12 documents found, page 1 of 2

Reaction of naphthoquinones with substituted nitromethanes. Facile synthesis an...

We report here a simple entry into naphtho[2,3-d]isoxazole-4,9-dione system containing a EWG in position 3 using the readily available 2,3-dichloro-1,4-naphthoquinone and nitromethyl derivatives in the presence of base. Antifungal activity of synthesised naphthoquinones was evaluated against ATCC and PYCC reference strains of Candida. The results suggest that the naphtho[2,3-d]isoxazole-4,9-dione scaffold has t...

Dopamine- and tyramine-based derivatives of triazenes

A range of triazene derivatives were synthesized and investigated as prodrug candidates for melanocyte-directed enzyme prodrug therapy (MDEPT). The prodrugs contained a tyramine or dopamine promoiety required for tyrosinase activation and this was joined via a urea functional group to the cytotoxic triazene. The stability of each of the prodrugs in phosphate buffer, human plasma and in mushroom tyrosinase is di...

Azetidine-2,4-diones (4-oxo-beta-lactams) as scaffolds for designing elastase i...

A new class of inhibitors 4-oxo-beta-lactams (azetidine-2,4-diones), containing the required structural elements for molecular recognition, inhibit porcine pancreatic elastase (PPE) but show a dramatically lower reactivity toward hydroxide compared with the analogous inhibitors 3-oxo-beta-sultams. Inhibition is the result of acylation of the active site serine and electron-withdrawing substituents at the N-(4-a...

Unanticipated acyloxymethylation of sumatriptan indole nitrogen atom and its im...

Sumatriptan is a potent and selective 5-HT1B and 5-HT1D agonist used in the symptomatic treatment of migraine; it shows poor oral bioavailability ascribed, in part, to its low lipophilicity. In an attempt to develop acyloxymethyl prodrugs of sumatriptan suitable for oral administration, we carried out the reaction of sumatriptan with chloromethyl esters. To our surprise, acyloxymethylation occurred preferential...

Facile synthesis of Naphtho[2,3-d]isoxazole-4,9-diones derivatives

The 1,4-naphthoquinone scaffold in the design of cysteine protease inhibitors

A series of 1,4-naphthoquinone derivatives diversely substituted at C-2, C-3, C-5 and C-8, prepared by reaction of amines, amino acids and alcohols with commercial 1,4-naphthoquinones, has been evaluated against papain and bovine spleen cathepsin B. These 1,4-naphthoquinone derivatives were found to be irreversible inhibitors for both cysteine proteases, with second-order rate constants, k(2), ranging from 0.67...

Aminocarbonyloxymethyl ester prodrugs of flufenamic acid and diclofenac

Aminocarbonyloxymethyl ester prodrugs are known to undergo rearrangement in aqueous solutions to form the corresponding N-acylamine side product via an 0 - N intramolecular acyl transfer from the carbamate conjugate base. Novel aminocarbonyloxymethyl esters of diclofenac and flufenamic acid containing amino acid amide carriers were synthesized and evaluated as potential prodrugs displaying less ability to under...

The efficiency of C-4 substituents in activating the beta-lactam scaffold towar...

The presence of a leaving group at C- 4 of monobactams is usually considered to be a requirement for mechanism- based inhibition of human leukocyte elastase by these acylating agents. We report that second- order rate constants for the alkaline hydrolysis and elastase inactivation by N- carbamoyl monobactams are independent of the pK(a) of the leaving group at C- 4. Indeed, the effect exerted by these substitue...

Crystallization and preliminary diffraction studies of porcine pancreatic elast...

Porcine pancreatic elastase (PPE) was crystallized in complex with a novel inhibitor at pH 5 and X-ray diffraction data were collected at a synchrotron source to 1.66 angstrom. Crystals belong to the orthorhombic space group P2(1)2(1)2(1), with unit cell parameters a = 50.25 angstrom, b = 57.94 angstrom and c = 74.69 angstrom. PPE is often used as model for drug target, due to its structural homology with the i...

Dipeptide vinyl sultams

The synthesis of phosphonate derivatives of N-phenyl- and N-benzyl-gamma and delta-sultams, and their application in the Wittig-Horner reaction with N-BOC-L-phenylalanine aldehyde to afford E- and Z-isomers, are described. These compounds were further processed to provide five dipeptide vinyl sultams, which were found to be inactive against papain at concentrations up to 50 mu M. In contrast, vinyl sultams demo...