Synthesis and Biological Evaluation of Pyrimidine-oxazolidin-2-arylimino Hybrid Molecules as Antibacterial Agents.

Roberto Romeo,Lucia Veltri,Daniela Iannazzo,Salvatore Giofrè,Gianluigi Broggini,Agata Campisi,Giulia Monciino,Maria Chiacchio

doi:10.3390/molecules23071754

Abstract

Pyrimidine-1,3-oxazolidin-2-arylimino hybrids have been synthesized as a new class of antibacterial agents. The synthetic approach exploits a Cu(II)-catalyzed intramolecular halkoxyhalogenation of alkynyl ureas, followed by a Suzuki coupling reaction with 2,4-dimethoxypyrimidin-5-boronic acid. Biological screenings revealed that most of the compounds showed moderate to good activity against two Gram-positive (B. subtilis, S. aureus) and three Gram-negative (P. aeruginosa, S. typhi, K. pneumonia) pathogenic strains. A molecular docking study, performed in the crystal structure of 50S ribosomal unit of Haloarcula marismortui, indicated that pyrimidine-oxazolidin-2-arylimino hybrids 8c and 8h exhibited a high binding affinity (−9.65 and −10.74 kcal/mol), which was in agreement with their good antibacterial activity. The obtained results suggest that the combination of pyrimidine and oxazolidone moieties can be considered as a valid basis to develop new further modifications towards more efficacious antibacterial compounds.

Highlights

The oxazolidinone unit is the important core structure of a class of synthetic antibacterial agents that possess activity against a variety of Gram-positive pathogenic bacterial strains and are highly potent against multidrug resistant bacteria [1,2,3,4,5,6,7,8]
Alkynylureas prepared by reaction of theofalkynyl amine with the suitable isocyanate the route 6a–i, illustrated in Figure synthetic approach proceeds through steps.isocyanate
6a–i, prepared by reaction of the2 alkynyl amine with theofsuitable isocyanate [29],amount were reacted with a catalytic amount of in the presence a stoichiometric were reacted with a catalytic amount of CuI2 in the presence of a stoichiometric amount of of reacted with a catalytic amountgood of CuI2 inthe thecorresponding presence of aiodooxazolidine stoichiometric amount of 7a–i

Summary

Introduction

The oxazolidinone unit is the important core structure of a class of synthetic antibacterial agents that possess activity against a variety of Gram-positive pathogenic bacterial strains and are highly potent against multidrug resistant bacteria [1,2,3,4,5,6,7,8]. Linezolid 1, the first oxazolidinone antibiotic clinically approved [9], and the strictly correlated Eperezolid 2 [5,10] and Tedizolid 3 (Figure 1) target the bacterial ribosome by inhibiting protein synthesis and preventing the initiation of mRNA translation [7,10]. Linezolid is associated with undesirable side effects, such as thrombocytopenia, myelosuppression, neuropathies, and bone marrow toxicity [11,12,13,14,15] due to the inhibition of mammalian mitochondrial protein synthesis. The development of antimicrobial resistance represents a serious health problem and contributes strongly to the urgent need for the discovery of new effective agents in this area

Methods

Results

Conclusion