Development of a new quantitative approach for the isobolographic assessment of the convulsant interaction between pefloxacin and theophylline in rats.

Purpose: A new mathematical approach was developed to quantify convulsant interaction between pefloxacin and theophylline in rats.

Methods: Animals received each compound separately or in different combination ratios. Infusion was stopped at the onset of maximal seizures.

A model allowing the design of modified nucleosides as HIV-RT inhibitors.

A chemical, structural, molecular electrostatic potential (MEP) analysis of modified nucleosides allows the understanding of how nucleosides interact with different receptors. The interaction with kinases is sensitive to base modifications, while the interaction with the reverse transcriptase receptor HIV active site is more affected by ribose modifications. The model herein indicates a geometrical lower limit in the width of the modified sugar that corresponds to the 3' erythro position.

Synthesis and antiviral activity of new carbonylphosphonate 2',3'-dideoxy-3'-thiacytidine conjugates.

The synthesis of new potential PFA-BCH-189 conjugate analogues is described and their molecular structure clearly identified through NMR and mass spectra techniques. The anti-HIV-1 activity was determined according to the inhibition of syncytium formation in MT-4 cells, while the anti-HBV activity was determined in infected duck hepatocytes. Both antiviral activities of the PFA-BCH-189 conjugates were much lower than those of the parent BCH-189 (2',3'-dideoxy-3'-thiacytidine) (1).

Inhibition of human immunodeficiency virus type 1 replication by phosphonoformate- and phosphonoacetate-2',3'-dideoxy-3'-thiacytidine conjugates.

The synthesis of potential "combined prodrugs" where phosphonoformic acid (PFA) or phosphonoacetic acid (PAA) was attached to the 5'-O or N4 position of 2',3'-dideoxy-3'-thiacytidine (BCH-189) is described. The anti-HIV-1 activity of 11 analogues which included carboxylic ester or phosphoric ester linkages of PFA or PAA to BCH-189 was determined in MT-4 cells. Of these compounds, the IC50 of analogues 3, 4, 6, and 7 ranged from 0.

Tetrazole isosteres of biologically active acids and their effects on enzymes.

A number of tetrazole analogs of carboxylic substrates and inhibitors have been tested. Lactic and pyruvic tetrazoles were found to be competitive inhibitors of rabbit muscle L-lactate dehydrogenase in both the pyruvate reduction and the lactate oxidation reactions (Ki's of 0.04 M and 0.