R. Di Santo

Antifungal agents. 1. Synthesis and antifungal activities of estrogen-like imidazole and triazole derivatives

Abstract The synthesis of some 2-aryl-1-(4-methoxyphenyl)-1-(1 H -imidazol-1-yl)ethane derivatives and related 1 H -1,2,4- and 1 H -1,3,4-triazoles is described. The molecular structure of new derivatives has been established by 1H NMR spectra and X-ray crystallographic analysis. When tested in solid agar cultures the azole derivatives showed from moderate to potent in vitro antifungal activity against Candida albicans and Candida spp.

1,2,5-Benzothiadiazepine and Pyrrolo[2,1-d]-[1,2,5]Benzothiadiazepine Derivatives with Specific Anti-Human Immunodeficiency Virus Type 1 Activity

We synthesized and tested as novel inhibitors of human immunodeficiency virus type 1 (HIV-1) bi- and tricyclic thiadiazine ring homologues of 7-chloro-2-ethyl-2H-1,2,4-benzothiadiazin-3-(4H)-one 1,1-dioxide, which is a compound endowed with anti-HIV-1 activity at low micromolar concentrations. Benzothiadiazepine derivatives were obtained by alkylation of 8-chloro-2,3-dihydro-3-methyl-1,2,5-benzothiadiazepin-4(5H)-one 1,1-dioxide, which was obtained by intramolecular cyclization of 2-(2-amino-5-chloro-benzenesulphonamido) propanoic acid. Pyrrolobenzothiadiazepines were synthesized from N-substituted 5-chloro-2-(1H-pyrrol-1-yl)benzenesulphonamides by treating with triphosgene. N6-substituted pyrrolo[2,1-d][1,2,5]benzothiadiazepin-7(6H)-one 5,5-dioxides were active, thoughnot very potent. Both a chlorine atom and an unsaturated alkyl chain were found to be determinants of anti-HIV-1 activity. The highest potency was shown by a derivative with a TIBO-related 3,3-dimethylallyl chain. 2,3-Dihydro-1,2,5-benzothiadiazepin-4(5H)-one 1,1-dioxides were scarcely active in HIV-1-infected MT-4 cell assays; however, the introduction of the dimethylallyl chain into 7-chloro-1,2,5-benzothiadiazepine moiety led to a bicyclic derivative which was more potent and less cytotoxic than the tricyclic pyrrole-containing counterpart.

Enantioselective liquid chromatography of C3-chiral 2,3-dihydro-1,2,5-benzothiadiazepin-4(5H)-one and thione 1,1-dioxides on polyacrylamide- and polysaccharide-based chiral stationary phases.

Optically active synthetic and semisynthetic polymers were utilized as chiral stationary phases (CSPs) for the direct chromatographic enantioseparation of a series of 8-chloro-2,3-dihydro-3-methyl-1,2,5-benzothiadiazepin-4(5H)-one and thione 1,1-dioxide. Evaluation of stereochemical integrity of chiral analytes was assessed by enantioselective temperature and flow-dependent HPLC. A stopped-flow high-performance liquid chromatography (sfHPLC) procedure was developed for the determination of the rate constants and free energy barriers of enantiomerization of enantiomers of 8-chloro-2-(3-methylbut-2-enyl)-2,3-dihydro-3-methyl-1,2,5-benzothiadiazepin-4(5H)-thione 1,1-dioxide (compound 2) in the presence of Chiraspher and Chiralcel OD CSPs. In order to study the chiroptical properties of the individual enantiomers of analytes investigated, semipreparative chromatographic resolutions were performed. The assignment of the absolute configuration was empirically established by comparing the CD spectra of the separated enantiomers with those obtained from structural analogues.

Analytical and semipreparative enantiomeric separation of azole antifungal agents by high-performance liquid chromatography on polysaccharide-based chiral stationary phases: Application to in vitro biological studies

High-performance liquid chromatography (HPLC) was used for the enantiomeric separation of chiral imidazole derivatives endowed with antimycotic activity. Enantioselective columns, containing carbamates of cellulose and amylose, were used. The influence of the nature and content of an alcoholic modifier in the mobile phase was studied. The isolated enantiomers, separated on semipreparative columns, were submitted to in vitro biological investigations.

Antifungal estrogen-like imidazoles. Synthesis and antifungal activities of thienyl and 1H-pyrrolyl derivatives of 1-aryl-2-(1H-imidazol-1-yl)ethane

Summary Reaction of arylacetyl chlorides on thiophene or pyrrole derivatives furnished 2-aryl-1-(2-thienyl)- or 2-aryl-1-(1 H -pyrrol-2-yl)-1-ethanones. Reduction of ketones to the corresponding carbinols and reaction of the latter compounds with 1,1′-sulfonyldiimidazole or 1,1′-carbonyldiimidazole gave 2-thienyl- and 1 H -pyrrol-2-yl-1-aryl-2-( 1 H -imidazol-1-yl)ethanes, respectively. The new compounds were tested in vitro against a variety of pathogenic fungi in comparison with miconazole and bifonazole. Some 5-chloro-2-thienyl derivatives were endowed with good antifungal activity, particularly against Candida albicans and Cryptococcus neoformans .

Antifungal agents. 5. Chloro and amino derivatives of 1,2-diaryl-1-(1H-imidazol-1-yl)ethane with potent antifungal activities

Abstract Various derivatives of 1,2-diaryl-1-(1H-imidazol-1-yl)ethane have been synthesized and tested against Candida albicans and Candida spp. In vitro essays showed chloro and amino derivatives to be as active as miconazole and bifonazole and more potent than ketoconazole. Structure-activity relationships of the new imidazole antifungal agents are discussed.

Competing sigmatropic shift rearrangements in excited allyl radicals

The competition between rearrangement of the excited allyl radical via a 1,3 sigmatropic shift versus sequential 1,2 shifts has been observed and characterized using isotopic substitution, laser excitation, and molecular beam techniques. Both rearrangements produce a 1-propenyl radical that subsequently dissociates to methyl plus acetylene. The 1,3 shift and 1,2 shift mechanisms are equally probable for CH(2)CHCH(2), whereas the 1,3 shift is favored by a factor of 1.6 in CH(2)CDCH(2). The translational energy distributions for the methyl and acetylene products of these two mechanisms are substantially different. Both of these allyl dissociation channels are minor pathways compared to hydrogen atom loss.

Pyrrolobenzodiazepines with antinociceptive activity: synthesis and pharmacological activities

Summary The synthesis of some N -[2-(1 H -pyrrol-1-yl)benzyl]arylacetamides and new 4-arylmethyl-5,6-dihydro-4 H -pyrrolo[1,2- a ]-[1,4]benzodiazepines as their conformationally restricted analogues is reported. The reduction of arylacetamides and N -methylation of pyrrolobenzodiazepines led to the corresponding N -[2-(l H -pyrrol-1-yl)benzyl]arylethylamines and the 4-arylmethyl-5-methyl-5,6-dihydro-4 H -pyrrolo[1,2- a ][1,4]benzodiazepines, respectively. The new compounds were subjected to pharmacological tests for evaluation of antinociceptive effects. Neurobehavioural assays were also carried out on selected compounds to acquire data on neurotoxicity. Among the derivatives tested, arylacetamides 7b and 7e and 4-(4-methoxybenzyl)-5-methyl-5,6-dihydro-4 H -pyrrolo[l,2- a ][1,4]benzodiazepine 10d were the most active derivatives in antinociceptive assays, showing high significance in both hot-plate and acetic-acid-induced writhing tests in mice without sedative or myorelaxant effects.

The Use Of Copper-(II) Bromide and N-Bromosuccinimide in the Bromination of 1-(1-Methyl-1H-pyrrol-2-yl)2-phenylethanone

Abstract Bromination of 1-(1-methyl-1H-pyrro]-2-yl)-2-phenylethanone with 1 mole of copper-(II) bromide in chloroform-ethyl acetate 1:1 mixture results in the regiospecific formation of 2-bromo-1-(1-methyl-1H-pyrrol-2-yl)-2-phenylethanone. Similar reaction with 1 mole of N-bromosuccinimide leads to α- and β-monosubstitution at pyrrole ring without affect the methylene group.