Anti-tubercular agents. Part 5: synthesis and biological evaluation of benzothiadiazine 1,1-dioxide based congeners.

In an effort to discover new and effective chemotherapeutic agents from this laboratory for the treatment of tuberculosis, here in we describe the synthesis and biological evaluation of a series of novel benzothiadiazine 1,1-dioxide (BTD) based congeners by using rifampicin, streptomycin; ciprofloxacin and amphotericin as positive controls. Further, to understand structural requirements for exploring the structure activity relationship of BTDs, cytotoxicity and in vivo study of recently reported potent molecule 4 (MIC = 1 microg/mL) is also discussed.

Chloro-substituted 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides as ATP-sensitive potassium channel activators: impact of the position of the chlorine atom on the aromatic ring on activity and tissue selectivity.

The synthesis of 5-chloro-, 6-chloro-, and 8-chloro-substituted 3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides is described. Their inhibitory effect on the insulin releasing process and their vasorelaxant activity was compared to that of previously reported 7-chloro-3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides. "5-Chloro" compounds were found to be essentially inactive on both the insulin-secreting and the smooth muscle cells. By contrast, "8-chloro" and "6-chloro" compounds were found to be active on insulin-secreting cells, with the "6-chloro" derivatives emerging as the most potent drugs. Moreover, the "6-chloro" analogues exhibited less myorelaxant activity than their "7-chloro" counterparts. 8-Chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (25b) and 6-chloro-3-cyclobutylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (19e) were further identified as K(ATP) channel openers by radioisotopic measurements conducted on insulin-secreting cells. Likewise, current recordings on HEK293 cells expressing human SUR1/Kir6.2 channels confirmed the highly potent activity of 19e (EC(50) = 80 nM) on such types of K(ATP) channels. The present work indicates that 6-chloro-3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides appear to be more attractive than their previously described 7-chloro-substituted analogues as original drugs activating the SUR1/Kir6.2 K(ATP) channels.

Inhibitors of HCV NS5B polymerase: synthesis and structure-activity relationships of N-alkyl-4-hydroxyquinolon-3-yl-benzothiadiazine sulfamides.

Substituted N-alkyl-4-hydroxyquinolon-3-yl-benzothiadiazine sulfamides were investigated as inhibitors of genotype 1 HCV polymerase. Structure-activity relationship patterns for this class of compounds are discussed.

2,1,3-Benzothiadiazine derivatives: synthesis and screening versus PDE4 enzyme.

A series of N-1,3 disubstituted 2,1,3-benzothiadiazine derivatives (BTDs) were synthesized and evaluated for their inhibitory activity versus enzymatic isoform PDE4 extracted from U937 cell line. Some of the tested compounds showed a high PDE4 inhibitory activity at 100 microM and the IC(50) value of the most interesting terms were evaluated. The structure-activity relationships of these compounds showed that the 3,5-di-tert-butyl-4-hydroxybenzyl moiety at N-1 position is important to obtain activity at micromolar level as previously reported. For the same compounds the antioxidant activity were evaluated highlighting 14 as the most significative one. The introduction of other bulky substituents in N-1 position is detrimental.

Benzyl derivatives of 2,1,3-benzo- and benzothieno[3,2-a]thiadiazine 2,2-dioxides: first phosphodiesterase 7 inhibitors.

The synthesis of a new family of benzyl derivatives of 2,1,3-benzo- and benzothieno[3,2-a]thiadiazine 2,2-dioxides was achieved. The biological data revealed the first heterocyclic family of compounds with PDE 7 inhibitory properties appearing to be a new objective for the treatment of T-cell-dependent disorders. The IC(50) values or percent inhibition values of the compounds against PDE 7 were calculated by testing them against human recombinant PDE 7 expressed in S. cerevisiae. In this expression system the only cyclic nucleotide hydrolyzing activity present in cell extracts corresponded to human PDE 7. Isoenzyme selectivity PDE 7 versus PDE 4 and PDE 3 was also measured. Considering simultaneously inhibition of the three different isoenzymes, monobenzyl derivatives 15 and 23 showed interesting PDE 7 potency (around 10 microM); although not statistically significant, a trend toward selectivity with respect to PDE 3 and PDE 4 was obtained. Benzothiadiazine 16, although less potent at PDE 7 (IC(50) = 25 microM), also showed a trend of selectivity toward PDE 3 and PDE 4. These compounds are considered the best leads for further optimization.

[Antimicrobial activity of derivatives of 1,2,4-benzothiadiazine-1,1-dioxide. VIII]. / Azione antimicrobica di derivati dell'1,2,4-benzotiadiazin-1,1-diossido. Nota VIII.

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).

[Cardiovascular action of 1,2,4-benzothiadiazine-1,1-dioxide derivatives. VII]. / Azione cardiovascolare di derivati del 1,2,4-benzotiadiazin-1,1-diossido. Nota VII.

A series of dimethylamino-, diethylamino-, pyrrolidyl- and morpholylalkyl derivatives of 3-amino-1,2,4-benzothiadiazine-1,1-dioxide (compounds I leads to XX) was prepared and tested for cardiovascular activity. It was found that substitution of the alkyl group with the above mentioned groups in 3-amino-1,2,4-benzothiadiazine-1,1-dioxide derivatives in most cases causes marked dissociation of hypotensive activity from bradycardial activity and also disappearance or great reduction in the effect on differential pressure. It was also found that hypotensive activity is particularly dependent on the nature of the basic chain in the two components: length of the carbon chain between the two nitrogens and nature of the basic grouping. For the first component a chain of three carbon atoms seems the most effective and for the second the diethylamino group seems the most favourable. In addition, substituents in the benzene ring influence hypotensive activity, often positively, and 6,7-dichlorosubstitution in some compounds also affects the increase of differential pressure.