Gerardo D. Francisco

Muraymycins, novel peptidoglycan biosynthesis inhibitors: semisynthesis and SAR of their derivatives.

Sixteen muraymycin derivatives 2-17 were synthesized based on selective reactions of the primary and secondary amino groups of muraymycin C1 (1) with isocyanates and aldehydes. Disubstituted derivatives 3-9 demonstrated no activity against either MraY or MurG at <or=100 microg/mL whereas mono substituted derivatives 11-17 demonstrated good inhibitory activity, well correlated with the lipophilicity of the substituent introduced. In particular, the activity of derivatives 13 and 14 was comparable to that of muraymycin C1 in this assay.

2-Phenyl-5,6-dihydro-2H-thieno[3,2-c]pyrazol-3-ol derivatives as new inhibitors of bacterial cell wall biosynthesis

Twenty-five 2-phenyl-5,6-dihydro-2H-thieno[3,2-c]pyrazol-3-ol derivatives were synthesized for evaluation as new inhibitors of bacterial cell wall biosynthesis. Many of them demonstrated good inhibitory activity against Staphylococcus aureus MurB, MurC and MurD enzymes in vitro and antimicrobial activity against gram-positive bacteria including MRSA, VRE and PRSP. However, when they were tested in the presence of 4% bovine serum albumin, the MIC values increased to greater than 128 microg/mL against PRSP. None of the compounds demonstrated activity against gram-negative bacteria at MIC <32 microg/mL.

6-(1-hydroxyalkyl)penam sulfone derivatives as inhibitors of class a and class C β-lactamases I

Two stereoselective processes for the synthesis of novel 3,6-disubstituted penam sulfone derivatives were developed. One 6beta-(1-hydroxyethyl) and four 6beta-hydroxymethyl penam sulfone derivatives were synthesized. All four 6beta-(hydroxymethyl)penam sulfone derivatives demonstrated good IC50 against both TEM-1 and AmpC beta-lactamases. Of these, 6beta-hydroxymethyl penam sulfone derivative 25 was the most active inhibitor which was able to restore the activity of piperacillin in vitro and in vivo against both TEM-1 and AmpC beta-lactamases producing organisms.

2,3,6-Substituted quinazolinones as angiotensin II receptor antagonists

Abstract The synthesis and biological evaluation of a series of 2,3,6-substituted 4(3H)quinazolinones is described. One of these compounds, CL329, 167, was found to be a potent, orally active, competitive angiotensin II receptor antagonist with a long duration of action.

The synthesis and structure activity relationships of enantiomerically pure hydroxylated oxotremorine derivatives

Abstract The synthesis and radioligand binding data of optically active hydroxylated oxotremorine derivatives are described. These are significant pharmacological differences between the enantiomers, most notably at the 3- and 4-position of the pyrrolidinone ring. In addition, there appears to be one side of the pyrrolidinone ring that accommodates substituents better than the other (facial selectivity).

Synthesis of substituted 5-amino-8-phenyl-3H,6H-1,4,5a,8a-tetraazaacenaphthalen-3-ones, a new class of agents for the improvement of cognition.

Abstract The synthesis of the novel 5-amino-8-phenyl-3H,6H-1,4,5a,8a-tetraazaacenaphthalen-3-one ring system has yielded several compounds which display activity in the reversal of cognition deficits in rats and mice as compared to existing reference agents. Activity was determined by improvements in Hypoxic Survival and Anoxic-Induced Amnesia tests. The synthesis and biological activity of the title compounds is described.