S. Boverie

New trends in the design of drugs against Alzheimer's disease

First described by Alois Alzheimer in 1907, Alzheimers disease (AD) is the most common dementia type, affecting approximately 20 million people worldwide. As the population is getting older, AD is a growing health problem. AD is currently treated by symptomatic drugs, the acetylcholinesterase inhibitors, based on the cholinergic hypothesis (1976). During the past decade, advances in neurobiology have conducted to the identification of new targets. Although some of these innovative approaches tend to delay onset of AD, others are still symptomatic. In this review, we present an overview of the several strategies and new classes of compounds against AD.

Study of the ring closure reaction of o-aminoarylsulfonamides with 1,1’-thiocarbonyldiimidazole

Abstract 1,1′-Thiocarbonyldiimidazole was used as a ring closure agent for o-aminoarylsulfonamides. Beside the formation of the expected 3-thioxo-2,3-dihydro-4H-1,2,4-arylthiadiazine 1,1-dioxide derivatives, a new kind of compound was also obtained, namely the 3-(imidazol-1-yl)-4H-1,2,4-arylthiadiazine 1,1-dioxides. The latter appeared to be good reaction intermediates. The use of 1,1′-thiocarbonyldiimidazole opens a new synthetic route to 3-alkylamino-4H-1,2,4-arylthiadiazine 1,1-dioxides, a heterocyclic ring system expressing important pharmacological properties. This work is the first study on the ring closure properties of this reagent.

Synthesis and structural studies of 3-alkylamino-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides: a new class of heterocyclic compounds with therapeutical promises

Abstract 3-Alkylamino-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide represents a new class of heterocyclic compounds expressing important pharmacological properties. According to the position of the CN double bond in the thiadiazine ring, this heterocyclic ring system may exist under three different tautomeric forms. By means of spectral and X-ray data collected from selected compounds, the most favourable tautomeric form adopted by 3-alkylamino-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides devoid of an alkyl substituent in the 2- or in the 4-position was determined. The present study giving new insights in the geometrical and conformational aspects of pyridothiadiazinedioxides is important considering the pharmacological potentialities of this class of heterocyclic compounds.

7-chloro-2-methyl-3-methylamino-2H-1,2,4-benzo-thiadiazine 1,1-dioxide

The title compound, C9H10ClN3O2S, was prepared for structural comparison with analogous products known as myorelaxants and inhibitors of insulin release. The 2H-tautomeric form is imposed by the presence of a methyl group in the 2-position. There are four independent molecules (A, B, C and D) in the asymmetric unit which have almost the same geometry. The C-N distances in the four thiadiazine rings [C-N single- and double-bond mean values of 1.405 (3) and 1.304 (3) Angstrom, respectively] may serve as reference to characterize the 2H-tautomeric form in analogous structures. The NH group of the methylamino substituent of each molecule participates in an intermolecular hydrogen bond with a sulfoxide O atom acting as acceptor. These four independent hydrogen bonds give rise to two types of infinite chains, both stretching along the a axis and having molecular compositions of...ABABAB... and...CDCDCD...

Impact of the Nature of the Substituent at the 3-Position of 4H-1,2,4-Benzothiadiazine 1,1-Dioxides on Their Opening Activity toward ATP-Sensitive Potassium Channels.

The synthesis of diversely substituted 3-isopropoxy-, 3-isopropylsulfanyl-, 3-isopropylsulfinyl-, and 3-isobutyl-4H-1,2,4-benzothiadiazine 1,1-dioxides is described. Their activity on pancreatic β-cells (inhibitory effect on the insulin releasing process) and on vascular and uterine smooth muscle tissues (myorelaxant effects) was compared to that of previously reported K(ATP) channel openers belonging to 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides. The present study aimed at evaluating the impact on biological activity of the isosteric replacement of the NH group of 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides by a O, S, S(═O), or CH(2) group. By comparing compounds bearing identical substituents, the following rank order of potency on pancreatic β-cells was observed: 3-isopropylamino > 3-isobutyl > 3-isopropoxy > 3-isopropylsulfanyl > 3-isopropylsulfinyl-substituted 4H-1,2,4-benzothiadiazine 1,1-dioxides (NH > CH(2) > O > S > S(═O)). A molecular modeling study revealed that 3-isopropoxy-, 3-isopropylsulfanyl-, and 3-isopropylamino-substituted compounds adopted a similar low-energy conformation (preferred orientation of the isopropyl chain). Moreover, no direct relationship was detected between the conformational freedom of the different classes of benzothiadiazines (from the most to the lowest conformationally constrained compounds: NH > O > S > CH(2)) and their biological activity on insulin-secreting cells. Therefore, the present study confirmed the critical role of the NH group at the 3-position for the establishment of a strong hydrogen bond responsible for optimal activity expressed by 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides on insulin-secreting cells. Radioisotopic and fluorimetric experiments conducted with 7-chloro-3-isopropoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide 10c demonstrated that such a compound, bearing a short branched O-alkyl group instead of the NH-alkyl group at the 3-position, also behaved as a specific K(ATP) channel opener. Lastly, the present work further identified 3-(alkyl/aralkyl)sulfanyl-substituted 7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxides as a class of promising myorelaxant drugs acting on uterine smooth muscles, at least in part, through the activation of K(ATP) channels.

Effect on insulin release of compounds structurally related to the potassium‐channel opener 7‐chloro‐3‐isopropylamino‐4H‐1,2,4‐benzothiadiazine 1,1‐dioxide (BPDZ 73): introduction of heteroatoms on the 3‐alkylamino side chain of the benzothiadiazine 1,1‐dioxide ring

7‐Chloro‐3‐pyridyl(alkyl)amino‐4H‐1,2,4‐benzothiadiazine 1,1‐dioxides and 3‐alkylamino‐7‐chloro‐4H‐1,2,4‐benzothiadiazine 1,1‐dioxides containing one or more heteroatoms on the side chain in the 3 position have been synthesized in an attempt to discover new potent KATP‐channel openers. The compounds were tested as putative pancreatic B‐cells KATP channel openers by measuring their inhibitory activity on the insulin releasing process. The influence on the biological activity of the nature of the side chain in the 3 position is discussed.

1,4,2-Benzo/pyridodithiazine 1,1-Dioxides Structurally Related to the ATP-Sensitive Potassium Channel Openers 1,2,4-Benzo/pyridothiadiazine 1,1-Dioxides Exert a Myorelaxant Activity Linked to a Distinct Mechanism of Action

The synthesis of diversely substituted 3-alkyl/aralkyl/arylamino-1,4,2-benzodithiazine 1,1-dioxides and 3-alkylaminopyrido[4,3-e]-1,4,2-dithiazine 1,1-dioxides is described. Their biological activities on pancreatic β-cells and on smooth muscle cells were compared to those of the reference ATP-sensitive potassium channel (KATP channel) openers diazoxide and 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide. The aim was to assess the impact on biological activities of the replacement of the 1,2,4-thiadiazine ring by an isosteric 1,4,2-dithiazine ring. Most of the dithiazine analogues were found to be inactive on the pancreatic tissue, although some compounds bearing a 1-phenylethylamino side chain at the 3-position exerted a marked myorelaxant activity. Such an effect did not appear to be related to the opening of KATP channels but rather reflected a mechanism of action similar to that of calcium channel blockers. Tightly related 3-(1-phenylethyl)sulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxides were also found to exert a pronounced myorelaxant activity, resulting from both a KATP channel activation and a calcium channel blocker mechanism. The present work highlights the critical importance of an intracyclic NH group at the 4-position, as well as an exocyclic NH group linked to the 3-position of the benzo- and pyridothiadiazine dioxides, for activity on KATP channels.

2-alkyl-3-Alkylamino-2H-Benzo- and pyridothiadiazine 1,1-dioxides: from K+ATP channel openers to Ca++ channel blockers?

Abstract A series of 2-alkyl-3-alkylamino-2Hbenzo and 2-alkyl-3-alkylamino-2Hpyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides, structurally related to BPDZ 44 and BPDZ 73, two potent pancreatic Bcells K+ ATP channel openers, were synthesized and tested on rat pancreatic islets (endocrine tissue) as well as on rat aorta rings (vascular smooth muscle tissue). Alkylation of the 2-position led to double bond tautomerization and formation of compounds with a 2Hconformation. In contrast to the previously described pyridothiadiazine dioxides, such as BPDZ 44, and 7-chlorobenzothiadiazine dioxides, such as BPDZ 73, the 2-alkylsubstituted analogs were found to be poorly active on the insulin releasing process although most drugs exhibited a vasorelaxant activity. As a result, the new 2-alkylsubstituted pyridinic compounds expressed a selectivity profile (vascular smooth muscle tissue vs pancreatic tissue) opposite to that of their nonalkylsubstituted counterparts, i.e. BPDZ 44. Additional investigations revealed that, in contrast to their non 2-alkylsubstituted analogs, the most interesting 2-methylsubstituted derivatives did not express the pharmacological profile of classical K+ATP channel openers. The pharmacological results rather suggest that alkylation of the 2-position of the thiadiazine ring led to drugs that could act as Ca2+ channel blockers rather than as potassium channel openers.

Synthesis and Biological Effects of New 3‐Alkylamino‐4H‐1,2,4‐Benzothiadiazine 1,1‐Dioxides on Insulin‐secreting Cells

3-Alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides with nitro, amino or acetylamino groups in the 7-position have been synthesized in an attempt to discover new tissue-selective KATP-channel openers. The compounds were tested as putative pancreatic β-cells KATP-channel openers by measuring their inhibitory activity on the insulin releasing process. The influence of the substituent in the 7-position on the acidic character (pKa) and on biological activity is discussed. The nitrobenzene derivatives were biologically active, but less so than the un-derivatized parent pyridothiadiazine dioxides.

Crystal structure of 7-chloro-3-isopropoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide monohydrate, C10H13CIN2O4S H2O

Abstract C10H13ClN2O4S, monoclinic, C12/m1 (no. 12), a = 16.6352(6) Å, b = 6.8145(7) Å, c = 12.2805(6) Å, β = 107.921(3)°, V = 1324.6 Å3, Z = 4, Rgt(F) = 0.043, wRref(F2) = 0.126, T = 293 K.