antioxidant potential was also calculated for the compounds (<b>7a</b>–<b>f</b>), which exhibited good to low activity. 1-(2-Methoxyphenyl)-3-(1,3-dioxoisoindolin-2-yl)urea (<b>7f</b>) and 1-(4-Methoxyphenyl)-3-(1,3-dioxoisoindolin-2-yl)urea (<b>7d</b>) demonstrated significant antioxidant activity with IC<sub>50</sub> values of 15.99 ± 0.10 and 16.05 ± 0.15 µM, respectively. The 2- and 4-methoxysubstitutions on the <i>N</i>-phenyl ring showed good antioxidant activity among the series of compounds (<b>7a</b>–<b>f</b>). An in silico ADMET prediction studies showed the compounds’ adherence to Lipinski’s rule of five: they were free from toxicities, including mutagenicity, cytotoxicity, and immunotoxicity, but not for hepatotoxicity. The toxicity prediction demonstrated LD<sub>50</sub> values between 1000 and 5000 mg/Kg, putting the compounds either in class IV or class V toxicity classes. Our findings might create opportunities for more advancements in cancer therapeutics. |
| first_indexed | 2024-03-08T15:01:19Z |
| format | Article |
| id | doaj.art-615bc7e727964141b37e88e3b04adac4 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-08T15:01:19Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-615bc7e727964141b37e88e3b04adac42024-01-10T15:04:02ZengMDPI AGMolecules1420-30492023-12-012916710.3390/molecules29010067An Efficient Synthesis of 1-(1,3-Dioxoisoindolin-2-yl)-3-aryl Urea Analogs as Anticancer and Antioxidant Agents: An Insight into Experimental and <i>In Silico</i> StudiesObaid Afzal0Mohamed Jawed Ahsan1Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi ArabiaDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Jahangirabad Institute of Technology (JIT), Jahangirabad Fort, Jahangirabad 225203, Uttar Pradesh, IndiaThe present investigation reports the efficient multistep synthesis of 1-(1,3-dioxoisoindolin-2-yl)-3-aryl urea analogs (<b>7a</b>–<b>f</b>) in good yields. All the 1-(1,3-dioxoisoindolin-2-yl)-3-aryl urea analogs (<b>7a</b>–<b>f</b>) were characterized by spectroscopic techniques. Five among the six compounds were tested against 56 cancer cell lines at 10 µM as per the standard protocol. 1-(4-Bromophenyl)-3-(1,3-dioxoisoindolin-2-yl)urea (<b>7c</b>) exhibited moderate but significant anticancer activity against EKVX, CAKI-1, UACC-62, MCF7, LOX IMVI, and ACHN with percentage growth inhibitions (PGIs) of 75.46, 78.52, 80.81, 83.48, 84.52, and 89.61, respectively. Compound <b>7c</b> was found to exhibit better anticancer activity than thalidomide against non-small cell lung, CNS, melanoma, renal, prostate, and breast cancer cell lines. It was also found to exhibit superior anticancer activity against melanoma cancer compared to imatinib. Among the tested compounds, the 4-bromosubstitution (<b>7c</b>) on the phenyl ring demonstrated good anticancer activity. Docking scores ranging from −6.363 to −7.565 kcal/mol were observed in the docking studies against the molecular target EGFR. The ligand <b>7c</b> displayed an efficient binding against the EGFR with a docking score of −7.558 kcal/mol and displayed an H-bond interaction with Lys745 and the carbonyl functional group. Compound <b>7c</b> demonstrated a moderate inhibition of EGFR with an IC<sub>50</sub> of 42.91 ± 0.80 nM, in comparison to erlotinib (IC<sub>50</sub> = 26.85 ± 0.72 nM), the standard drug. The antioxidant potential was also calculated for the compounds (<b>7a</b>–<b>f</b>), which exhibited good to low activity. 1-(2-Methoxyphenyl)-3-(1,3-dioxoisoindolin-2-yl)urea (<b>7f</b>) and 1-(4-Methoxyphenyl)-3-(1,3-dioxoisoindolin-2-yl)urea (<b>7d</b>) demonstrated significant antioxidant activity with IC<sub>50</sub> values of 15.99 ± 0.10 and 16.05 ± 0.15 µM, respectively. The 2- and 4-methoxysubstitutions on the <i>N</i>-phenyl ring showed good antioxidant activity among the series of compounds (<b>7a</b>–<b>f</b>). An in silico ADMET prediction studies showed the compounds’ adherence to Lipinski’s rule of five: they were free from toxicities, including mutagenicity, cytotoxicity, and immunotoxicity, but not for hepatotoxicity. The toxicity prediction demonstrated LD<sub>50</sub> values between 1000 and 5000 mg/Kg, putting the compounds either in class IV or class V toxicity classes. Our findings might create opportunities for more advancements in cancer therapeutics.https://www.mdpi.com/1420-3049/29/1/67ADMETanticancerantioxidantcell linesphthalimidemolecular docking |
| spellingShingle | Obaid Afzal Mohamed Jawed Ahsan An Efficient Synthesis of 1-(1,3-Dioxoisoindolin-2-yl)-3-aryl Urea Analogs as Anticancer and Antioxidant Agents: An Insight into Experimental and <i>In Silico</i> Studies Molecules ADMET anticancer antioxidant cell lines phthalimide molecular docking |
| title | An Efficient Synthesis of 1-(1,3-Dioxoisoindolin-2-yl)-3-aryl Urea Analogs as Anticancer and Antioxidant Agents: An Insight into Experimental and <i>In Silico</i> Studies |
| title_full | An Efficient Synthesis of 1-(1,3-Dioxoisoindolin-2-yl)-3-aryl Urea Analogs as Anticancer and Antioxidant Agents: An Insight into Experimental and <i>In Silico</i> Studies |
| title_fullStr | An Efficient Synthesis of 1-(1,3-Dioxoisoindolin-2-yl)-3-aryl Urea Analogs as Anticancer and Antioxidant Agents: An Insight into Experimental and <i>In Silico</i> Studies |
| title_full_unstemmed | An Efficient Synthesis of 1-(1,3-Dioxoisoindolin-2-yl)-3-aryl Urea Analogs as Anticancer and Antioxidant Agents: An Insight into Experimental and <i>In Silico</i> Studies |
| title_short | An Efficient Synthesis of 1-(1,3-Dioxoisoindolin-2-yl)-3-aryl Urea Analogs as Anticancer and Antioxidant Agents: An Insight into Experimental and <i>In Silico</i> Studies |
| title_sort | efficient synthesis of 1 1 3 dioxoisoindolin 2 yl 3 aryl urea analogs as anticancer and antioxidant agents an insight into experimental and i in silico i studies |
| topic | ADMET anticancer antioxidant cell lines phthalimide molecular docking |
| url | https://www.mdpi.com/1420-3049/29/1/67 |
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