The Synthesis of Substituted Penicillins and Simpler Structural Analogs. XII. 6-Benzylsulfonamidopenicillanic Acid

Design, Synthesis, Crystal Structures, and Antimicrobial Activity of Sulfonamide Boronic Acids as β-Lactamase Inhibitors

“…It therefore seemed interesting to replace the ubiquitous carboxamide, present in the R 1 side chain of both β-lactams and their boronic acid mimics, by a sulfonamide (Scheme ). Whereas sulfonamide replacements for carboxamides date back to the seminal synthetic work of Sheehan in the 1950s, these derivatives were never used clinically and, as far as we know, have never been explored among β-lactamase inhibitors previous to this year. Very recent work by Tan et al at Merck revealed two arylsulfonamide boronic acids with activity in the low micromolar range (IC 50 a Abbreviations: LE, ligand efficiency (=(Δ G binding (kcal/mol))/(number of non-hydrogen atoms)); PDB, Protein Data Bank; IC 50 , half-maximal inhibitory concentration; SAR, structure−activity relationship; MIC, minimum inhibitory concentration; CLSI, Clinical and Laboratory Standards Institute; CAZ, ceftazidime; FOX, cefoxitin; THF, tetrahydrofuran; TLC, thin layer chromatography. between 0.57 and 5.6 μM) against five different β-lactamases …”

β-Lactam Antibiotics: Their Physicochemical Properties and Biological Activities in Relation to Structure

“…Sheehan and his colleagues achieved the p-lactam synthesis (21,22), which led to the formation of 5phenylpenicillin (23,24) and the sulfonyl analog of benzylpenicillin (25). This group also succeeded in the total synthesis of penicillin V (26,27) and other penicillins (28).…”

Thiazine Derivatives. III. The Synthesis of Some 2-Substituted 5,6-Dihydro-1,3(4H)-thiazines and Tetrahydro-1,3-thiazines Related to Cephams1

“…These procedures have been shown to be effective in closing the /3-lactam ring in the penicillin series. 16,17 Employing , '-dicyclohexylcarbodiimide18 in a variety of solvents and solvent mixtures also failed to produce the desired product. When this reagent and IIIg-HCl were refluxed overnight in tetrahydrofuran, a 60% yield of the thiazineurea hydrochloride (VI) compound was quantitative.…”

“…B. Boron Trifluoride Method.-A solution of 12.09 g (0.1 mole) of 3-hydroxy-3-methylbutane-l-thiol, 16.0 g (0.14 mole) of ethyl cyanoaeetate, and 60 ml of freshly distilled boron trifluoride etherate in 200 ml of dry ether was flushed with nitrogen and allowed to stand at room temperature for 7 days. The solvent was removed under aspirator pressure, and 200 ml of water was added to the residue.…”

“…2-(2-Carbomethoxyethyl)-4,4-dimethyl-5,6-dihydro-l,3(4H)thiazine (Ilf).-A solution of 12.0 g (0.1 mole) of 3-hydroxy-3methyl-n-butanethiol, 16.0 g (0.14 mole) of methyl 3-cyanopropionate, 60 ml of boron trifluoride etherate in 200 ml of anhydrous ether was flushed with nitrogen and allowed to stand for 10 days at room temperature. The ether solution was extracted four times with 75-ml portions of cold water and the aqueous extracts were neutralized with 5% sodium carbonate.…”