Joseph P. Sanchez

A new class of anti-HIV-1 agents targeted toward the nucleocapsid protein NCp7: The 2,2′-dithiobisbenzamides

As part of the National Cancer Institutes Drug Screening Program, a new class of antiretrovirals active against the human immunodeficiency virus HIV-1 has been identified, and the HIV-1 nucleocapsid protein NCp7 was proposed as the target of antiviral action. The 2,2-dithiobis-[4-(sulfamoyl)benzanilide] (3x) and the 2,2-dithiobis(5-acetylamino)benzamide (10) represented the prototypic lead structures. A wide variety of 2,2-dithiobisbenzamides were prepared and tested for anti-HIV-1 activity, cytotoxicity, and their ability to extrude zinc from the zinc fingers for NCp7. The structure-activity relationships demonstrated that the ability to extrude zinc from NCp7 resided in the 2,2-dithiobisbenzamide core structure. The 3,3 and the 4,4 isomers were inactive. While many analogs based upon the core structure retained the zinc extrusion activity, the best overall anti-HIV-1 activity was only found in a narrow set of derivatives possessing carboxylic acid, carboxamide, or phenylsulfonamide functional groups. These functional groups were more important for reducing cytotoxicity than improving antiviral potency or activity vs NCp7. All of the compounds with antiviral activity also extruded zinc from NCp7. From this study several classes of low microM anti-HIV agents with simple chemical structures were identified as possible chemotherapeutic agents for the treatment of AIDS.

Chapter 11. New Approaches and Agents to Overcome Bacterial Resistance

Publisher Summary This chapter discusses the challenges posed by anti-bacterial resistance (AR) in four sections, covering the magnitude and scope of AR and the problem organisms, the mechanistic aspects of AR, new bacterial targets and the methods for screening and synthesis, and a review of the selected anti-bacterials reported to offer some solution or promise toward overcoming AR. Anti-bacterial resistance is a serious health and worldwide problem with catastrophic potential. Several overviews on the general mechanisms, by which bacteria acquire resistance, have appeared and the modes of quinolone resistance in particular have been described in the chapter. Gyrase and topoisomerase IV are the quinolone targets in bacteria. All high level quinolone resistance in gram-negatives, methicillin resistant S. aureus (MRSA), S. pneumoniae , and Enterococci, have been shown to be associated with double mutations in gyrase at the Ser 83 and the amino acid (AA) at 87 (E. coli numbering). Porin and efflux mutations play minor roles in high level resistance. Mechanisms of tetracycline resistance involve efflux and ribosomal protection. The glycylglycines are the first tetracylines to overcome this resistance. The mechanism of vancomycin resistance has been described in this chapter. Enterococci with the vanB phenotype are resistant to vancomycin but not teicoplanin. This resistant phenotype has been shown to originate with the two component signaling proteins vanS and vanR that activate the gene cascade, leading to vancomycin resistance (VRE). In the vanB phenotype, the histidine kinase fails to recognize teicoplanin. Aminoglycoside (AG) resistance arises from acetylation, adenylation, or phosphorylation by AG modifying enzymes. To defeat MRSA, MecA (the modified penicillin binding protein), and several essential auxiliary gene products for cell wall synthesis are suggested as targets. Such genes have been identified by a novel selection technique.

An efficient synthesis and mechanism of formation of 6-acetyl-1,2-dihydro-2-oxo-3-pyridinecarboxylic acid

Abstract Starting with 3,3-dimethoxy-2-butanone (biacetyl monoketal) ( 1 ), 6-acety1-l,2-dihydro-2-oxo-3-pyridinecarboxylic acid ( 9a ) has been prepared in large quantities by a highly efficient synthetic sequence. The isolation of 2-cyano-5-hydroxy-6-oxo-2,4-heptadienamide ( 6 ) and the identification of 2-cyano-6,6-dimethoxy-5-oxo-2-heptenamide ( 4a ) from the reaction mixture suggests that the final ring closure may involve a dehydration of this sterically hindered enamide.