<abstract xmlns="http://www.w3.org/1999/xhtml">
<p>A diastereomeric mixture of racemic 3-phthalimido-<italic>b</italic>-lactam <bold>2a</bold>/<bold>2b</bold> was synthesized by the Staudinger reaction of carboxylic acid activated with 2-chloro-1-methylpyridinium iodide and imine <bold>1</bold>. The amino group at the C3 position of the <italic>b</italic>-lactam ring was used for further structural upgrade. <italic>trans</italic>-<italic>b</italic>-lactam ureas <bold>4a–t</bold> were prepared by the condensation reaction of the amino group of <italic>b</italic>-lactam ring with various aromatic and aliphatic isocyanates. Antimicrobial activity of compounds <bold>4a–t</bold> was evaluated <italic>in vitro </italic>and neither antibacterial nor antifungal activity were observed. Several of the newly synthesized <italic>trans</italic>-<italic>b</italic>-lactam ureas <bold>4a–c</bold>, <bold>4f</bold>, <bold>4h</bold>, <bold>4n</bold>, <bold>4o</bold>, <bold>4p</bold>, and <bold>4s</bold> were evaluated for <italic>in vitro</italic> antiproliferative activity against liver hepatocellular carcinoma (HepG2), ovarian carcinoma (A2780), breast adenocarcinoma (MCF7) and untransformed human fibroblasts (HFF1). The <italic>b</italic>-lactam urea <bold>4o</bold> showed the most potent antiproliferative activity against the ovarian carcinoma (A2780) cell line. Compounds <bold>4o</bold> and <bold>4p</bold> exhibited strong cytotoxic effects against human non-tumor cell line HFF1. The <italic>b</italic>-lactam ureas <bold>4a–t</bold> were estimated to be soluble and membrane permeable, moderately lipophilic molecules (log<italic>P</italic> 4.6) with a predisposition to be CYP3A4 and P-glycoprotein substrates. The tools PASS and SwissTargetPrediction could not predict biological targets for compounds <bold>4a–t</bold> with high probability, pointing to the novelty of their structure. Considering low toxicity risk, molecules <bold>4a</bold> and <bold>4f</bold> can be selected as the most promising candidates for further structure modifications.</p>
</abstract>

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.

Novel (±)-<italic>trans</italic>-<italic>β</italic>-lactam ureas: Synthesis, <italic>in silico </italic>and <italic>in vitro</italic> biological profiling

Division of Organic Chemistry and Biochemistry

Division of Materials Chemistry Laboratory for Aquaculture in Biotechnology

Division of Physical Chemistry Laboratory for Biocolloids and Surface Chemistry

Acta Pharmaceutica

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Novel (±)---lactam ureas: Synthesis, and  biological profiling

A diastereomeric mixture of racemic 3-phthalimido-b-lactam 2a/2b was synthesized by the Staudinger reaction of carboxylic acid activated with...

Novel (±)-trans-β-lactam ureas: Synthesis, in silico and in vitro biological profiling

Data publikacji: 30 mar 2024

Zakres stron: 37 - 59

Przyjęty: 13 sty 2024

DOI: https://doi.org/10.2478/acph-2024-0008

Słowa kluczowe
(±)---lactam ureas, antiproliferative activity, ADMET prediction, biological profiling

© 2024 Mladenka Jurin et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Novel (±)-trans-β-lactam ureas: Synthesis, in silico and in vitro biological profiling

Data publikacji: 30 mar 2024

Zakres stron: 37 - 59

Przyjęty: 13 sty 2024

DOI: https://doi.org/10.2478/acph-2024-0008

Słowa kluczowe(±)---lactam ureas, antiproliferative activity, ADMET prediction, biological profiling

© 2024 Mladenka Jurin et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Słowa kluczowe
(±)---lactam ureas, antiproliferative activity, ADMET prediction, biological profiling