Structure-activity relationship (SAR) studies on oxazolidinone antibacterial agents. 2. Relationship between lipophilicity and antibacterial activity in 5-thiocarbonyl oxazolidinones

5-Thiourea and 5-dithiocarbamate oxazolidinones were synthesized as a continuation of research on 5-thiocarbonyl oxazolidinone antibacterial agents considering the hydrophobic parameters of the molecule. The structure-activity relationship (SAR) study revealed that the antibacterial activity on 5-thiocarbonyl oxazolidinones was significantly affected by the lipophilicity, especially the calculated log P value and the balance between 5-hydrophilic (or hydrophobic) substituent and hydrophobic (or hydrophilic) substituents on the benzene ring. Some of 5-thiocarbonyl oxazolidinones were found to have good in vitro antibacterial activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).     

Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A

Natural products have historically been a major source of antibiotics and therefore novel scaffolds are constantly of interest. The lipoxazolidinone family of marine natural products, with an unusual 4‐oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow‐up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogues to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4‐oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.     

Synthesis of Urea‐Tethered Disaccharides in Water

A new method for the synthesis of urea‐linked disaccharides in aqueous media has been developed. The key feature of our approach is two strained Steyermark‐type gluco‐ and galactopyranosyl oxazolidinones. Each oxazolidinone is attached to a pyranose ring in a di‐equatorial trans‐annulation framework. Reaction of these oxazolidinones with 4‐aminohexopyranose in water proceeded smoothly to afford the urea‐tethered cellobiose and lactose analogues. The galactose‐type oxazolidinone proved to be more reactive than the glucose‐type, which is explained by the presence of an axial hydroxy group at C4 in the former.     

Convenient synthesis of oxazolidinones by the use of halomethyloxirane, primary amine, and carbonate salt

[reaction: see text] Primary amines reacted with carbonate salts (Na2CO3, K2CO3, Cs2CO3, and Ag2CO3) and halomethyloxiranes in the presence of a base such as DBU or TEA to give oxazolidinones in high yields. The use of K2CO3 among these carbonate gave the best yield in this synthesis. A reaction mechanism was proposed that the oxazolidinone was obtained from an oxazinanone intermediate via a bicyclo[2.2.1] intermediate. The present reaction can be widely applied to convenient synthesis of useful N-substituted oxazolidinones and chiral oxazolidinones.     

Solution-phase parallel synthesis of a library of delta(2)-pyrazolines

A parallel synthesis of a library (80 members) of 2-pyrazolines in solution phase is described. The 2-pyrazoline core was accessed through the [3 + 2] cycloaddition of nitrilimines with enoyl oxazolidinones. The cycloaddition provided two regioisomers, the major product being the C regioisomer. The oxazolidinone moiety was further reduced to the primary alcohol, producing another library of 5-hydroxymethyl-2-pyrazolines. The Lipinski profiles and calculated ADME properties of the compounds are also reported.     

Factors affecting relative stabilities and proton affinities of oxazolidinone and its N,C5-formyl derivatives

The proton affinities of all the potential sites of oxazolidinone (OXA) and formyl substituted OXA have been evaluated using ab initio and DFT methods. N4- and C5-formyl oxazolidinone isomers and their protonated structures have been analyzed for relative stabilities. The proton affinity (PA) of carbonyl oxygen of oxazolidinone is observed to be highest in un-substituted and formyl substituted OXA molecules. The PA values decrease for the potential sites in the range 0.5–15.51 kcal/mol as a result of the presence of the formyl substituent. Atomic charges and electron delocalization of neutral and protonated species have been analyzed with the application of NBO. The various factors such as variation in geometrical parameters, atomic charge redistribution, alterations in conjugative interactions, effect of formyl substituent, the presence of intramolecular hydrogen bonding and electronic effects have been explored to rationalize the relative stabilities and proton affinities of OXA and its N,C5 formyl derivatives.     

SmI2-promoted intra- and intermolecular C-C bond formation with chiral N-acyl oxazolidinones

The suitability of chiral oxazolidinones in the SmI₂-mediated C-C bond generation between the imide functionality of an N-acyl oxazolidinone unit and an olefinic radical acceptor, in both inter- and intramolecular reactions, was investigated. It was shown that the products from an Evans asymmetric alkylation can undergo direct carbon-carbon bond formation with an acrylamide providing chiral acyclic ketones in reasonable yields. These examples represent the first transformation of such N-acyl oxazolidinones where this chiral auxiliary is removed under the conditions for ketone formation. 5-exo-trig Cyclization studies were also undertaken with the same type of substrates, providing trans-2,5-disubstituted cyclopentanones in yields of approx. 50%. However, attempts to cyclize heteroatom-containing equivalents were less rewarding.     

Synthesis of α,ω‐Bis(oxazolidinone)polyoxyethylene via a Lithium Bromide–Catalyzed Reaction of Oligoethylene Glycol Diglycidyl Ethers with Isocyanates

The synthesis of bis(oxazolidinone)polyoxyethylene derivatives 2a–h from oligoethylene glycols diglycidyl ethers 1a–e and isocyanates is reported. The reaction was achieved by lithium bromide and tributylphosphine oxide. These bis‐oxazolidinones may have important antibacterial activity.     

Synthesis of 5,5-diallyl-substituted oxazolidin-2-one derivatives,based on reductive diallylation of amino acids

An efficient synthesis of 5,5-diallyl-substituted oxazolidinone derivatives, based on reductive diallylation of available α-amino acids, was developed. It was demonstrated that the obtained oxazolidinones can be readily converted into the corresponding derivatives of 3-azaspiro[4,4]-non-7-en-2-one via the metathesis reaction in the presence of the 1st generation Grubbs catalyst.

     

Direct catalytic synthesis of enantiopure 5-substituted oxazolidinones from racemic terminal epoxides

A venerable scaffold for asymmetric synthesis and drug development, chiral 5-substituted oxazolidinones are obtained in almost enantiomerically pure form (up to 99.9% ee) starting from racemic terminal epoxides. The salient features of this process include the very simple and convenient experimental protocol and the employment of a readily accessible catalyst and inexpensive, easily handled starting materials. An enantioconvergent approach for the total conversion of racemic epoxide into a single stereoisomeric oxazolidinone is also described.     

Chiral oxazolidinones as electrophiles: Intramolecular cyclization reactions with carbanions and preparation of functionalized lactams

The intramolecular cyclizations of oxazolidinones with carbanions adjacent to sulfones, sulfoxides, and phosphonates proceed in high yields to obtain functionalized γ and δ lactams. The chiral oxazolidinone precursors can be readily synthesized from commercial amino acids. The lactams from this study are useful synthetic intermediates, as demonstrated by the synthesis of a precursor for levetiracetam, an antiepileptic drug.     

Mechanistic evidence for intermolecular radical carbonyl additions promoted by samarium diiodide

In this work, mechanistic studies were performed to understand the SmI2/H2O-mediated coupling of N-acyl oxazolidinones with acrylates and acrylamides, providing gamma-keto esters and amides, respectively. Our results provide experimental evidence that C-C bond formation via intermolecular radical addition reactions to carbonyl substrates can be promoted by samarium diiodide. Coupling reactions with N-cyclopropylcarbonyl-2-oxazolidinone suggest the alpha,beta-unsaturated esters/amides are reduced by the low-valent lanthanide reagent and not the N-acyl oxazolidinones, as originially proposed (J. Am. Chem. Soc. 2005, 127, 6544). Rate measurements support the preferred reduction of an acrylate or acrylamide by SmI2/H2O in the presence of an N-acyl oxazolidinone. In the absence of the N-acyl oxazolidinone, SmI2/H2O promotes dimerization of the acrylates, whereas the C=C bond of the acrylamides is reduced. In addition, coupling of the Pfp ester of Cbz-protected phenylalanine with an acrylamide leads only to reduction of the acrylamide and recovered ester, whereas the same coupling with the N-acyl oxazolidinone derivative provides the gamma-keto amides. These results imply that a pathway involving nucleophilic acyl substitution cannot take place and that a radical mechanism must be invoked to explain the C-C bond formation. We propose that the acrylate/acrylamide is reduced to a conjugated ketyl radical that adds to the exocyclic carbonyl group of the N-acyl oxazolidinone, activated through bidentate coordination to a lanthanide ion.     

Development and validation of micellar liquid chromatographic methods for the determination of antibiotics in different matrixes

Antibiotics are the most important bioactive and chemotherapeutic compounds to be produced by microbiological synthesis, and they have proved their worth in a variety of fields, such as medicinal chemistry, agriculture, and the food industry. Interest in antibiotics has grown in parallel with an increasingly high degree of productivity in the field of analytical applications. Therefore, it is necessary to develop chromatographic procedures capable of determining various drugs simultaneously in the shortest possible time. Micellar liquid chromatography (MLC) is an RP-HPLC technique that offers advantages over conventional HPLC as far as sample preparation, selectivity, and versatility are concerned. Its main advantage is that samples can be injected directly into the chromatographic system with no previous preparation step. This paper mainly focuses on the results of the authors' own recent research and reports the chromatographic conditions for determination of various antibiotics (penicillins, quinolones, and sulfonamides) in different matrixes (pharmaceuticals, biological fluids, and food). The work of other authors on MLC-based antibiotic determination has been included.     

Preferential intramolecular ring closure of aminoalcohols with diethyl carbonate to oxazolidinones

The closure by cyclization with diethyl carbonate (EtO)(2)CO from aminoalcohols 1 as starting material can lead to the oxazolidinones 2a, b and 2c, respectively. In the reaction of trans-isomer (6) and (EtO)(2)CO, isolated products were also only 5-membered oxazolidinone derivative (7), containing its dehydrated derivative 8. The preferential formation of the 5-membered oxazolidinone ring system apparently indicated that this process (5-Exo-Trig ring closure) is more favorable than that of 6- or 7-membered ring derivative (3 or 9) by 6- or 7-Exo-Trig ring closure.     

Diastereoselective atom transfer radical cyclization reactions of unsaturated α-bromo oxazolidinone imides catalyzed by Lewis acids

A new Lewis acid-catalyzed atom transfer radical cyclization reaction of unsaturated α-bromo oxazolidinone imides is reported. In the presence of Lewis acids such as Mg(ClO₄)₂ and Yb(OTf)₃, a series of trans cyclic products was obtained in high yield (up to 87%) between 0°C and room temperature. The loading of strong Lewis acids, such as Yb(OTf)₃, can be reduced to 0.1 equiv. without significantly compromising the yield. Excellent diastereoselectivity could be achieved by using 1,2-stereocontrol or a chiral oxazolidinone auxiliary. For substrates 1e and 1f bearing a β-methyl substituent and the chiral auxiliary, (S)-(−)-4-benzyl-5,5-dimethyl-2-oxazolidinone, respectively, the diastereomeric ratio of the products was greater than 50:1.     

New Chiral Auxiliaries for Dynamic Kinetic Resolution: From Theory to Experiment

New efficient chiral auxiliaries for dynamic kinetic resolution (DKR) of bromides into amines are proposed, based on a theoretical rationalisation of known literature results. One example was synthesized and tested, affording diastereoselectivities up to 100 %. Several results of DKR reactions are known, based on oxazolidinone or imidazolidinone units as chiral auxiliaries. Nevertheless, their behaviour was not fully understood until a recent paper that we published. We now used our proposed mechanism to rationalize the behaviour of other similar chiral auxiliaries and to propose small structure changes in imidazolidinone rings which could largely improve their performance. We could show that the good performance of these molecules as chiral auxiliaries for DKR reactions where bromine is the leaving group and a primary or secondary amine is the nucleophile is due, in a first step, to the formation of a hydrogen bond between the amine and the ring carbonyl oxygen and, in a second step, to the strong electrostatic interaction between the leaving bromide and the carbonyl oxygen in the C‐3 substituent. Considering the behaviour of this substituent which rotates to minimize the electrostatic repulsion with the bromide when reaching the transition state, we proposed the introduction of a second substituent in the C‐4 position of the imidazolidinone ring, which prevents such rotation, thus increasing the energy difference between the transition states of the two distereoisomers. With such an auxiliary we were able to increase the best de known in literature (88 %), when benzylamine is used as nucleophile, to 99, or even 100 %, when iodide replaces the bromide in the substrate.     

Synthesis of a new chiral oxazolidinone auxiliary based on d-xylose and its application to the Staudinger reaction

The synthesis of a new chiral oxazolidinone auxiliary based on d-xylose is described which is employed in diastereoselective Staudinger-type β-lactam syntheses. Using 2-chloro-1-methylpyridinium iodide as the dehydrating reagent, the reaction of auxiliary tethered acetic acid with acyclic or cyclic imines gave the desired β-lactams in good yields with excellent cis- or trans-selectivity depending on the geometry of the imine. X-Ray structure determination of one of the obtained compounds corroborated the absolute configuration for all cis products.     

Synthesis and comparative study of cytotoxicity and anticancer activity of Chalconoid-Co(II) metal complexes with 2-hydroxychalcones analogue containing naphthalene moiety

A series of six C1–C6 chalconoid based Co(II) complexes were prepared from bi-dentate 2-hydroxychalcones ligands L1-L6 containing naphthalene moiety. All synthesized metal-complexes have been evaluated to determine their cytotoxicity and anticancer activity against liver cancer cell line (Hep G2). Compared to standard 5-fluorouracil (IC₅₀ ?= ?98.61 ?μg/mL), the metal complex C6 exhibits more potency with IC₅₀ value 64.21 ?μg/mL against liver cancer cell line. While the remaining metal complexes such as C2, C4 and C5 are moderately active with IC₅₀ value 314.93, 414.05 and 376.00 ?μg/mL respectively. The complexes C1 and C3 with IC₅₀ value ?> ?1000 ?μg/mL are inadequate to display anticancer activity against Hep G2. Our perception towards the presence of organic group in the main structural moiety of complex C6 which associated with di-hydroxy (-OH) substituent at 3 and 4-position found more potent than complex C2, C4 and C5 which associated with halo (-Cl) substituent. The MTT assay revealed that the cytotoxicity and anticancer activity enhanced upon coordination of bio-ligand compared to free chalcone ligands. Therefore the present study may lead to the development of new class of anticancer drugs with structural modification.     

Conformation of nucleoside antibiotics

Minor modifications or substitutions in the sugar or in the base part of pyrimidine and purine nucleosides have a profound effect on their biological activity. These modified nucleosides usually become antiviral, antibacterial, or cancerostatic agents and they are collectively called nucleoside antibiotics. The conformational properties of some of these nucleoside antibiotics have been studied by the PCILO method. The results obtained from such study indicate that the conformational preferences of these nucleoside antibiotics are very similar to those of their parent nucleosides and especially so in the situations that occur in aqueous solutions. The important biological significance of these results is that these nucleoside antibiotics can easily get incorporated into growing chains of DNA and RNA by mimicking their parent nucleosides and can interfere with the protein synthesis of RNA or DNA synthesis.     

Front Cover: Facile Multicomponent Synthesis of Oxazolidinones from Primary Amines and Cesium (Hydrogen)Carbonate (Eur. J. Org. Chem. 27/2023)

A facile multicomponent, catalyst-free oxazolidinone synthesis from primary aliphatic or aromatic amines, dibromoethane (DBE), and the usage of either cesium carbonate or cesium hydrogencarbonate as the simultaneous base and C1 source is reported. The applicability of this technically simple reaction was demonstrated by a broad scope with generally high yields, enabling concise late-stage functionalization of amino groups into N-substituted oxazolidinones. The proposed operating reaction mechanism consists of a first-step nucleophilic substitution reaction between DBE and the primary amine, followed by the formation of a carbamate or carbonate intermediate and subsequent cyclization. Additional versatility of the herein-developed protocol has been showcased in a medicinal chemistry approach by the generation of an oxazolidinone-modified dipeptidyl peptidase 8 (DPP8) inhibitor.