Formal synthesis of Thienamycin.

A formal synthesis of Thienamycin from ethyl (E)-crotonate and a cyclic five-membered nitrone derived from 2-deoxy-d-ribose is described. The synthesis involves 1,3-dipolar cycloaddition, cleavage of the N-O bond in the adduct, and intramolecular N-acylation to afford a bicyclic carbapenam skeleton. Subsequent transformations of the five-membered ring substituents provide the title compound.

Preparation and Optimization of Meropenem-Loaded Solid Lipid Nanoparticles: In Vitro Evaluation and Molecular Modeling.

Encapsulation of antibiotics into nanocarriers has the potential to overcome resistance and disadvantages associated with conventional dosage forms as well as increase half-life of an antibiotic. Encapsulation of meropenem (MRPN) into solid lipid nanoparticles (SLNs) remains unexplored among the limited work reported on nanoformulation incorporating MRPN. The study aimed to use an experimental design, to optimize MRPN-loaded SLNs, and to undertake in vitro and in silico evaluations. A Box-Behnken design (BBD) was used to optimize manufacturing conditions of glycerol monostearate (GMS) SLNs loaded with MRPN. The SLNs were prepared using hot homogenization and ultrasonication method. Optimized MRPN-SLNs showed particle size, zeta potential, and entrapment efficiency of 112.61 ± 0.66 nm, -20.43 ± 0.99 mV, and 89.94 ± 1.26%, respectively. The morphology of the SLNs revealed nearly spherical shaped particles. Differential scanning calorimetry and X-ray diffraction analysis showed that meropenem was present in amorphous form in the SLNs. Controlled in vitro MRPN release from SLNs was achieved and followed the Korsmeyer-Peppas model (R 2 = 0.9679). Prolonged in vitro antibacterial activity against Escherichia coli was also observed. The molecular modeling showed that both hydrophobic interactions and hydrogen bonding led to a stable MRPN-GMS complex formation, which was confirmed by its low heat of formation (-5536.13 kcal/mol). This stable complex could have contributed to the controlled release of MRPN from the SLNs and subsequent sustained antibacterial activity.

Synthesis of Thienamycin methyl ester from 2-deoxy-D-ribose via Kinugasa reaction.

A novel synthesis of thienamycin is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from D-lactic acid and suitable, partially protected, five-membered cyclic nitrone obtained from 2-deoxy-D-ribose. The reaction was performed in the presence of tetramethylguanidine as a base to provide 5,6-trans substituted carbapenam as the main product. Thus obtained carbapenam 11 with (5R,6S) configuration at the azetidinone ring was subsequently subjected to oxidation/deprotection/oxidation reaction sequence to afford the ß-keto ester 20, which was directly transformed into N,O-protected methyl ester of thienamycin.

Oxazoline N-oxide mediated [2 + 3] cycloadditions. Application to a formal synthesis of (+)-carpetimycin A.

[formula: see text] Cycloaddition between gamma,delta-unsaturated beta-enamino ester 9 and camphor-derived oxazoline N-oxide 8 afforded a single adduct, 14. Dipolarophile 9 proved to be very reactive despite the substitution on the double bond. Stereoselective sodium cyanoborohydride reduction of the imminium intermediate 14a gave rise stereoselectively to beta-amino ester derivative 15a. Oxidative acidic hydrolysis, oxidation of the resulting aldehyde 18, deprotection, and cyclization afforded the beta-lactam 23, a direct precursor of (+)-carpetimycin A.

Synthesis of some thieno gamma lactam monocarboxylic acids with high antibacterial activity: a new look at an old molecular system.

Synthesis and antibacterial activity of some novel monocyclic thienyl gamma lactams are reported. The compounds have been synthesized by a two-step process consisting of, first, intermolecular Michael addition, followed by intramolecular amidification between suitable arylamino malonate and 3-(2'-thienyl) acryloyl chloride and then hydrolysis cum in situ decarboxylation of the diacid. The compounds showed moderate to high antibacterial activity against gram positive and gram negative bacteria.

Synthesis and antibacterial activity of novel 4-pyrrolidinylthio carbapenems--I. 2-Alkoxymethyl derivatives.

The synthesis and in vitro antibacterial activity of a novel series of 2-alkoxymethyl-4-pyrrolidinylthio-1 beta-methyl carbapenems are described. As a result of these studies, we discovered that FR27743 (19j) containing a novel 2-fluoroethoxymethyl substituent possesses a broad spectrum of antibacterial activity against both Gram-positive and Gram-negative organisms, including Pseudomonas aeruginosa. Furthermore, FR27743 exhibited excellent stability against renal dehydropeptidase-I (DHP-I), good urinary recovery, and superior in vivo activity compared to that for Meropenem against several systemic infections.

Heteroaryliumthio substituted carbapenem derivatives: synthesis and in vitro activity of 1 beta-methyl-2-(dihydropyrrolotriazoliumthio)carbapenems.

The syntheses of five thiols, including three dihydropyrrolotriazoliumthiol salts, 1,4-dimethyl-5-mercaptomethyl-1,2,4-triazolium trifluoromethanesulfonate, and 6-mercapto-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium chloride; and the addition of these thiols to 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphono)oxy-6-[1(R)-hydroxyethyl]-1-met hylcarbapen-2-em-3-carboxylate and the subsequent hydrogenolysis of the addition products is described. The latter thiol provides a new route towards the preparation of L-627 (LJC 10,627). The compounds were evaluated in vitro against a panel of Gram-positive and Gram-negative bacteria and their antibacterial activities compared with imipenem. The compounds were measured for their hydrolytic stability to dehydropeptidase I (DHP-I) relative to imipenem. The five compounds generally had poorer Gram-positive and Pseudomonas activity than imipenem, although their Gram-negative activity was variably improved. The monocyclic triazolium analog was nearly comparable in overall activity to the four bicyclic heterarylium analogs evaluated, including L-627 (LJC 10,627). All compounds were more stable to DHP-I than imipenem, although minor differences existed among them.

The synthesis, antibacterial, and beta-lactamase inhibitory activity of a novel asparenomycin analog.

An analog, 6-(2'-hydroxyethylidene)-4 beta-methyl-1-azabicyclo[3.2.0]hept-2-ene-2- carboxylate (11), of the carbapenem beta-lactamase inhibitor, asparenomycin A, was synthesized. It possessed a spectrum of antibacterial activity that was comparable to that of asparenomycin A but was less effective as a beta-lactamase inhibitor. With ampicillin, it only exhibited a moderate level of synergy against a variety of beta-lactamase-producing organisms. Although the presence of a 4 beta-methyl group in the analog brought about a significant increase in chemical stability relative to that of asparenomycin A, it did not result in an increase in stability to kidney dehydropeptidase enzyme.

Carbapenem and penem antibiotics. V. Synthesis and antibacterial activity of 2-functionalized-methyl 1-methylcarbapenems related to asparenomycins.

The synthesis of 1 alpha- and/or 1 beta-methylcarbapenems, 2-unsubstituted and 2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl derivatives having a 1-(hydroxy)methylethylidene or cyclic carbonate side chain at the C-6 position, is described. The in vitro antibacterial activities of these compounds and their corresponding 1-unsubstituted carbapenems are compared.

Synthesis and antibacterial activity of 5-methylcarbapenems.

Four possible racemic isomers of N-acetyl-5-methylthienamycin derivatives were synthesized and their antibacterial activities are discussed in relation to their physico-chemical properties. 5-Methylcarbapenems having various C-2 side chains were also prepared.

Synthetic studies of 1-beta-methylcarbapenem antibiotics.

The diastereoselective synthesis of the 1-beta-methylcarbapenems, (1R,5R,6S)-6-((R)-1-hydroxyethyl)-2-((S)-1-acetimidoylpyrrolidin-3 - ylthio)-1- methyl-1-carbapen-2-em-3-carboxylic acid and sodium (1R,5R,6S)-6-((R)-1-hydroxyethyl)-2-(5-chloro-2-oxobenzoxazolin-3- y l)-1- methyl-1-carbapen-2-em-3-carboxylate has been achieved. The key step was an aldol reaction between the achiral boron enolate which was generated from dibutylboron triflate and 3-propionyl-2-oxobenzoxazoline, and (3R,4R)-4-acetoxy-3-((R)-1-hydroxyethyl)azetizin-2-one.

Synthesis and in vitro activity of 1 beta-methyl C-2 quaternary heterocyclic alkylthio carbapenems.

New 1 beta-methylcarbapenems having various (substituted) quaternary heterocyclic alkythio groups at the C-2 position were synthesized and tested for antibacterial activity and renal dipeptidase susceptibility. Compounds having the 1 beta-methyl substituent were found to possess an increased stability to the enzyme. In addition, combination of the 1 beta-methyl substituent and the C-2 quaternary heterocyclic alkylthio side chain generated compounds with excellent antipseudomonal activity and improved stability toward hydrolysis by renal dipeptidase.

Synthesis and in vitro activity of C-2 quaternary heterocyclic alkylthio carbapenems.

The synthesis of new carbapenems having various (substituted) quaternary heterocyclic alkylthio groups at the C-2 position is described. The in vitro antibacterial activity and the dehydropeptidase-I susceptibility were examined. Some of these compounds (e.g., 11, 16, 26 and 27) showed an excellent wide spectrum of in vitro antibacterial activity including activity against Pseudomonas aeruginosa and greater stability than imipenem toward the dehydropeptidase-I.

Modification of the cysteamine side chain of thienamycin. II.

A new type of thienamycin derivatives (3a-3j, 4a, 4b), having a monothioacetal or a thioacetal side chain at the C-2 position was prepared, and the susceptibility to renal dehydropeptidase-1 (DHP-1) and the antimicrobial activity of these compounds were determined. The structure-activity relationships of these derivatives are also discussed.

Ester-imine condensations: preparation of racemic intermediates for the synthesis of the carbapenem antibiotics PS-5 and PS-6.

The lithium enolates of ethyl butyrate and ethyl isovalerate react with N-p-methoxyphenylcinnamaldimine in tetrahydrofuran (THF)-hexamethylphosphoric triamide (HMPA) to afford predominantly trans beta-lactams 9 (67%) and 20 (78%), respectively. beta-Lactam 9 was converted to PS-5 intermediate 18 in 21% overall yield (8 steps). Beta-lactam 20 was converted to PS-6 analog 28 in 22% overall yield using an eight step sequence.