Miron T. Caproiu

Carbonic anhydrase inhibitors: sulfonamides incorporating furan-, thiophene- and pyrrole-carboxamido groups possess strong topical intraocular pressure lowering properties as aqueous suspensions

Important physiological and physio-pathological functions are played by several carbonic anhydrase (CA, EC 4.2.1.1) isozymes, which are strongly inhibited by aromatic and heterocyclic sulfonamides. Here we report several new types of such sulfonamides, incorporating furan-, thiophene- and pyrrole-carboxamide moieties in their molecules. Some of these compounds showed very good CA II and CA IV inhibitory properties. with affinities for the enzymes in the low nanomolar range. Due to their relatively low water solubility, some of the most active CA II inhibitors reported here have been formulated as aqueous suspension for topical administration as antiglaucoma agents. in normotensive and glaucomatous rabbits. The derivatives incorporating furan- and pyrrole-carboxamide moieties (but not the corresponding thiophene-substituted derivatives), showed effective and long-lasting intraocular pressure (IOP) lowering both in normotensive as well as glaucomatous animals, with potencies superior to dorzolamide and brinzolamide, the two available topically acting sulfonamide drugs. This is the first example of non-water soluble sulfonamides that significantly lower IOP, being thus similar with the recently introduced drug brinzolamide, which belongs to a completely different chemical family of antiglaucoma sulfonamides.

Protease inhibitors: synthesis of bacterial collagenase and matrix metalloproteinase inhibitors incorporating arylsulfonylureido and 5-dibenzo-suberenyl/suberyl moieties.

Novel matrix metalloproteinase (MMP)/bacterial collagenase inhibitors are reported, considering the sulfonylated amino acid hydroxamates as lead molecules. A series of compounds was prepared by reaction of arylsulfonyl isocyanates with N-(5H-dibenzo[a,d]cyclohepten-5-yl)- and N-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl) methyl glycocolate, respectively, followed by the conversion of the COOMe to the carboxylate/hydroxamate moieties. The corresponding derivatives with methylene and ethylene spacers between the polycyclic moiety and the amino acid functionality were also obtained by related synthetic strategies. These new compounds were assayed as inhibitors of MMP-1, MMP-2, MMP-8 and MMP-9, and of the collagenase isolated from Clostridium histolyticum (ChC). Some of the new derivatives reported here proved to be powerful inhibitors of the four MMPs mentioned above and of ChC, with activities in the low nanomolar range for some of the target enzymes, depending on the substitution pattern at the sulfonylureido moiety and on the length of the spacer through which the dibenzosuberenyl/suberyl group is connected with the rest of the molecule. Several of these inhibitors also showed selectivity for the deep pocket enzymes (MMP-2, MMP-8 and MMP-9) over the shallow pocket ones MMP-1 and ChC.

Synthesis and antimicrobial properties of new 2-((4-ethylphenoxy)methyl)benzoylthioureas

New acylthiourea derivatives, 2-((4-ethylphenoxy)methyl)-N-(phenylcarbamothioyl)benzamides, were tested by qualitative and quantitative methods on various bacterial and fungal strains and proved to be active at low concentrations against Gram-positive and Gram-negative bacteria as well as fungi. These compounds were prepared by the reaction of 2-((4-ethylphenoxy)methyl)benzoyl isothiocyanate with various primary aromatic amines, and were characterised by melting point and solubility. The structures were identified by elemental analysis, 1H and 13C NMR, and IR spectral data. The level of antimicrobial activity of the new 2-((4-ethylphenoxy)methyl)benzoylthiourea derivatives was dependent on the type, number and position of the substituent on the phenyl group attached to thiourea nitrogen. The iodine and nitro substituents favoured the antimicrobial activity against the Gram-negative bacterial strains, while the highest inhibitory effect against Gram-positive and fungal strains was exhibited by compounds with electron-donating substituents such as the methyl and ethyl groups.

Structural factors influencing the reaction rates of 4-aryloxy-7-nitrobenzofurazans with amino acids

An interesting observation was made when studying the SNAr reaction between several 4-aryloxy-7-nitrobenzofurazans (2) and several amino acids leading to the apparition of detectable fluorescence from the substitution products3. Acidic amino acids reacted very slowly=while basic amino acids react fastest with2 having an unsubstituted phenyl or a 4-formyl-phenyl Ar group. Amongst neutral amino acids, proline reacts fastest at room temperature after 100 min. With2 having a methoxy-subtituted Ar group.

Synthesis of 2,4-dimethyl-6-oxo-2,4-heptadienoic acid derivatives from 2,4,6-trimethylpyrylium salts

Reaction 2,4,6-trimethylpyrylium salts with sodium cyanide in boiling water yielded the bicyclic lactone 1,3,5-trimethyl-6,8-dioxabicyclo[3.2.1]oct-2-en-7-one (6) along with a series of stereoisomers of 2,4-dimethyl-6-oxo-2,4-heptadienonitrile (5), which were the sole products when the reaction was carried out at room temperature. Compound 6, along with 3,5-dimethylphenol (7), was also obtained by refluxing 5 briefly in aqueous sodium hydroxide. However, when 5 was refluxed for a prolonged period in aqueous sodium acetate, 3,5-dimethyl-5-(2-oxopropyl)-furan-2-one (8), along with some 7, was generated instead. Compound 8 could also be produced from 6 on prolonged refluxing with aqueous sodium acetate, indicating that 6 was the kinetically-controlled and 8 the thermodynamically-controlled product.

Oxidation ofN-Benzyl Aziridine by Molecular Iodine: Competition of Electron Transfer and Heterolytic Pathways

Excess N-benzyl aziridine (1) reacts with I2 to afford dimer 2, tetramer 3, benzaldehyde (4), and iodoamine 5. The reaction is interpreted as occurring by both electron transfer (ET) and heterolytic mechanisms. An ET mechanism is substantiated for the oxidation by I2 of dimer 2 and tetramer 3, both being substrates easier to oxidise by electron abstraction than 1. Several auxiliary reactions were performed on 1 in order to firmly establish the boundaries to the competition between the ET and heterolytic mechanisms. For the reaction of 1 with 5 a reaction scheme is proposed; in a particular case, a pseudo-first order kinetic law is followed.

Chemical and biological evaluation of some new antipyrine derivatives with particular properties.

Starting from 4-amino-antipyrine, six new compounds were synthesized and characterized. The new compounds contain moieties with particular properties, such are ionophore (benzo-15-crown-5), fluorescent (nitrobenzofurazan), stable free radical (nitroxide), or other types of biological active residues, like nitroderivatives, antipyrine or isoniazid residues. They were fully characterized by appropriate means ((1)H and (13)C NMR, IR, UV-Vis, fluorescence, EPR, elemental analysis) and some of their biological properties were evaluated. Hydrophobicity (R(M0), log P), total antioxidant capacity (TAC), and antimicrobial properties are also presented and discussed.

Synthesis of 4-aryloxy-7-nitrobenzofurazan derivatives from 4-chloro-7-nitrobenzofurazan and various phenoxide anions (including pharmaceuticals) in the presence of crown ethers

Abstract4-Chloro-7-nitrobenzofurazan reacts by nucleophilic substitution with phenoxide anions derived from estriol (2c), ethynylestradiol (2d), phenol (3e), guaiacol (3f), 2,6-dimethoxyphenol (3g), eugenol (3h), isoeugenol (3i), the cytostatic Etoposide (4), and Reichardt’s betaine (5) in the presence of crown ethers affording the corresponding 4-aryloxy-7-nitrobenzofurazan derivatives 6c, 6d, 7e-7i, 8, and 9. The structure of these compounds was confirmed by NMR spectra. Hydrophobicity/hydrophilicity parameters were investigated by reverse phase thin-layer chromatography.

O-Methyloximes of Testosterone and of 17α-Methyltestosterone: TLC and QSPR Study of R F Values

The Z (1b and 2b, respectively) and E diastereomers (1c and 2c, respectively) of the O-methyloximes of testosterone (1a) and 17a-methyltestosterone (2a) have been synthesized and separated by TLC. 1H NMR assignments confirmed the corresponding structures. The TLC RF values of these six compounds could be rationalized by a quantitative structure-property relationship (QSPR) using one topological/topographical index.

1,3-bis(2,4,6-trinitrophenylaminooxy)propane and its 4-cyano-2,6-dinitrophenyl congener: Synthesis and properties

AbstractStarting from N-hydroxyphthalimide (5) and 1,3-dibromopropane (6) we obtained 1,3-bis(phthalimidooxy)propane (7) which led to 1,3-bis(aminooxy)propane dihydrochloride (8). From its reaction with picryl chloride or 4-cyano-2,6-dinitrochlorobenzene, the two title compounds (4b, 4a) were obtained. 1H-NMR and 13C-NMR spectra are presented. For comparison with the analogous N-methoxy-2,6-dinitro-4-R-anilines 1a, 1b (R=CN or R=NO2), wer report the hydrophobic characteristics (by RPTLC), electronic spectra for the neutral compounds and their anions, pKa values, and the behavior towards oxidizers (DPPH, PbO2, Pb(CH3COO)4, KMnO4 and Ag2O); DPPH converts compounds 1a, 1b and 4a, 4b into betainic structures 2a, 2b respectively.