Novel (±)-trans-β-lactam ureas: Synthesis, in silico and in vitro biological profiling
A diastereomeric mixture of racemic 3-phthalimido-b-lactam 2a/2b was synthesized by the Staudinger reaction of carboxylic acid activated with 2-chloro-1-methylpyridinium iodide and imine 1. The amino group at the C3 position of the b-lactam ring was used for further structural upgrade. trans-b-lacta...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Sciendo
2024-03-01
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| Series: | Acta Pharmaceutica |
| Subjects: | |
| Online Access: | https://doi.org/10.2478/acph-2024-0008 |
| _version_ | 1797229562724089856 |
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| author | Jurin Mladenka Stepanić Višnja Bojanić Krunoslav Vadlja Denis Kontrec Darko Dražić Tonko Roje Marin |
| author_facet | Jurin Mladenka Stepanić Višnja Bojanić Krunoslav Vadlja Denis Kontrec Darko Dražić Tonko Roje Marin |
| author_sort | Jurin Mladenka |
| collection | DOAJ |
| description | A diastereomeric mixture of racemic 3-phthalimido-b-lactam 2a/2b was synthesized by the Staudinger reaction of carboxylic acid activated with 2-chloro-1-methylpyridinium iodide and imine 1. The amino group at the C3 position of the b-lactam ring was used for further structural upgrade. trans-b-lactam ureas 4a–t were prepared by the condensation reaction of the amino group of b-lactam ring with various aromatic and aliphatic isocyanates. Antimicrobial activity of compounds 4a–t was evaluated in vitro and neither antibacterial nor antifungal activity were observed. Several of the newly synthesized trans-b-lactam ureas 4a–c, 4f, 4h, 4n, 4o, 4p, and 4s were evaluated for in vitro antiproliferative activity against liver hepatocellular carcinoma (HepG2), ovarian carcinoma (A2780), breast adenocarcinoma (MCF7) and untransformed human fibroblasts (HFF1). The b-lactam urea 4o showed the most potent antiproliferative activity against the ovarian carcinoma (A2780) cell line. Compounds 4o and 4p exhibited strong cytotoxic effects against human non-tumor cell line HFF1. The b-lactam ureas 4a–t were estimated to be soluble and membrane permeable, moderately lipophilic molecules (logP 4.6) with a predisposition to be CYP3A4 and P-glycoprotein substrates. The tools PASS and SwissTargetPrediction could not predict biological targets for compounds 4a–t with high probability, pointing to the novelty of their structure. Considering low toxicity risk, molecules 4a and 4f can be selected as the most promising candidates for further structure modifications. |
| first_indexed | 2024-04-24T15:14:34Z |
| format | Article |
| id | doaj.art-199e7ac933ef4756b379fef727260399 |
| institution | Directory Open Access Journal |
| issn | 1846-9558 |
| language | English |
| last_indexed | 2024-04-24T15:14:34Z |
| publishDate | 2024-03-01 |
| publisher | Sciendo |
| record_format | Article |
| series | Acta Pharmaceutica |
| spelling | doaj.art-199e7ac933ef4756b379fef7272603992024-04-02T09:28:44ZengSciendoActa Pharmaceutica1846-95582024-03-01741375910.2478/acph-2024-0008Novel (±)-trans-β-lactam ureas: Synthesis, in silico and in vitro biological profilingJurin Mladenka0Stepanić Višnja1Bojanić Krunoslav2Vadlja Denis3Kontrec Darko4Dražić Tonko5Roje Marin6Division of Organic Chemistry and Biochemistry, Laboratory for Chiral Technologies, Ruđer Bošković Institute 10000 Zagreb, CroatiaDivision of Electronics, Laboratory for Machine Learning and Knowledge Representation, Ruđer Bošković Institute, 10000, Zagreb CroatiaDivision of Materials Chemistry Laboratory for Aquaculture in Biotechnology, Ruđer Bošković Institute 10000 Zagreb, CroatiaDivision of Materials Chemistry Laboratory for Aquaculture in Biotechnology, Ruđer Bošković Institute 10000 Zagreb, CroatiaDivision of Organic Chemistry and Biochemistry, Laboratory for Chiral Technologies, Ruđer Bošković Institute 10000 Zagreb, CroatiaDivision of Physical Chemistry Laboratory for Biocolloids and Surface Chemistry, Ruđer Bošković Institute10000ZagrebDivision of Organic Chemistry and Biochemistry, Laboratory for Chiral Technologies, Ruđer Bošković Institute 10000 Zagreb, CroatiaA diastereomeric mixture of racemic 3-phthalimido-b-lactam 2a/2b was synthesized by the Staudinger reaction of carboxylic acid activated with 2-chloro-1-methylpyridinium iodide and imine 1. The amino group at the C3 position of the b-lactam ring was used for further structural upgrade. trans-b-lactam ureas 4a–t were prepared by the condensation reaction of the amino group of b-lactam ring with various aromatic and aliphatic isocyanates. Antimicrobial activity of compounds 4a–t was evaluated in vitro and neither antibacterial nor antifungal activity were observed. Several of the newly synthesized trans-b-lactam ureas 4a–c, 4f, 4h, 4n, 4o, 4p, and 4s were evaluated for in vitro antiproliferative activity against liver hepatocellular carcinoma (HepG2), ovarian carcinoma (A2780), breast adenocarcinoma (MCF7) and untransformed human fibroblasts (HFF1). The b-lactam urea 4o showed the most potent antiproliferative activity against the ovarian carcinoma (A2780) cell line. Compounds 4o and 4p exhibited strong cytotoxic effects against human non-tumor cell line HFF1. The b-lactam ureas 4a–t were estimated to be soluble and membrane permeable, moderately lipophilic molecules (logP 4.6) with a predisposition to be CYP3A4 and P-glycoprotein substrates. The tools PASS and SwissTargetPrediction could not predict biological targets for compounds 4a–t with high probability, pointing to the novelty of their structure. Considering low toxicity risk, molecules 4a and 4f can be selected as the most promising candidates for further structure modifications.https://doi.org/10.2478/acph-2024-0008(±)-trans-b-lactam ureasantiproliferative activityin silico admet predictionin silico biological profiling |
| spellingShingle | Jurin Mladenka Stepanić Višnja Bojanić Krunoslav Vadlja Denis Kontrec Darko Dražić Tonko Roje Marin Novel (±)-trans-β-lactam ureas: Synthesis, in silico and in vitro biological profiling Acta Pharmaceutica (±)-trans-b-lactam ureas antiproliferative activity in silico admet prediction in silico biological profiling |
| title | Novel (±)-trans-β-lactam ureas: Synthesis, in silico and in vitro biological profiling |
| title_full | Novel (±)-trans-β-lactam ureas: Synthesis, in silico and in vitro biological profiling |
| title_fullStr | Novel (±)-trans-β-lactam ureas: Synthesis, in silico and in vitro biological profiling |
| title_full_unstemmed | Novel (±)-trans-β-lactam ureas: Synthesis, in silico and in vitro biological profiling |
| title_short | Novel (±)-trans-β-lactam ureas: Synthesis, in silico and in vitro biological profiling |
| title_sort | novel trans β lactam ureas synthesis in silico and in vitro biological profiling |
| topic | (±)-trans-b-lactam ureas antiproliferative activity in silico admet prediction in silico biological profiling |
| url | https://doi.org/10.2478/acph-2024-0008 |
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