Reactions of 5-amino-3-methylisoxazole-4-carboxylic acid hydrazide with carbonyl compounds: immunological activity and QSAR studies of products.

A series of 4-imino derivatives of the 5-amino-3-methylisoxazole-4-carboxylic acid hydrazide and 5-amino-3-methylisoxazole[5,4-d]-6,7-dihydropyrimidine has been prepared by condensation of 5-amino-3-methylisoxazole-4-carboxylic acid hydrazide with carbonyl compounds. The resulting products were evaluated for their immunological activities in the models of the humoral and cellular immune responses of mice in vivo and concanavalin A (Con A) and lipopolysaccharide (LPS)-induced splenocyte proliferation. In addition, effects on polyclonal antibody production by human peripheral blood cells in culture were investigated. For all studied compounds we carried out quantum chemical calculations at ab initio B3LYP 6-31G(d, p) level. The stimulatory or inhibitory effects depended strongly on the origin and location of substitunets, which is described in the conclusions and was supported by QSAR studies.

RM-11, a new izoxasole derivative, is a potent stimulator of the humoral and cellular immune responses in mice.

In this report we describe immunostimulatory properties of RM-11 in several in vivo and in vitro tests in the murine model. We found that RM-11 significantly stimulated the humoral immune response to sheep erythrocytes (SRBC) when given intraperitoneally (i.p.) at doses of 10 and 100 microg or per os (doses of 20 and 200 microg) 3 h before immunization. The compound was also stimulatory with regard to generation of delayed type hypersensitivity (DTH) to SRBC when given i.p. or per os (doses of 10, 100 and 500 microg/mouse). The described immunostimulatory activities of RM-11 were higher compared to that of the reference drug, levamisole. RM-11 stimulated, in addition, concanavalin A (ConA)-induced splenocyte proliferation. Lastly, we showed that RM-11 was not toxic when given to mice per os at doses 250 mg/kg body weight. Taken together, RM-11 appeared to be a universal stimulator of the immune response in mice. Lack of toxicity and the ability to stimulate the immune response, when administered per os, predispose the compound for further preclinical studies.

Immunological activity of new heterocyclic amides of 5-amino-3-methylisoxazole-4-carboxylic acid.

In the present study, some new amides of 5-amino-3-methylisoxazole-4-carboxylic acid were obtained. All new structures possessed markedly different groups of electron acceptor character, different spatial structure and they contained nitrogen heteroatom, enabling formation of salts and, at the same time, higher biological availability. They were examined for immunomodulating activity in comparison with cyclosporine A (CsA). We investigated effects of the compounds on the lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) by human peripheral blood cells. Some compounds exhibited suppressory action which corresponded with increasing electronoacceptor nature of the amide substituent. Two compounds, characterized by flat aromatic rings, demonstrated quite different properties. Much higher activity was expressed by compounds which contained -NH group, the group which conditioned immunostimulatory activity in other compounds described previously.

Synthesis and immunological activity of new 5-amino-3-methyl 4-amido and 4-ureilene isoxazole derivatives.

5-Amino-3-methylisoxazole-4-carboxylic acid amides and ureilenes have been synthesized from 5-amino-3-methylisoxazole-4-carbonyl azide. The compounds were investigated for potential immunotropic activity in several immunological tests. The most interesting suppressory activities in the humoral and cellular immune response were compared to activities of analogous compounds previously described as immunostimulatory.

Immunomodulating action and structure-activity relationships of substituted phenylamides of 5-amino-3-methylisoxazole-4-carboxylic acid.

A series of 5-amino-3-methylisoxazole-4-carboxylic acid amides has been prepared by condensation of 5-amino-3-methylisoxazole-4-carboxylic acid with ethyl chloroformate. The resulting mixed anhydride undergoes condensation with appropriate phenylamides to form the corresponding amides 6-16. The compounds obtained were evaluated for their immunological activities in cultures of human peripheral blood mononuclear cells (PMBC). We found that the activities of the compounds in the proliferation test and in the lipopolysaccharide (LPS)-induced cytokine production in PBMC cultures were differential. The stimulatory or inhibitory effects depended strongly on the origin and location of substituents in the phenyl ring which is described in the discussion and was supported by QSAR studies.

2-Substituted-3-oxoisothiazolo[5,4-b]pyridines as potential central nervous system and antimycobacterial agents.

The 2-[3-(substituted-amino)-2-hydroxypropyl]-4,6-dimethyl-3-oxo-2,3- dihydroisothiazolo[5,4-b]pyridines 3 were synthesized and pharmacologically evaluated in animal models. The preliminary pharmacological screening study showed that the investigated compounds were toxic and had no significant activity in central nervous system (CNS) tests. Additionally, compounds 3, and several other 2-substituted-4,6- dimethyl-3-oxo-2,3-dihydroisothiazolo[5,4-b]pyridines described here (2), together with those (4) reported in a previous paper, were evaluated in vitro against Mycobacterium tuberculosis H37Rv. For comparison, products of the rearrangement of some isothiazolopyridine 1,1-dioxides (4a,b) with the corresponding pyrido[3,2-e]-1,2-thiazines (5a,b) and different N2-substituted derivatives of the latter (5c-i) were also prepared and investigated in antimycobacterial tests. The most potent antituberculars of the 23 compounds assayed are 2-[3-(4-benzylpiperidin-1-yl)-2-hydroxypropyl]-4,6-dimethyl-3-oxo- 2,3- dihydroisothiazolo[5,4-b]pyridine 3d and ethyl (4,6-dimethyl-3-oxo-2,3-dihydroisothiazolo[5,4-b]pyridin-2-yl)acet ate 4c (MIC < 12.5 micrograms/ml, 100 and 98% inhibition, respectively).

Synthesis and cytostatic properties of 5-substituted derivatives of 3-methylisoxazolo[5,4-d]1,2,3-triazine-4-ones and 3-methyl-5-triazene 4-isoxazolecarboxylic acid ethyl esters.

Six new 5-substituted derivatives of 3-methyl-isoxazolo[5,4-d]1,2,3-triazine-4-one and 3-methyl-5-triazene-4-isoxazolecarboxylic acid ethyl ester have been synthesized from 5-amino-3-methylisoxazole-4-carboxylic acid amides, and ethyl ester. They were examined for cytostatic activity in comparison with Dacarbazine. The 3-methyl-5-(4-chlorophenyl)isoxazolo[5,4-d]1,2,3-triazine-4-one showed better activity than Dacarbazine.

Synthesis and structure elucidation of 5-aminomethinimino-3-methyl-4-isoxazolecarboxylic acid phenylamides and their immunological activity.

A series of 5-aminomethinimino-3-methyl-4-isoxazolecarboxylic acid phenylamides 4 has been prepared by condensation of 5-amino-3-methyl-4-isoxazolecarboxylic acid phenylamides 1 with trichloroacetic aldehyde. Alcoholysis of trichloro derivatives 2 gave 5-alkoxymethine derivatives 3 which, on reaction with an appropriate amine, formed the corresponding compounds 4. The compounds obtained were evaluated for their immunological activity. The properties of three compounds, described in this report, permitted inhibition of the immune response in all possible ways: diminishing both types of immune response (4d), humoral immune response (4a), or cellular immune response (4c). Preparation 4d is comparable in its effectiveness to CsA, so it may be potentially used as an agent for prolongation of the function of transplanted organs. Two other compounds may potentially be used in cases where only one type the immune response is required for combating pathogen invasion.

The 5-amino-3-methyl-4-ureidoisoxazoles, synthesis and antileucemic activity.

Some new substituted 5-amino-3-methyl-4-ureidoisoxazoles and the 4-ethyl urethane of the 5-amino-3-methyl-isoxazole have been synthesized from 5-amino-3-methyl-4-isoxazolecarboxylic acid azide. Some representative ureides with primary, secondary, and heterocyclic amines were tested for their antileucemic activity.

Synthesis and pharmacological properties of derivatives of isoxazolo [5,4-d]-6,7-dihydropyrimidines.

The synthesis of 4-hydroxy-4-amino substituted 5-phenylisoxazolo [5,4-d]-6,7-dihydropyrimidines was described. The compounds with alkylamine and semicarbazide substituents in position 4 showed the activity against sarcoma Sa-180, while those with heterocyclic substituents at the same position have analgesic properties.

Synthesis and biological properties of 5-benzoylamino-3-methyl-4-isoxazolocarboxylic acid derivatives.

A series of amides of 5-amino-3-methyl-4-isoxazolocarboxylic acid derivatives was synthesized and tested for antiinflammatory and antibacterial activity. P-etoxyphenylamid and p-chlorophenylamid of 5-benzoylamino-3-methyl-4-isoxazolocarboxylic acid displayed strong antiinflammatory and antibacterial effect. The most potent effect of these amides is accounted for the presence of benzoyl group in position 5 of isoxazole group.