SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF NEW SULFONAMIDE ISOXAZOLO[5,4-b]PYRIDINE DERIVATIVES.

A series of novel sulfonamide isoxazolo[5,4-b]pyridines were synthesized. The substrates for their synthesis were 3-aminoisoxazolo[5,4-b]pyridine and selected aryl sulfonic chlorides, chlorosulfonic acid and selected amines. Reactions were carried out using the classical and microwave methods. Selected compounds were tested towards antibacterial and antiproliferative activity. The structure of the obtained new derivatives was determined by elemental analysis and acquired IR and 1H NMR spectra. Among the tested compounds: N- isoxazolo[5,4-b]pyridine-3-yl-benzenesulfonamide (2) and N-isoxazolo[5,4-b]pyridine-3-yl-4-methylbenzene-sulfonamide (5) showed antimicrobial activity towards Pseudomonas aeruginosa (ATCC 27853) and Escherichia coli (ATCC 25922) at doses: 125, 250 and 500 µg. Both compounds showed a 50% inhibition of proliferation of breast carcinoma cell line MCF7 at concentrations of 152.56 µg/mL and 160 161.08 µg/mL, respectively.

The synthesis of 3,5,6,7-tetrasubstituted isoxazolo[4,5-b]pyridines and an evaluation of their in vitro antiproliferative activity.

BACKGROUND: Derivatives of isoxazolopyridines exhibit diverse biological activity. One method of synthesizing isoxazolo[4,5-b]pyridines is Friedlander condensation. OBJECTIVES: To establish the conditions necessary for conventional and microwave synthesis of new 3,5,6,7-tetrasubstituted isoxazolo[4,5-b]pyridines and their antiproliferative activity. MATERIAL AND METHODS: The substrates in the synthesis of new isoxazolo[4,5-b]pyridines were 4-amino-5-benzoylisoxazole-3-carboxamide and selected carbonyl compounds containing a reactive a-methylene group. Reactions were carried out using classical methods in the presence of catalysts ZnCl2 or In (OTf)3, and in a microwave reactor in the presence of ZnCl2 under solvent-free conditions. Selected compounds were tested in vitro on eight tumor cell lines to assess their antiproliferative activity. RESULTS AND DISCUSSION: A series of new derivatives of 3,5,6,7-tetrasubstituted isoxazolo [4,5-b]pyridines was obtained from Friedlander condensation of 4-amino-5-benzoyloisoxazolo-3-carboxamide with selected carbonyl compounds with an active methylene group. The compounds were obtained by conventional and microwave methods, in the presence of catalysts ZnCl2 or In (OTf)3. The structures of the products were determined on the basis of elemental analysis and infrared (IR), Nuclear Magnetic Resonance (1H NMR) and Mass Spectrometry (MS) data. Selected compounds were tested in vitro on eight tumor cell lines in the direction of antiproliferative activity. CONCLUSIONS: Only the use of conventional heating in a thermostated oil bath in the presence of catalysts ZnCl2, or In (OTF)3 or microwave irradiation in the presence ZnCl2 in the solvent-free conditions allowed good yields of the new derivatives of poly-substituted isoxazolo[4,5-b]pyridines to be obtained. Among the compounds tested in vitro only 6-benzoyl-5, 7-difenyloisoxazolo[4,5-b]pyridine showed antyproliferative activity at a concentration of 3.9 microg/ml.

Synthesis and antiproliferative activity in vitro of new 2-, 3- or 4-substituted pyrido[2',3':3,4]pyrazolo[1, 5-a]pyrimidines.

The synthesis of several new 2-, 3- or 4-substituted pyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidines is described. The obtained compounds were tested for their antiproliferative activity in vitro. Two of them: 3-chloro-2-methylpyrido[2',3':3,4]pyrazolo[1,5-a] pyrimidin-4-one [X] and 2,3-cyclopentylpyrido [2',3':3,4] pyrazole[1,5-a]pyrimidin-4-one [XII] revealed weak cytotoxic activity against the cells of human bladder cancer cell lines: LoVo, MCF-7, MES-SA and HCTV29T. The structures of the products II - XII were established on the basis of elemental analysis and spectral data (IR, 1H NMR and MS).

Synthesis and antiproliferative activity in vitro of new 3-substituted aminoisoxazolo[5,4-b]pyridines.

The synthesis of 3-aminoisoxazolo[5,4-b]pyridine [III] and of several new 3-substituted aminoisoxazolo[5,4-b]pyridines is described. 3-Aminoisoxazlo[5,4-b]pyridine [III] was subjected to reactions with the acid halides and substituted aromatic aldehydes, leading to the production of the corresponding amides IV-VII, IX, XI-XVI and new tricyclic pyridoisoxazolopyrimidine VIII and Schiff bases XX-XXIV. 4-Chlorobutyroamide IX cyclized into 3-(pyrrolidinon-1-yl)isoxazolo[5,4-b]pyridine [X]. 3-Chloroacetylaminoisoxaxolo[5,4-b]pyridine [V] in reaction with secondary amines gave 3-aminoacetylaminoisoxazolo[5,4-b]pyridines XVII-XIX. The structures of the products II-XXIV were established on the basis of elemental analysis and spectral data IR, 1H NMR and MS. Selected compounds were tested for their antiproliferative activity in vitro. Two of them: 3-chloroacetyl-[V] and 3-2-bromo-propionylaminoisoxazolo[5,4-b]pyridine [VI] revealed cytotoxic activity against the cells of 8 various human or mouse tumor cell lines applied. Their ID50 (inhibitory dose 50%) values are in the range of the international activity criterion for synthetic agents (4 microg/ml).

Synthesis and antiproliferative activity in vitro of new 3-substituted aminopyrazolo[3,4-b]pyridines.

The synthesis of several new 3-substituted aminopyrazolo[3,4-b]pyridines is described. The obtained compounds were tested for their antiproliferative activity in vitro. Two of them: 3-chloroacetylaminopyrazolo[3,4-b]pyridine [II] and 3-(2-bromopropionyl-amino)pyrazolo[3.4-b]pyridine [III] revealed cytotoxic activity against the cells of 5 human tumor cell lines applied. Their ID50 values were in the range of the international activity criterion for synthetic agents (4 microg/ml). The structures of the products II-XVII were established on the basis of elemental analysis and spectral data (IR, 1H NMR and MS).