Synthesis and in Vitro Evaluation of N-[[4-[2-(Carboxyl)-1-Cycloalken-1-yl]Phenyl]Methyl]Imidazoles as Nonpeptide Angiotensin II Receptor Antagonists

A series of nonpeptide angiotensin II receptor antagonists was synthesized via palladium-assisted cross coupling of aryl stannane and cycloalkenyl triflates and subsequent alkylation of silyl-protected imidazole. Our compounds, which have a terminal five- to seven-membered cycloalkenyl ring, are compared to DuPont EXP7711, an N-[(2′-carboxybiphenylyl)methyl]imidazole, which has a terminal phenyl moiety. Physicochemical properties of the compounds, such as lipophilicity, steric bulk, conformation, and the relative spatial proximity of the 2-carboxyl and the middle phenyl, are quantitated by computational chemistry. Potency in terms of binding affinity to AT₁ receptors in rat adrenal glomerulosa and rabbit aorta is maximized when the terminal ring is aromatic.     

OBSERVATIONS ON THE SYNTHESIS AND in vivo PHOTODYNAMIC ACTIVITY OF SOME BENZOCHLORINS

An improved synthesis of benzochlorins is reported. Demetallation of the meso-hydroxymethylvinyl derivative of octaethylporphyrin, followed by treatment with sulfuric acid results in cyclization to generate the corresponding octaethylbenzochlorin in high yield. Prolonged treatment with acid generates the sulfonated derivative. These sensitizers were shown to be efficient photodynamic agents in vivo. Animals bearing a transplanted N-[4-(5-nitro-2-furyl)-2-thiazoly]formamide induced urothelial tumor were treated with either the benzochlorin or its sulfonated derivative. Irradiation of tumors 24 h later resulted in a significant tumoricidal effect in a short term assay. We conclude that benzochlorins warrant further examination as potential agents for use in photodynamic therapy.     

Synthesis and in Vitro Evaluation of New Cephalosporins Exhibiting Antimicrobial Activity against Gram-Positive Bacteria,in Particular Methicillin-Resistant Staphylococci

The preparation and biological evaluation of 7β-[[2-(phenyl)thiazol-4-yl]acetamido]cephalosporins and 7β-[[(2-(pyridin-2-yl)thiazol-4-yl]acetamido]cephalosporins, 9a-o , substituted at the 3-position with acetyloxymethyl, chlorine, hydrogen, and methyl are described. Hantzsch's thiazole synthesis is employed to provide thiazoleacetic acids 5a-e , subsequently followed by Morpho CDI-assisted amidation to complete the synthesis of target cephalosporins 9a-o . These compounds display activity selectively against Gram-positive bacteria, but are inactive against most Gram-negative bacteria tested. Those with acetyloxymethyl at the 3-position, i.e., 9a, 9e, 9i, 9m , and 90 , exhibit activity with minimal inhibitory concentrations of 16 (μg/mL or lower against four strains of methicillin-resistant staphylococci, namely Staphylococcus aureus X400 and S13E and Staphylococcus epidermidis 270 and 222. Notably, 9a displays an activity profile similar to that of vancomycin regarding its spectrum and potency.     

VERDINS: NEW PHOTOSENSITIZERS FOR PHOTODYNAMIC THERAPY

The in vivo cytotoxic effect of verdins was determined by histological methods, using the FANFT-induced urothelial tumor line (AY-27). The results indicate that the verdins may be good alternatives to hematoporphyrin derivative for photodynamic therapy.