Noel D. Jones

Indole inhibitors of human nonpancreatic secretory phospholipase A2. 3. Indole-3-glyoxamides.

Phospholipases (PLAs) produce rate-limiting precursors in the biosynthesis of various types of biologically active lipids involved in inflammatory processes. Increased levels of human nonpancreatic secretory phospholipase A2 (hnps-PLA2) have been detected in several pathological conditions. An inhibitor of this enzyme could have therapeutic utility. A broad screening program was carried out to identify chemical structures which could inhibit hnps-PLA2. One of the lead compounds generated by the screening program was 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (13a). We describe the syntheses, structure−activity relationships, and pharmacological activities of a series of indole-3-acetamides and related compounds derived from this lead. This SAR was undertaken with the aid of X-ray crystal structures of complexes between the inhibitors and hnps-PLA2 which were of great value in directing the SAR.

A83543A-D, unique fermentation-derived tetracyclic macrolides

Abstract A multi-factored complex of structurally-unique macrolides was isolated from culture broths of a new species of Saccharopolyspora. The core structure consists of a 5,6,5-cis-anti-trans-tricyclic ring system fused to a 12-membered macrocyclic lactone, which is further substituted by an amino- and a neutral sugar.

Molecular modeling of γ-lactam analogues of β-lactam antibacterial agents: synthesis and biological evaluation of selected penem and carbapenem analoques

Abstract Computational chemistry made possible the prediction of the three-dimensional structures of γ-lactam analogues of penems and carbapenems before the analogues were made. Molecular superpositioning showed that these novel structures with a 7β-acylamino side-chain present the pharmacophoric groups in close spatial similarity to the groups in biologically active cephalosporin and penicillin antibiotics. This suggests that 8-oxo-7-acylamino-1-azabicyclo[3.3.0]-oct-2-ene-2-carboxylates and the 4-thia-analogues can be accommodated in the same active sites of essential bacterial penicillin-binding proteins where cephalosporins and penicillins are recognized. The syntheses of these compounds are reported. The γ-lactams exhibit low, but detectable levels of antibacterial activity and suggest promise that substantial activity can be achieved with other γ-lactams.

γ-Lactam analogues of carbapenems

Abstract γ-Lactam analogues of carbapenems have been synthesized using a [3+2] cyclization approach. Slight antibiotic activity was observed in one case.

D-Phe-Pro-p-Amidinobenzylamine: A potent and highly selective thrombin inhibitor

Abstract The design, synthesis, and enzyme inhibitory profile of D-Phe-Pro-p-Amidinobenzylamine are presented. This compound has inhibitory activity equivalent to D-Phe-Pro-Arg-H, two orders of magnitude more potent than D-Phe-Pro-Agmatine. The results indicate that binding energy provided by the covalent bond of a transition-state analog can be replaced with noncovalent interactions.

Bicyclic pyrazolidinones, steric and electronic effects on antibacterial activity

Abstract Bicyclic pyrazolidinones were synthesized as γ-lactam analogs of the β-lactam antibiotics. Several of these compounds exhibited broad spectrum in vitro antibacterial activity.

Serine protease selectivity of the thrombin inhibitor D-Phe-Pro-Agmatine and its homologs

Abstract Analogs of D-Phe-Pro-Agmatine were assayed for inhibititory activity versus thrombin, trypsin, plasmin, n-tPA and urokinase. The X-ray structure of the thrombin/D-Phe-Pro-Agmatine co-crystal revealed that the agmatine and analogous arginals have very similar bound conformations.

Pyrazomycin B: Isolation and characterization of an α-C-nucleoside antibiotic related to pyrazomycin

Abstract This communication reports the isolation and structure of pyrazomycin B, the α-anomer of the anti-tumor and anti-viral antibiotic pyrazomycin. Spectral, chemical and x-ray crystallographic evidence is provided.

C(3)-azido cephem II

Abstract The major product from the thermolysis and photolysis of C(3)-azido cephem 2 is the ring expanded 1,4,6-thiadiazepine azetidinone.

N-substituted glycines as replacements for proline in tripeptide aldehyde thrombin inhibitors

Abstract We have prepared a series of tripeptide arginine aldehydes in which the P2 proline has been replaced with a variety of N -substituted glycines. The effects of these modifications on thrombin inhibitory potency and serine protease selectivity were evaluated.