Bacterial production of 7-formamidocephalosporins. Isolation and structure determination.

Two new 7-formamidocephalosporins have been isolated as their acetyl derivatives (SQ 28,516 and SQ 28,517) from fermentations of a Flavobacterium sp. SC 12,154. Structure 1 was deduced for SQ 28,516 from its spectroscopic properties while structure 2 was proposed for SQ 28,517. SQ 28,516 exhibits weak antibacterial activity.

Binding of monobactams to penicillin-binding proteins of Escherichia coli and Staphylococcus aureus: relation to antibacterial activity.

A series of novel monocyclic beta-lactam antibiotics having side chains related to penicillin, piperacillin, azlocillin, and cefotaxime were examined with respect to binding to essential penicillin-binding proteins (PBPs) in Escherichia coli and Staphylococcus aureus. In the penicillin series, there was poor binding to all essential PBPs of E. coli (greater than 100 micrograms/ml) but good binding to PBPs 1, 2, and 3 of S. aureus (approximately 1 microgram/ml). In the piperacillin and azlocillin series, there was good binding to PBP 3 of E. coli (0.1 microgram/ml) and PBPs 1, 2, and 3 of S. aureus (approximately 1 microgram/ml). In the cefotaxime series, there was generally good binding to PBP 3 of E. coli (0.1 micrograms/ml) but poor binding to PBPs 1, 2, and 3 of S. aureus (greater than or equal to 100 micrograms/ml). With a few exceptions in the cefotaxime series, antibacterial activity paralleled essential PBP binding. Binding studies with radioactively labeled compounds revealed no additional essential monobactam-binding proteins in the two organisms. The studies suggest that monobactams are intrinsically active against both gram-positive and gram-negative bacteria; the activity spectrum of a given monobactam is determined by the binding to essential PBPs, which in turn is determined by the nature of the substituents on the beta-lactam nucleus.

Interaction between monobactams and Streptomyces R61 DD-carboxypeptidase.

The monobactams are a novel family of monocyclic beta-lactam antibiotics characterized by the 2-oxoazetidine-1-sulfonic acid moiety. A series of monobactams bind covalently to the Streptomyces R61 DD-carboxypeptidase in a manner similar to that for bicyclic beta-lactams, especially cephalosporins. The similarity of interaction was established by the following criteria: inhibition of binding by diisopropylfluorophosphate and alpha-dicarbonyls; stoichiometry of binding; similarity of partial proteolysis products of radiolabelled enzyme; rates of release of bound beta-lactams; nature of hydrolysis and hydroxylaminolysis products.

Nondepressant beta-adrenergic blocking agents. 1. Substituted 3-amino-1-(5,6,7,8-tetrahydro-1-naphthoxy)-2-propanols.

A series of 3-amino-1-(5,6,7,8-tetrahydronaphthoxy)-2-propanols was synthesized and investigated for beta-adrenergic blocking activity and direct myocardial depressant action. The cis- and trans-diols 12--15 were found to retain the beta-blocking potency of propranolol but to lack its myocardial depressant action. Compound 15 (nadolol) is currently undergoing extensive clinical evaluation as a potential antianginal, antiarrhythmic, and antihypertensive agent.

Diastereomeric 7-ureidoacetyl cephalosporins. II. 7beta [[[(Aminocarbonyl) amino]-2-thienylacetyl] amino]-7-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl) thio] methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

The synthesis and antibacterial activity in vitro of 7-methoxylated cephalosporins having a thienylureidoacetyl or a thienylglycyl C-7 side-chain are described. Acylation of 7 beta-amino-7-methoxycephems with a novel 2-aminooxazolone hydrochloride under neutral conditions gave the thienylureidoacetyl derivatives in good yield with retention of configuration. 7 beta-[[D-[(Aminocarbonyl)amino]-2-thienylacetyl]amino]-7-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio] methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (SQ 14,359) was found to have a broad-spectrum of antibacterial activity in vitro, particularly against beta-lactamase-producing organisms.

Prepartion of 16alpha-alkoxy and 16alpha-acyloxy derivatives of 21-chloro-17-acyloxy corticosteroids and determination of their vasoconstrictor activities in humans.

A number of number of 16alpha-alkoxy and 16alpha-acyloxy derivatives of 21-chloro-17-acyloxy corticosteroids have been prepared. The synthetic routes used were (a) reaction of the 16alpha,17-disubstituted 21-mesylate with lithium chloride and (b) reaction of the 16alpha-substituted 17,21-cyclic ortho ester with triphenylmethyl chloride. The vasoconstrictor activities in humans exhibited by these compounds were significantly lower than that of a 16beta-methyl analogue.