Synthesis and antibacterial activity of 2-oxocephalosporins.

The first reported synthesis of 2-oxocephalosporin derivatives has been achieved via ozonolysis of the corresponding 2-methylenecephalosporins. The new cephalosporin derivatives showed some antibacterial activity against Gram-positive bacteria, but the 2-oxo analogue of cephalothin was much less active than cephalothin itself.

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 antibacterial activity of 2-[(methoxycarbonyl)methylene]cephalosporins.

The synthesis and in vitro activities of a series of 2-[(methoxycarbonyl)methylene]-3-cephem-4-carboxylic acids with methyl or acetoxymethyl at the 3-position are described. The key step in the synthesis includes the stereospecific formation of the 2-[(Z)-(methoxycarbonyl)methylene] group by Pummerer rearrangement of the sulfoxides 3a and 3b. It was also possible to isomerize photochemically the C-2 olefin of 4a to its E isomer, 9. The new derivatives exhibited significant in vitro Gram-positive antibacterial activity.

A new class of acyclic phosphonate nucleotide analogues: phosphonate isosteres of acyclovir and ganciclovir monophosphates as antiviral agents.

Novel phosphonate isosteres of acyclovir (ACV) and ganciclovir (DHPG) monophosphates were found to be potent and selective antiherpesvirus agents. In the series of phosphonate analogues of ACV monophosphate, only the guanine analogue 20 exhibited activity against herpesviruses, similar to the structure-activity relationship observed for base modification of ACV analogues. The phosphonate isostere of ACV monophosphate (20) was more effective than ACV in the HSV-1 infected mouse model. The 3'-carba analogues of 9-[3-hydroxy-2-(phosphonomethoxy)propyl]purines/pyrimidines (adenine, HPMPA; guanine, HPMPG; cytosine, HPMPC) are devoid of antiherpesvirus activity. This result confirms that the beta-oxygen atom of the phosphonomethyl ether functionality in HPMP-purines/pyrimidines plays a critical role for activity against herpesviruses.

Acyclic purine phosphonate analogues as antiviral agents. Synthesis and structure-activity relationships.

A series of 9-(phosphonoalkyl)purines, which are analogues of 9-[2-(phosphonomethoxy)ethyl]purines (guanine, PMEG, 1; adenine, PMEA, 2), were synthesized. The analogues were tested for activity against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), human cytomegalovirus (HCMV), Rauscher murine leukemia virus (R-MuLV), and human immunodeficiency virus type 1 (HIV-1). With variations in the length of the alkyl chain, the optimal activity was achieved with two carbons between the purine base and the phosphonomethoxy functionality. Despite the structural similarity and the close pKa2 value of 8 to that of PMEG, no phosphorylation of 8 was observed by the bovine brain guanylate kinase. Since all isosteric analogues of PMEG (7-9) were not inhibitory against HSV-1 and HSV-2, the presence of the 3'-oxygen atom in the PME purines proved critical for anti-HSV activity. Introduction of the 1'-methyl group on the PMEG side chain significantly reduced its anti-HSV activity. Analogue 11, which is a mimic of the phosphate by incorporation of the alpha,alpha-difluoro carbon, was ineffective against HSV-1 and HSV-2. These results suggest that the structural requirements of PME purines for anti-HSV activity appear to be very strict.

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.

4-Thiazolidinones: novel inhibitors of the bacterial enzyme MurB.

4-Thiazolidinones were synthesized and evaluated for their ability to inhibit the bacterial enzyme MurB. Selected 4-thiazolidinones displayed activity against the enzyme in vitro. This activity, coupled with the design principles of the thiazolidinones, supports the postulate that 4-thiazolidinones may be recognized as diphosphate mimics by a biological selector.