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 -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 (log P 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.