Donato Pocar

Chemistry of Biologically Active Isothiazoles

The isothiazole ring as well as the corresponding benzo- and heterocondensed rings are present in many chemically interesting compounds. The isothiazole ring can be a substituent of a bioactive scaffold or the pharmacophore of bioactive molecules. New compounds have been designed, synthesised and tested towards different biological targets and, in many cases, they display interesting pharmaceutical activities. Different SAR studies are reported starting from already known isothiazole derivatives or from new compounds characterised by a particular substitution pattern aiming to improve the biological activity. Agrochemical applications are also reported.

Isothiazole dioxides: synthesis and inhibition of Trypanosoma brucei protein farnesyltransferase.

A series of isothiazole dioxides was synthesized and evaluated as inhibitors of protein farnesyltransferase from the parasite that causes African sleeping sickness (Trypanosoma brucei). The most potent compound in the series inhibited the parasite enzyme with an IC(50) of 2 microM and blocked the growth of the bloodstream parasite in vitro with an ED(50) of 10 microM. The same compound inhibited rat protein farnesyltransferase and protein geranylgeranyltransferase type I only at much higher concentration.

Isothiazoles. Part VI. Cycloaddition of azides to isothiazole dioxides: Synthesis of thiadiazabicyclo[3.1.0]hexene derivatives and their thermal rearrangement to thiazete dioxides, 1,2,6-thiadiazine dioxides and pyrazoles

Abstract 3-Diethylamino-4-(4-methoxyphenyl)-isothiazole 1,1-dioxide ( 1 ) was made to react with arylalkyl- and arylazides 2 . Cycloadducts 3 , which could be isolated in some cases, afforded N-arylalkyl- or N-aryl-thiadiazabicyclo[3.1.0]hexene derivatives 4 through N 2 -elimination. Thermal rearrangements of N-aryl- and N-β-phenylethyl substituted compounds 4b-e , produced derivatives of 1,2-thiazete 1,1-dioxide 5 , 1,2,6-thiadiazine 1,1-dioxide 6 and pyrazole 7 . The reaction can be optimized to afford compounds 6 in synthetically useful yield. In the case of N-benzyl-thiadiazabicyclo[3.1.0]hexene derivative 4a the different substitution on the aziridine nitrogen produced a different reaction course, affording the thiadiazine derivative 6a and the pyrimidine derivative 8 .

2-Amidinylindole-3-carbaldehydes: Versatile Synthons for the Preparation of α-Carboline Derivatives

Abstract The 2-amidinylindole-3-carbaldehydes 1 are the key starting materials for the preparation of three classes of carbolines 2 , 6 and 7 in which the pyridine ring is characterised by a different substitution patterns. The carbolines 2 which are functionalized with an amino group in position 2, were obtained directly by heating 1 in presence of SiO 2 . The condensation of amidines 1 with arylmethylketones afforded unsaturated ketones 5 which on heating were transformed into 2,9-dialkyl-3-aroyl-9 H -pyrido[2,3- b ]indoles 7 . Instead, prolonged reaction of amidines 1 with arylmethylketones in t -BuOH/ t -BuOK gave 2-aryl-9 H -pyrido[2,3- b ]indoles 6 .

Enamines—XXXIX : Enamines from cyclopropylketones

The enamines from cyclopropyl-methyl-, -ethyl- and -cyclopentylketone have been prepared by reaction of the ketone with a secondary amine and TiCl4. Their vinylcyclopropane structure has been demonstrated by NMR. The reaction of dicyclopropylketone, cyclopropylphenylketone or cyclopropyl-α-thienylketone with secondary amines and TiCl4 afforded homoallylic rearrangement products, namely 1-cyclopropyl-, 1-phenyl- and 1-(α-thienyl)-1,4-diamino-1-butene, respectively.

Masked constrained cysteines: diastereoselective and enantioselective synthesis of 1-amino-2-mercaptocyclopropanecarboxylic acid derivatives

Abstract A diastereoselective and enantioselective synthesis of (Z)-1-benzoylamino-2-tritylsulfanylcyclopropanecarboxylic acid derivatives 8a,b and 9a,b was achieved starting from (−)- or (+)-menthyl 2-benzoylamino-3-tritylsulfanylacrylates 3a,b. Compounds 3 were reacted with diazomethane giving the corresponding pyrazolines 4a,b and 5a,b. These compounds, on melting, were transformed, under steric control, into the cyclopropaneamino acid derivatives (R,R)-8a,b and (S,S)-9a,b. The synthesis of a large class of chiral 2-S-alkyl-1-aminocyclopropanecarboxylic acid derivatives is possible after removing the trityl protecting group and subsequent alkylation reactions.

New esters of R-(+)-usnic acid

Abstract By reacting R -(+)-usnic acid ( 1 ) with propionic anhydride and chloroacetyl chloride and pyridine the corresponding diesters at the 8-OH and 9-OH groups ( 2b and c , respectively) were obtained. On reaction of compound 1 with aroyl chlorides and pyridine, the esterification occurred on OH-3 and on the enol form of the acetyl group at C-2 yielding the diesters 3a,c . A tetrabenzoate ( 4a ) and a diacetate-dibenzoate ( 4b ) of compound 1 were also produced.

v-Triazolines. Part 37. Rearrangement reactions of 5-amino-1-(2-formyl-, -benzoyl-, -cyano-aryl)-ν-triazolines: new synthesis of 2-amino- and 2,4-diamino-quinolines and 2,4-diamino-1,7-naphthyridines

2-Aminoquinolines 4 were obtained in an one-pot reaction from arylacetaldehydes 1, secondary amines 2 and aryl azides 3 in refluxing benzene or xylene. 2,4-Diaminoquinolines and 2,4-diamino-l,7-naphthyridines 9 were prepared by heating arylacetaldehydes 1 with secondary amines 2 and aryl or pyridyl azides 8 and reaction with bases. Reaction intermediates were shown in certain cases to be 5-amino-ν-triazolines 5 and 10 undergoing thermal rearrangement to amidines 7 and 11 followed by intramolecular base-catalysed cyclocondensation.

N-halogenoamidines. Part 1. Amino-imidazolines and -imidazoles from N-chloro-N′-arylamidines and enamines

The reaction between N-chloro-N′-arylamidines and enamines derived from aldehydes affords 4-amino-4,5-di-hydro-imidazoles and/or -imidazoles. Imidazole-ring formation was not observed with enamines from ketones and from aldehydes bearing two alkyl groups in the β-position. In the former case chlorinated enamines were obtained, and in the latter a rearrangement to N-(2-amino-2,2-dialkyl)ethylidene-amidines was observed. The reaction mechanism is discussed.

5(4H)-Oxazolones. Part VIII.1 An Efficient Synthesis of Δ1-Pyrroline-2-carboxylic Acid derivatives through Michael and Wittig condensation

Abstract Reaction of oxazolones 4 with triphcnylvinylphosphonium bromidc 3 afforded, through a Michael addition, the α-aminocstcrs 7 or acids 8 functionalized with a triphcnylphosphonium group. Compounds 7 and 8 were transformed in good yields in the corresponding Δ 1 -pyrroline-2-carboxylic acids 2 or esters 1 by intramolecular Wittig condensation in presence of sodium alkoxidc in refluxing toluene. Intermolccular Wittig reaction of 7 with 4-nitrobcnzalhdeyde afforded protected unsaturated α-aminoestcrs 9 .