Role of 1,4-benzothiazine derivatives in medicinal chemistry.

1,4-Benzothiazine (1,4-BT) derivatives have been reported to exhibit a wide range of pharmacological properties including antifungal, immunostimulating, anti-aldoso-reductase, anti-rheumatic, anti-allergic, vasorelaxant, anti-arrhythmic, anti-hypertensive, neuroprotective and cytotoxic activities. These different effects indicate that 1,4-BT is a template potentially useful in medicinal chemistry research and therapeutic applications.

Induction of apoptosis by 1,4-benzothiazine analogs in mouse thymocytes.

1,4-benzothiazine (1,4-B) derivatives exert numerous effects in vivo and in vitro, including neurotoxicity and antitumor cytotoxicity. To analyze the mechanisms responsible for 1,4-B-induced cytotoxicity, we performed experiments to evaluate the possible apoptotic effect. For that purpose, we used mouse thymocytes, a cell population well sensitive to induction of apoptosis that has been used to assay apoptosis in many experimental systems. Results indicate that a number of 1,4-B analogs are able to induce both thymocyte apoptosis in vitro and thymus cell loss in vivo. Moreover, analysis of the structure-activity relationship indicate that the sulfur (S) oxidation state, the presence of the carbonyl group, and the nature and position of the side chain modulate the apoptotic efficacy. Moreover, results of in vitro experiments show that the 1,4-B-induced apoptosis associates with different biochemical events including phosphatidylcholine-specific phospholipase C activation, acidic sphingomyelinase activation and ceramide generation, loss of mitochondrial membrane potential (DeltaPsi(m)) and cytochrome c release, and caspase-8, -9, and -3 activation. These results indicate that 1,4-B analogs induce apoptosis through a complex of biochemical events.

Antifungal and immunomodulating activities of 1,4-benzothiazine azole derivatives: review.

We reviewed the studies on the in vitro and in vivo antifungal activity of 1,4-benzothiazine azole derivatives (1,4-BT). A number of different 1,4-BT have been tested for anti-Candida activity, investigating their N-4 substitution, sulfur oxidation state, presence of the carbonyl group in C-3, insertion of the side chain on C-6, C-7 or C-8 of benzothiazine nucleus, the nature of azolic substituent (triazole or imidazole), which tend to differ. Moreover, benzoxazine analogues have been tested to evaluate the effect of sulfur bioisosteric substitution on their activity. We found that their antifungal activity correlates with well-defined chemical characteristics including the presence of ether substitution at the side chain. In fact, ether derivatives are the most active compounds in vivo, although they have little anti-Candida effect in vitro. This discrepancy could be attributed to the fact that 1,4-BT are metabolized to active antifungal compounds and may have in vivo activity through improvement of protective immune response and direct antifungal effects. In fact, 1,4-BT also show immunomodulating activity so that the direct antifungal activity, in combination with the capability to stimulate the immune response, could result in a significant increase in in vivo efficacy.

(1,4-Benzothiazinyloxy)alkylpiperazine derivatives as potential antihypertensive agents.

A series of compounds having a piperazine moiety variously linked to the benzothiazine nucleus were synthesized and evaluated for their in vitro alpha-adrenoceptor affinity by radioligand receptor binding assays. Some compounds bearing a oxyalkyl-(2-methoxyphenyl)piperazine side chain were good alpha1-adrenoreceptor ligands.

A new azole derivative of 1,4-benzothiazine increases the antifungal mechanisms of natural effector cells.

The most widely used drug for treatment of candidiasis is fluconazole (FCZ). Recently, a new derivative of 1,4-benzothiazine, compound FS5, was developed. FS5 had an appreciable protective effect against murine candidiasis. The present study was designed to dissect the antifungal mechanisms triggered by FS5 and to establish whether this compound could enhance the antimicrobial abilities of natural effector cells. The results show that intraperitoneal injection of FS5 in mice (i) induced an increase in circulating neutrophil levels comparable to that observed in FCZ-treated mice; (ii) enhanced phagocytosis and the killing activities of macrophages (Mphis) isolated from the spleen or peritoneal cavity, with the latter effect correlating with induction of nitric oxide synthesis and production by Mphis; and (iii) increased the levels of expression and synthesis of tumor necrosis factor alpha. These results suggest that the compound-induced synthesis of antimicrobial and proinflammatory molecules by heterogeneous Mphi populations is part of the beneficial effect of FS5 exerted against murine candidiasis.

Azole derivatives of 1,4-benzothiazine as antifungal agents.

A series of azole derivatives of 1,4-benzothiazine 7-14 was synthesized and evaluated for the in vitro and in vivo activity against Candida albicans. Secondary alcohol 10 and its ether derivative 13 showed very good efficacy against systemic candidiasis in a murine experimental model.

o-Chlorobenzenesulfonamidic derivatives of (aryloxy)propanolamines as beta-blocking/diuretic agents.

A series of compounds 1b-f, 2b-f, and 3b-f having an o-chlorobenzenesulfonamidic diuretic moiety variously linked to the nitrogen side chain of the beta-blocking (aryloxy)propanolamine pharmacophore were prepared and tested for their beta 1-adrenoceptor affinity. For all the active compounds, beta-blocking and diuretic activities were investigated in rats; the structure--activity relationships are discussed. Some of the compounds displayed varying levels of both properties and among these, compounds 1c and 2c have been chosen for further development.

Enantiomers of 8-(3-tert-butylamino-2-hydroxypropoxy)-3,4-dihydro-3-oxo-2H- (1,4)benzothiazine: racemic resolution, chiral synthesis and biological activity.

We report the resolution of racemic (+/-)-1 with (R)-(+)-methylbenzyl isocianate and the synthesis of (R)-1 and (S)-1 via Sharpless chiral epoxidation. The enantio- and tissue-selectivity of such enantiomers, as beta- and alpha-adrenoceptor antagonists, were studied. Compound 1, while confirming the potent beta-blocking activity, displayed a modest enantio-selectivity towards beta 1- and beta 2-adrenoceptors. All the compounds displayed no activity as alpha-adrenoceptor blockers.

Synthesis and antiinflammatory/analgesic activities of N-heterocyclic carboxamides of thiopyrano-1,2-benzothiazine.

We report the synthesis of N-heterocyclic carboxamides of 5-methyl-4-oxo-2,3,4,5-tetrahydrothiopyrano [3,2-c][1,2]benzothiazine 6,6-dioxide, their antiinflammatory and analgesic activities and the attempts to obtain a corresponding sulfoxidate series. Compounds (II c) and (II l) showed a good antiinflammatory activity which is comparable to that of piroxicam. No compound showed any significant analgesic activity.

[In vitro study of the antifungal activity of two chlorine derivatives to be used in antisepsis]. / Studio "in vitro" dell'attivita' antifungina di due cloroderivati per l'impiego nell'antisepsi.

The activity of two chlorine derivates, sodium hypochlorite in water solution with NaCl (product A) and electrolytic chloroxidant (product B) has been tested in vitro against potentially human pathogenic fungi (Aspergillus niger, Aspergillus fumigatus, Microsporum gypseum, Candida albicans, Cryptococcus neoformans, Trichophyton mentagrophytes, Microsporum canis, Epidermophyton floccosum, Trichophyton rubrum, Sporotrix schenkii). For A. niger, the relation of the two compounds has also been considered between mycelial and sporidial forms. Dilutions used ranged from 0.15 to 10% (corresponding to 17.2-1150 ppm of active principle for product A, and to 18.3-1220 ppm of active principle for product B). These were applied for different times in order to assess the minimal inhibitory concentration (M.I.C.) and to evaluate the survival time of the microorganisms tested, which were strains from the collection of the Institute of Mycology, (Faculty of Agrarian Science, Perugia) and recently isolated ones from animal and vegetable tissues, cultivated on Sabouraud medium. The cell suspension to be tested was obtained on nutrient broth in shaken flasks (120 rpm) at 28 degrees C for 48 h, and was separated by centrifugation and 10000 rpm at 5 degrees C for 20 min, repeatedly washed with sterile physiologic saline and resuspended in sterile water where it was submitted to delicate pressure in order to fragment the mycelium. Activity tests were carried out on Sabouraud broth and Sabouraud agar with controls for every case without the active principle. Aliquots of the suspensions (microrganism++ + disinfectant) were transferred at regular intervals (1, 3, 5 and 10 minutes) to the two substrates in liquid and solid state, and the growth of microorganisms was followed at 28 degrees C for 48-72 h in the case of yeasts, and for up to 21 days in the case of sower growing fungi. The cell content of the different suspensions was found to range from 10(4) to 10(9) UFC/ml. The active chlorine contents of the two compounds was evaluated by iodometry simultaneously with the pH of the different solutions. Useful data were obtained from the comparison of the two systems of activity assessment of the fluid and agarized substrate. It was thus found that the two compounds were equally active against the species tested. Some of these (A. fumigatus, M. gypseum, A. niger, C. albicans, C. neoformans) were less sensitive to the compounds examined (doses for cell inactivation 0.62-2.5% for product A, and O.15-1.25% for product B) where at any rate product B was more active.(ABSTRACT TRUNCATED AT 400 WORDS)

Synthesis and beta-adrenergic blocking activity of oxipropanolamines of 3,4-dihydro-3-oxo-2H(1,4)benzothiazine.

The synthesis of a series of oxypropanolamines of 3,4-dihydro-3-oxo-2H(1,4)benzothiazine is reported. Some of these compounds proved more potent than propranolol and carteolol as beta-adrenergic blocking agents in in vitro tests. The 8-(3-tert-butylamino-2-hydroxy)propoxy-3,4-dihydro-3-oxo-2H(1,4) benzothiazine fumarate (XVI a), which gave better results, confirmed its remarkable activity in in vivo tests.

[Synthesis and pharmacologic activity of benzothiopyranopyrazole and benzothiopyranoisoxazole carboxamides]. / Sintesi ed attività farmacologica di carbossiammidi di benzotiopiranopirazoli e benzotiopiranoisossazoli.

A series of carboxamides of benzotiopyranopyrazoles and benzothiiopyranoisoxazoles was synthesized starting from benzothiopyran-4-one-3-methylglyoxylates through two synthetic methods and tested for anti-inflammatory, analgesic and cardiovascular activity. Some of these compounds display pronounced antiarrhythmic activity.