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1. Patch-clamp technique was used in primary cultures of cerebellar granule neurons to study the modulation of the cyclothiazide analogue (IDRA21) and of the diazoxide derivative (IDRA 5) on KA-evoked currents. 2. The dose-response of kainic acid (KA) reveals an EC50=90 microM and an Hill coefficient of 1.3. IDRA 21 and cyclothiazide potentiate KA-evoked current in a dose dependent way, being cyclothiazide more potent but less efficacious than IDRA 21. Conversely IDRA 5 acts as a negative modulator of KA evoked -current. 3. Application of IDRA 21 and cyclothiazide results in a current potentiation of 125+/-18% and 80+/-12% respectively, while IDRA 5 decreases KA-current (-21+/-5%). Coapplication of cyclothiazide and IDRA 21 produces a potentiation of 110+/-17%, suggesting a competition of the two drugs for the same site. 4. In the same experimental model we studied the ability of IDRA compounds of promoting toxicity through AMPA-receptor activation. Under basal conditions AMPA treatment (50 microM for 1 hour) results in a negligible excitotoxicity. 5. In contrast similar treatment with AMPA + IDRA 21 (1 mM) or + IDRA 5 (1 mM) or + cyclothiazide (100 microM) induces citotoxicity. The neurotoxic damage induced by IDRA 21 and cyclothiazide is blocked by GYKI 53655 (50 microM) and by NBQX (10 microM). Interestingly GYKI and NBQX are ineffective in reducing IDRA 5 toxicity.

A series of 3,4-dihydro derivatives of 6-chloro-, 7-chloro-, 5,7-dichloro-, 6,7-dichloro-, 5,7-dibromo-, 5-nitro-7-chloro-, 7-nitro-, 7-amino-1,2,4-benzothiadiazine-1,1-dioxide, various substituted on the heterocyclic carbon, was prepared and tested for cardiovascular activity. It was found that in this series of compounds cardiac activity predominates and is exclusively of the depressant type. Bradycardial activity seems to be affected both by the nature of the substituent on the heterocyclic carbon atom and by the substituents on the benzene ring. An alkyl chain of three carbon atoms, normal or alpha-ethylsubstituted, on C3 and the presence of a chlorine atom in positions 6 or 7 seem to be the most significant structural features for this activity. Some of the substances tested showed a pressor effect (hypotension and/or increase in differential pressure).

A series of quaternary ammonium salts of 3-alkylaminoderivatives of 1,2,4-benzothiadiazine-1,1-dioxide were prepared and tested for cardiovascular activity. Almost all the substances tested proved to have some measure of depressant activity on arterial pressure and the most interesting compounds in this respect were (XII), (XIII), (XV) and (XIX) for which hypotensive values between 60 and 70% with respect to the base level were recorded. Compound (XV) also caused increase in the differential pressure and decrease of cardiac frequency. The later however was increased by some other compounds [(XII), (XVIII)]. The structure-activity relationships are discussed taking into account also the activity of the parent tertiary amines.

A series of 3-(4H-1,2,4-benzothiadiazine-1,1-dioxide-3-yl-thio)-propanoic acids was synthesized in order to study their possible antiinflammatory in comparison with the corresponding lower homologues and isosters previously studied. Most of the compounds proved effective against carrageenan-induced plantar oedema. The possible influence of some chemico-physical parameters on the occurrence of this biological activity was investigated.

A series of carboxy- and carbomethoxyalkyl derivatives of 3-amino-1,2,4-benzothiaidazin-1,1-dioxide either substituted or unsubstituted in the benzene ring [compounds (I leads to XVIII)] was prepared and tested for cardiovascular activity. It was found that the introduction of a carboxy-or carbalkoxy-group in the omega position of 3-alkylamino derivatives of 1,2,4-benzothiadiazine-1,1-dioxide usually causes marked decrease or abolition of the cardiovascular activity shown by the parent compounds. The negative effect on the pressor trace (hypotension and increase in differential pressure) is more frequent and significant than that on bradycardial activity.

A new series of monoalkylcarbamic esters of 3-mercapto-1,2,4-benzothiadiazine-1,1-dioxide (I) and of its 6-chloro- and 5,7-dichloroderivatives [compounds (II leads to XVI)] and a series of monoalkylthiocarbamic esters of (I) [compounds (XVII leads to XIX)] were synthesized and evaluated in vitro for antimicrobial activity. All the substances studied have been found to possess an inhibiting action on one or more strains of mycetes of the genus Candida and on some strains of Gram-positive bacteria belonging to the genus Staphylococcus. Moreover, some compounds have shown a bacteriostatic effect on a strain belonging to the genus Streptococcus. None of the substances tested was active on Gram-negative schizomycetes.

A series of (3-oxodihydro-1,2,4-benzothiadiazin-1,1-dioxide-3-yl)acetic acids [compounds of type (A)] and (1,2,4-benzothiadiazin-1,1-dioxide-3-yl)oxyacetic acids [compounds of type (B)] were synthesised and tested for antiinflammatory activity. Preliminary tests showed certain compounds to have a significant level of antiinflammatory activity in rat paw edema induced by carrageenan. It was found that the antiinflammatory activity of this series of compounds depends on the nature, number and position of the substituents on the benzene ring.

The antimicrobial activity of a series of fluoro derivatives of benzothiadiazine and sulfonamides was studied. The compounds tested can be grouped as: a) 3-alkylmercapto derivatives of 6-trifluoromethyl-1,2,4-benzothiadiazine-1,1-dioxide (III leads to VI); the 3-mercapto precursor (VII) and the related 3-picolinic salt (VIII); b) 3-trifluoromethyl derivatives of 1,2,4-benzothiadiazine-1,1-dioxide and of its benzene substituted derivatives (IX leads to XVI); c) trifluoroacetylaminobenzenesulfonamides (XVII leads to XXV). Two of the 3-alkylmercapto compounds [(V) and (VI)] showed marked inhibitory activity against some strains of Staphylococcus, Streptococcus and Diplococcus. None of the compounds tested proved active against Gram-negative schizomycetes (genera Salmonella, Shigella, Escherichia, Proteus, Pseudomonas, Enterobacter, Klebsiella, Serratia, Yersinia, Providencia) or against yeasts (Candida).

The bromination of 3-amino-1,2,4-benzothiadiazine-1,1-dioxide (1) in N,N-dimethylformamide has been studied. Depending on the operating conditions the reaction produces 7-bromo-3-amino-1,2,4-benzothiadiazine-1,1-dioxide (II) or 5,7-diabromo-3-amino-1,2,4-benzothiadiazine-1,1-dioxide (III). Derivatives halogenated at the nitrogen were not isolated in any of the experiments.

A series of dialkylamino, pyrrolidyl and morpholyl-alkyl-derivatives of 3-amino-1,2,4-benzothiadiazine-1,1-dioxide, 7- or 5,7-halogen substituted in the benzenoid moiety, was prepared and their cardiovascular activity studied. Most of the substances in question were capable of inducing a significant decrease in mean arterial blood pressure; some of them tended to increase pulse pressure or to cause bradycardia, an effect which was noted particularly in the case of compound 10 which reduced heart-rate by 85%. The structure/activity relationship of these substances, of the 6- and 6,7-halogen substituted isomers and of their corresponding non-substituted progenitors is examined.

A series of iodo derivatives of 2-aminobenzensulfonamide and its derivatives has been prepared by reaction with iodine chloride in N,N-dimethylformamide or N,N-dimethylacetamide. The structure of each compound was confirmed by transformation with formic acid into the corresponding 1,2,4-benzothiadiazine and comparison with the same compounds prepared via the Sandmeyer reaction starting form amino derivatives of known structure. It was found that the iodination reaction in N,N-dimethylformamide, can lead, depending on the nature of the starting material, to the formation of benzothiadiazine derivatives apparently generated from sulfonamide via a formylation reaction due to N,N-dimethylformamide.