Synthesis and antimicrobial properties of cephalosporin derivatives substituted on the C(7) nitrogen with arylmethyloxyimino or arylmethyloxyamino alkanoyl groups.

Some 7-aminocephalosporanic acid (7-ACA) derivatives substituted on the C(7) nitrogen with 2-(arylmethyloxyimino)propionyl (3a-f), 2-(arylmethyloxyamino)propionyl (4a-d) and (arylmethyloxyamino)acetyl (2a-d) moieties were synthesized by reaction of the appropriate acylating agents with 7-ACA protected as a t-butyl ester, followed by removal of the t-butyl protecting group. The new compounds, tested in vitro for their antimicrobial activity against Gram-positive and Gram-negative bacteria, proved to possess a modest activity directed only against Gram-positive microorganisms.

Synthesis and aldose reductase inhibitory activity of new N-(benzyloxy) glycine derivatives.

This paper reports the synthesis and aldose reductase (AR) inhibitory properties of some N-(benzyloxy) glycine derivatives (compounds 2-6), structurally related to the previously described N-(aroyl)-N-(arylmethyloxy) glycines A which had proved to possess an appreciable AR inhibitory activity. In compounds 2-5, spacers of different lengths and degrees of rigidity were inserted between the phenyl ring and the carbonyl group of type A derivatives; compound 6 differs from the most active type A derivative (compound 1) in the replacement of the methoxy moiety in the para position of the benzoyl side-chain with a group with different electronic characteristics, such as the trifluoromethyl moiety. Biological results indicated that among compounds 2-5 only derivative 3, which presents a CH2CH2 spacer between the phenyl and the carbonyl moiety, proved the possess AR inhibitory properties analogous to those of 1, while all the other compounds proved to be devoid of any significant activity. Furthermore, compound 6 showed an inhibitory activity about 3 times lower than that of 1.

A structure-activity study of a C-terminal endothelin analogue.

We report a structure-activity study of an endothelin (ET) analogue, obtained by introduction of a non-aminoacidic portion on the C-terminal ET pentapeptide. The peptidic moiety was modified with systematic replacement of each residue by alanine (Ala scan); further modifications were performed at the C-terminus. The biological activity was analyzed at both ET(A) and ET(B) receptor subtypes, showing that the two C-terminal residues (Ile-Trp) are very important for the activity. On the contrary, the aminoacidic central portion of the molecule appears to be much more tolerant toward modifications.

Toward the rational development of peptidomimetic analogs of the C-terminal endothelin hexapeptide: development of a theoretical model.

In an early report on the structure-activity relationship of endothelin (ET) peptides, it was reported that the C-terminal hexapeptide ET(16-21), His-Leu-Asp-Ile-Ile-Trp, is the minimum ET fragment which maintains biological activity in some, but not all the tissues responding to ETs. Subsequently, other authors described a series of analogs of this peptide, in which the His 16 residue was replaced by non-natural amino acids, characterized by bulky aromatic side chains. Among them, two well-characterized non-selective ETA/ETB antagonists were PD 142893 and PD 145065; interest in these potent ET antagonists was, however, reduced by their peptidic structure which was likely to lead to undesirable properties such as poor bioavailability and short duration of action. On the basis of these premises, our previous studies led to the development of a peptidomimetic ligand of ET receptors (compound 3), based on the replacement of the His 16 residue of ET(16-21) with an (E)-N-(benzyloxy)iminoacyl moiety; compound 3 proved to possess a certain affinity for ET receptors, albeit lower than that shown by PD 142893 and PD 145065. We report here on ETA/ETB binding affinity of compounds 4-12, designed as a new series of ET(16-21) analogs. Compounds 4 and 5 were practically devoid of any affinity; derivatives 6-12 exhibited appreciable affinity indices for ETB receptors higher than that shown by 3, even if still lower than that obtained for PD 145065. This paper also describes the development of a pharmacophoric model able to explain the ET receptor binding properties of our hexapeptide analogs compared with those of PD 142893 and PD 145065 and IRL2500, recently reported as a potent ETB selective endothelin antagonist.

Synthesis and antimicrobial activity of 7 beta-(S)- and 7 beta-[(R)-3-(methyleneaminoxy)-2-methylpropionamido]substituted cephalosporanic acid derivatives.

Some 7-amino cephalosporanic acid derivatives substituted on the C(7) nitrogen with (S)-and (R)-3-(methyleneaminoxy)-2-methylpropionyl groups were synthesised and tested in vitro for their antimicrobial activity against Gram-positive and Gram-negative bacteria. Some of the new compounds showed a modest activity directed only against Gram-positive microorganisms.

Synthesis and antimicrobial activity of 7 beta-[N-(arylmethyloxyimino) acetamido]cephalosporanic acid derivatives.

Some cephalosporanic acid derivatives substituted on the C(7) amino nitrogen with (arylmethyloxyimino)acetyl moieties were synthesized and tested in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria. The new compounds showed a modest activity directed only against Gram positive microorganisms.