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One-Pot, Telescopic Approach for the Chemoselective Synthesis of Substituted Benzo[e]pyrido/pyrazino/pyridazino [1,2-b] [1,2,4]thiadiazine dioxides and its Significance in Biological Systems Ramsingh Dhanbahadur Padmaja, Musuvathi Motilal Balamurali, and Kaushik Chanda J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00869 • Publication Date (Web): 22 Aug 2019 Downloaded from pubs.acs.org on August 22, 2019

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The Journal of Organic Chemistry

One-Pot, Telescopic Approach for the Chemoselective Synthesis of Substituted Benzo[e]pyrido/pyrazino/pyridazino [1,2-b][1,2,4]thiadiazine dioxides and its Significance in Biological Systems Ramsingh Dhanbahadur Padmaja,a Musuvathi Motilal Balamurali,b* Kaushik Chandaa* aDepartment

of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore-632014, India

bChemistry

Division, School of Advanced Sciences, Vellore Institute of Technology, Chennai600127, India Email: [email protected] [email protected]

This article is dedicated to Prof Chung Ming Sun for his enormous contribution in diversity oriented synthesis (DOS) Abstract The one-pot telescopic approach has been developed for the chemoselective synthesis of substituted benzo[e]pyrido/pyrazino/pyridazino[1,2-b][1,2,4]thiadiazine dioxides using readily available 2-aminopyridines/pyrazines/pyridazine and 2-chloro benzene sulfonyl chloride. This one-pot

procedure

involves

the

chemoselective

sulfonylation

of

2-

aminopyridines/pyrazines/pyridazine with 2-chloro benzene sulfonyl chloride followed by Cu(I) catalyzed

Ullmann-type

C-N

coupling

reaction

to

obtain

benzo[e]pyrido/pyrazino/pyridazino[1,2-b][1,2,4]thiadiazine dioxides with broad substrate scope and high functional group tolerance. The synthetic sequence merges well with the nucleophilic attack on the 2-amino group of pyridines/pyrazines/pyridazines on the 2-chloro benzene sulfonyl chloride followed by, Cu(I) catalyzed ipso chloro displacement to C-N bond formation resulting in a more modular and straightforward approach. Moreover, the biological significance of the

1

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synthesized benzothiadiazine dioxides was evaluated by following their ability to bind to protein macromolecules and their anti-inflammatory activity. Graphical Abstract

NH2 Cl

Y

R1

X

N

X= C, N Y= C, N

+

R2

K2CO3, CH3CN

ClO2S

r.t., 10 h

NH

Y R1X

N O

S

Cl

O

N

R2

Y CuI (5 mol%) R K2CO3, CH3CN 1 N X S reflux, 3 h O O X= C, N Y= C, N

Biological Significance Anti-inflammatory Activity

Experimental Approach

Biomolecular Binding Affinity Computational Approach

2


R2

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Introduction The six-membered heterocyclic rings with pyridine moieties are important skeletons in some natural products as well as in drug molecules.1 Similarly, benzothiadiazine dioxide ring is an attractive candidate for drug development and active against a number of diseases and conditions, which includes diabetes, anticancer, and antiviral activities.2 Molecules with benzothiadiazine dioxide moieties are being investigated as potassium channel openers (A), for AMPA potentiators (B), as active against human cytomegalovirus and human herpesvirus, and human herpesvirus 6 (C) as depicted in Figure 1.3

O

N

S N H

R4 N

O N N H

R

Potassium channel opener (A)

N

O N

O

S R2 O

N N S O O O

R

AMPA potentiators (B) Human cytomegalovirus (C), R=OCH3 Human herpesvirus 6 (C), R=CH3

Figure 1. Biologically active benzothiadiazine dioxide moieties. In view of their wide ranging bioactivities in pharmacological and biological investigations, particularly in the designing of new drug candidates, so far only a few synthetic methods involving multistep synthesis have been reported for the construction of this class of framework. Moreover, the five membered analogues of isothiazole oxides are also abundantly reported in the literature.4 Likewise, Wu and his coworkers demonstrated the synthetic advancement achieved for diverse heterocycles using 2-aminopyridine as starting material.5 In 2008 for the first time, Chang et al. demonstrated the use of ammonium chloride as an inexpensive reagent for the Cu(I) catalyzed one-pot sequential reaction of terminal alkynes and sulfonyl azide to benzothiadiazine dioxides.6 Subsequently in 2009, microwave assisted one-pot protocol has been developed for the 3



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synthesis of benzothiadiazin-3-one-1,1-dioxides using Cu(I) catalyzed N-arylation of αbromobenzenesulfonamides with amines followed by rapid cyclization using carbonyl diimidazole (CDI).7 Similarly, an Fe (III) catalyzed one-pot oxidative route has been developed in the conversion of primary alcohols into benzothiadiazine 1,1-dioxide derivatives.8 Recently, Wang and his coworkers developed the Cu(I) catalyzed domino synthesis of fused benzothiadiazine dioxides via an Ullmann-type N-arylation and intramolecular C−H amination of

2-bromo-N-phenylbenzenesulfonamides

and

benzimidazole

derivatives.9

In

1959,

Grammaticakis et al. reported the sufonylation of 2-aminopridine.10 However, the majority of those synthetic sequences suffer from partial diversity with the practice of a multistep method under harsh reaction conditions. Moreover, to the best of our knowledge, synthesis of the pyridine, pyrazine or pyridazine containing benzothiadiazine dioxide frameworks has not been reported so far. Therefore, our preliminary aim is to develop an efficient, new and practical method for the synthesis of this new kind of diversely structured heterocycles which could possibly possess important biological activity. The N-S and C−N bond formation is of fundamental and immense importance in synthetic organic chemistry because of its extensive utility in natural products, bioactive compounds, drug molecules, and materials synthesis. Over the past decade, because of the ready availability and low toxicity of copper catalysts and their ligands, great advances have been made in Cu(I) catalyzed C−N bond formation, and some N-heterocycles were synthesized using this coupling.11 Furthermore, for economical and environmental reasons, there is an increasing demand for telescoped reaction approach. The one-pot telescoped reaction approach involves the sequential addition of reagents, one at a time without post-synthetic work up which reduces the number of purification steps along with operational simplicity which boosts the reaction result.12 4


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In continuation with our ongoing studies on the synthesis of biologically interesting heterocyclic molecules,13 herein we demonstrated an efficient one-pot, telescopic approach for the

chemoselective

synthesis

of

substituted

benzo[e]pyrido/pyrazino/pyridazino

[1,2-

b][1,2,4]thiadiazine dioxides, a new class of N-heterocycles with potential biological activity. These reactions proceeds very well under mild conditions and provides a good range of products in excellent yields with excellent regioselectivity and were evaluated for their potential antiinflammatory activity and protein binding ability.

Results and Discussion At the outset, we considered the reaction of 2-amino pyridine 1a with 2,4-dichloro benzene sulfonyl chloride 2a as a template. For this transformation, we have investigated the key factors and optimized reaction conditions. To this end, first we have examined the effect of solvent as depicted in Table 1. In particular, 2-amino pyridine 1a skeleton is oriented in such a way that there is a possibility of nucleophillic attack of the ring N-atom of pyridine moiety and amino group on the sulfonyl chloride, generating two sulfonamide moieties 3a or 3b as depicted in Figure 2. The difference between the formations of two sulfonamide moieties 3a or 3b rests in the attachment of sulfone moiety with the nitrogen atom. Cl NH2 N

Cl

ClO2S 2a

NH

K2CO3, Solvent reaction conditions

N O

1a

S

Cl

Cl +

O 3a

H N N

S O Cl

O

3b

Figure 2. Two different modes of sulfonamide formation.

5


Cl


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To our delight, at room temperature condition, in the presence of K2CO3 as base (2 equiv) in THF solution, the desired sulfonamide product 3a or 3b was isolated in 10% yield after 12 h (Table 1, entry 1). However, under refluxing condition, the yield of the sulfonamide intermediates (3a or 3b) was increased upto 50% (Table 1, entry 2). By replacing the solvent system to CH3CN at room temperature condition, the yield of the products increased to 90% (Table 1, entry 3). However, multiple spots on TLC plate were observed when refluxing the reaction mixture in CH3CN in order to obtain the higher yield, as shown in (Table 1, entry 4). Unfortunately, the reaction did not afford any desired sulfonamide products using solvents such as DMF, and DMSO at room temperature as well as upon heating the reaction mixture at 80 oC condition (Table 1, entries 5-6). Table 1. Optimization of chemoselective sulfonylation reaction of 2-aminopyridine 1a with 2,4-dichloro benzene sulfonyl chloride 2a. NH2 N

Cl

Cl +

reaction conditions

ClO2S 2a

1a

a

NH

K2CO3, Solvent

Cl

N

S O O 3a(exclusively)

Cl +

H N N

S O Cl

O Cl

3b

entry

solvent

temperature

time

3a yield%b

1

THF

rt

10 h

10%

2

THF

reflux

10 h

50%

3

CH3CN

rt

10 h

90%

4

CH3CN

reflux

10 h

Decomposed

5

DMF

80oC

10 h

0%

6

DMSO

80oC

10 h

0%

reaction was performed using 1a (1 mmol), 2a (1 mmol), bYield of the isolated product.

However to ascertain whether the compound 3a is formed over 3b, we have isolated the newly formed product in 90% yield and subjected to spectroscopic analysis. Spectroscopic analysis of 6


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the obtained product did not match the structure of the isomeric sulfonamide 3b. The corresponding peak of the C5-H proton between the two chlorine group was observed at δ = 7.97 ppm in the proton NMR spectrum, while there was no peak for sulfonamide NH proton, which clearly ascertains the exclusive formation of 3a. Further the analysis of IR data noticeably demonstrated the chemoselective formation of 3a over 3b with the presence of peaks at 1649 cm1

and 3273 cm-1 due to the C=N and NH bonds stretching frequencies respectively. However, in

addition, we have obtained the UV-Vis spectra of compound 3a with a single band centered ~ 310 nm in acetonitrile, which confirms the presence of only one product 3a rather than compound 3b (Supporting information Figure S4). It was well known from the literature that the imine form of 2-amino pyridine is the more pronounced tautomer under polar environment, even though it is weakly stable than the amine form.14 This weak stability forms the driving force for the reaction to proceed towards forming the product 3a rather than 3b, which would have been the major product in the case of amine tautomer. The next step of the synthetic sequence involved the formation of six membered benzothiadiazine dioxide frameworks which could be achieved via intramolecular Cu(I) catalyzed Ullmann-type C-N coupling reaction by the ipso chloro displacement to C-N bond formation. Subsequently, the compound 3a was subjected to Cu(I) catalyzed ipso chloro displacement to C-N bond formation reaction in refluxing CH3CN for 3 hr using K2CO3 as base to obtain benzothiadiazine dioxide 4a shown in Scheme 1.

NH2 N 1a

Cl

Cl

+

NH

K2CO3, CH3CN N

r.t., 10 h

ClO2S 2a

Cl

Cl

S

O O 3a(exclusively)

CuI (5 mol%) K2CO3, CH3CN reflux, 3 h

N N O

S

Cl

O

4a

Scheme 1. Synthesis of 2-chlorobenzo[e]pyrido [1,2-b][1,2,4]thiadiazine 5,5-dioxide 4a. 7



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After successfully executing the N-sulfonylation and intramolceular Cu(I) catalyzed Ullmanntype C-N coupling reaction to obtain the benzothiadiazine 5,5-dioxide 4, our next attempt to obtain the chemoselectivity in one-pot telescoped manner. For this purpose, we performed onepot telescoped reaction where the reaction of substituted 2-aminopyridine 1 with substituted 2chloro benzene sulfonyl chloride 2 in presence of K2CO3 as base under anhydrous acetonitrile solution at room temperature resulted in the formation of N-sulfonylated product 3. Without isolating the intermediate product 3, the same reaction mixtures were refluxed for another 3 h with in-situ addition of CuI (5 mol%) to obtain desired benzothiadizine 5,5-dioxides 4 as shown in Scheme 2. Upon completion of the reaction, the 1H NMR spectrum of the synthesized compound indicated the formation of pure benzothiadizine 5,5-dioxides 4 in excellent yield.

NH2 R1

N 1

Cl +

R2

ClO2S

NH

K2CO3, CH3CN r.t., 10 h

R1

2

Cl

N

S R2 O O 3 (not isolated)

CuI (5 mol%) K2CO3, CH3CN R1 reflux, 3 h

N N O

R2 S

O

4

Scheme 2. Synthesis of one-pot telescopic approach to substituted benzo[e]pyrido[1,2b][1,2,4]thiadiazine 5,5-dioxides 4.

Consequently, this one-pot telescopic approach provided the direct access to the creation of benzo[e]pyrido[1,2-b][1,2,4]thiadiazine 5,5-dioxides 4 in excellent yields. To further examine the efficiency of this one-pot telescopic approach and to rapidly expand our unique compound library, we extended the substrate scope to 2-amino pyrazine and 2aminopyridazine as suitable substrates. As mentioned in Table 2, we could find a smooth

8


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transformation of 2-amino pyrazine and 2-amino pyridazine to benzo[e]pyrazino/pyridazino [1,2b][1,2,4]thiadiazine dioxides. Table 2. One-pot telescopic approach to benzo[e]pyrido/pyrazino/pyridazino [1,2b][1,2,4]thiadiazine dioxides 4.a,b NH2

Y

R1

X

N

Cl +

R2

K2CO3, CH3CN r.t., 10 h

ClO2S

X= C, N Y= C, N 1

2

N

Cl CH3

CH3

N

N

CH3

Cl

Cl

N

N

Cl

4i, 82% N

N

S O O Cl

4k, 88%

4l, 80% Cl

Cl

S O O

N

H3C

S O O Cl

4j, 80%

N

4h, 85%

N

S O O Cl

S O O

N

N

N

N

S O O

4g, 80% CH3

N

H3C

Cl

N

S O O

4f, 80%

4e, 88%

CH3

N

S O O

S O O

4d, 82%

N

N

N

S O O

4c, 84%

N

N

H3C

N

S O O

4b, 80%

4a, 90%

N

N

S O O

R2

Cl N

N

S O O

Cl

N Y CuI (5 mol%) R1 K2CO3, CH3CN N N X S S R1 X R2 reflux, 3 h O O O O X= C, N Y= C, N 3 (not isolated) 4 NH

Y

N N

4m, 85%

Cl

N

S O O

N

4n, 88%

N

N N

S O O Cl

N

N

4o, 84%

S O O 4p, 82%

aReaction

conditions: amines (1 mmol), substituted 2-chloro benzene sulfonyl chloride (1 mmol), K2CO3 (2 equiv), Cu(I) catalyst (5 mol%), Solvent CH3CN (5 mL). bIsolated yield

After

successful

completion

of

the

telescopic

reaction,

the

corresponding

benzo[e]pyrido/pyrazino/pyridazino[1,2-b][1,2,4]thiadiazine dioxide derivatives 4 were obtained with excellent yields followed by a simple work-up involving the removal of solvents under 9



Page 10 of 30

reduced pressure, extraction, and solvent evaporation. Finally the crude compounds were purified by column chromatography followed by spectroscopic characterization using 1HNMR, 13C

NMR, mass (MS), IR spectroscopy. Additionally, we have investigated the potential

synthetic applicability of this one-pot telescopic approach on a gram scale using the model reaction. As depicted in Scheme 3, the reaction could afford 2.15 g of 4a in 80% yield without any significant loss in its efficiency, demonstrating the potential applications of the present method for a large scale synthesis of 2-chorobenzo[e]pyrido[1,2-b]thiadiazine 5,5-dioxide 4a scaffold. NH2 N

Cl

Cl +

N

r.t., 10 h

ClO2S

10.6 mmol

NH

K2CO3, CH3CN O

10.6 mmol

1a

2a

S

Cl

Cl

O

CuI (5 mol%) K2CO3, CH3CN reflux, 3 h

N

Cl

N

S O O 2.15 g (80%) 4a

3a(exclusively)

Scheme 3. Gram-scale synthesis of 2-chlorobenzo[e]pyrido[1,2-b][1,2,4]thiadiazine 5,5dioxide 4a. A plausible mechanistic pathway for this N-sulfonylation and Cu(I) catalyzed Ullmann-type C-N coupling reaction is outlined in Scheme 4. The lone pair of electrons on pyridine N-atom in 1a underwent N-sulfonylation with the 2-chloro benzene sulfonyl chloride 2a under base mediated condition to Cl

N 1a

NH2 +

Cl Cl

S O O 2a

Cl

O S N O

K2CO3 -HCl

Cl

CuI in- situ

NH 3a (not isolated)

N N O

S

Cl

O

4a

10


O S N O X N Cu

Cl -CuI -HCl

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Scheme 4. Plausible mechanism for N-sulfonylation and Cu(I) catalyzed Ullmann-type C-N coupling reaction to benzo[e]pyrido[1,2-b][1,2,4]thiadiazine 5,5-dioxides 4a. generate the intermediate 3a with the loss of HCl molecule. Further in situ addition of CuI facilitates the coordination of Cu metal with nitrogen atom and activation of C-Cl bond followed by the exclusion of Cu atom and C-N bond formation to obtain the six membered heterocycle 4a. To further confirm the benzothiadiazine dioxides 4, we undertook the X-ray crystallographic study of compound 4l.15 Figure 3 depicts the ORTEP diagram of compound 4l (X-ray crystallographic data were specified in Supporting Information). The X-ray crystal structure of compound 4l indicates that methyl substitution on pyridyl group and chloro substitution on benzene sulfonyl moiety are present in the same plane with exclusive N-S bond formation which unequivocally confirms its structure. The bond lengths of N1-S1(O2) and C1-S1(O2) in the X-ray crystal structure of compound 4l are 1.6999 Ǻ and 1.7313 Ǻ respectively.

O O Cl S N H3C

N 4l

Figure 3. ORTEP diagram of compound 4l with 20% thermal ellipsoid probability. To determine the anti-inflammatory activities of substituted benzo[e]pyrido/pyrazino/pyridazino [1,2-b][1,2,4]thiadiazine dioxides 4, their ability to inhibit the albumin denaturation was evaluated. Inflammation is the initial response of a living system towards an invasion by pathogens, defective cells, toxins or an incurred injury involving many different inflammatory mediators and immune system cells.16 The ability of the synthesized molecules to inhibit the 11



denaturation of albumin reveals their anti-inflammatory activity, as inflammations are associated with one or more of the following symptoms like vascular permeability, protein denaturation, membrane alteration, etc.17 There are several anti-inflammatory drugs available in the market and much more are reported in the literature. In vitro albumin denaturation assay is one of the simplest methods to predict the anti-inflammatory activity of compounds. Moreover, several reports indicate that molecules which possess the ability to inhibit albumin denaturation can be potent candidates for anti-inflammatory agents.18 The evaluations were carried out in-vitro at different concentrations and compared with the well-known anti-inflammatory drug diclofenac sodium in Table 3. The percentage inhibition at 100 µM concentration of each compound in 2 % DMSO has been reported. Table 3.

Anti-inflammatory activity of substituted benzo[e]pyrido/pyrazino/pyridazino

[1,2-b][1,2,4]thiadiazine dioxides 4.

12


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% Inhibition of albumin denaturation

entry

product

1

4a

74.14

2

4b

65.51

3

4c

74.13

4

4d

68.97

5

4e

46.55

6

4f

55.17

7

4g

81.03

8

4h

62.07

9

4i

62.07

10

4j

41.38

11

4k

17.24

12

4l

67.24

13

4m

37.93

14

4n

65.51

15

4o

70.69

16

4p

12.07

17

Diclofenac Sodium

84.73

The estimated inhibitory activity of benzo[e]pyrido/pyrazino/pyridazino [1,2-b][1,2,4]thiadiazine dioxides 4 were measured and the results are given in Table 3. Most of the compounds exhibited moderate activity with the exception of compounds 4g without any substitution in the benzo[e]pyrido[1,2-b][1,2,4]thiadiazine 5,5-dioxide ring. In order to evaluate the potency of a synthesized molecule to be a drug candidate, its interaction with plasma protein macromolecules has been investigated.19,20 It has been reported in the literature that such investigations will aid in the design and development of new and active drugs.19 In the present study we have investigated the interaction of various synthesized benzo[e]pyrido/pyrazino/pyridazino [1,2-b][1,2,4]thiadiazine dioxides 4 with bovine serum albumin (BSA) by following Stern Volmer fluorescence quenching method (refer equation 1). 13



Page 14 of 30

Fo/F = 1 + KSV + [Q]

(1)

Where Fo and F are the fluorescence intensities in the absence and presence of substituted benzo[e]pyrido/pyrazino/pyridazino[1,2-b][1,2,4]thiadiazine

dioxides

4

(Quenchers)

respectively, KSV is the Stern Volmer quenching constant and [Q] is the concentration of the quencher molecule. It was observed that the plot of Fo/F vs [Q] was linear, indicating that the quenching interaction is of static type. In order to calculate the binding constant and the number of binding sites, the Scat chard equation 2 was adopted as shown below. log (Fo-F)/F = n log KA – n log 1/ ([Q] – [BSA]*(Fo-F)/Fo)

(2)

Where KA is the binding affinity towards BSA and n is the number of binding sites on the macromolecule. The binding constant KA can be obtained from the intercept of the plot of log [(Fo-F)/F] vs log 1/ ([Q] – [BSA]*(Fo-F)/Fo), while the number of binding sites can be obtained from its slope. The values of quenching constant and binding affinity are given in Table 4.

14


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Table 4. Binding parameters as deduced by the fluorescence quenching parameters and binding affinity with BSA.

Product 4a

KSV (M-1) x 103 34.6059

KA (M-1) X 103 43.6342

n 0.5

4b

40.4786

50.2711

0.7

4c

29.329

32.9278

1

4d

122.745

195.434

1

4e

144.845

188.582

1

4f

68.1845

85.8432

1

4g

17.1432

15.2427

0.8

4h

104.233

162.519

1

4i

12.2127

13.1576

0.9

4j

395.541

5346.59

0.5

4k

475.836

2033.36

1

4l

947.951

44095.9

1

4m

227.563

904.058

1

4n

101.753

379.963

0.5

4o

60.2888

93.6933

0.8

4p

67.1466

103.673

0.8

The results reveal that the binding affinity of compound 4l is very high when compared to other benzothiadiazine dioxide analogues. The value of n indicates that most of the analogues possess a single unique binding site on the macromolecule with the exception of 4a, 4j and 4n, where two sites of interactions are available on the macromolecule. Strong binding and a high quenching constant was observed in the presence of pyridine ring with chlorine substitution at C4 position of the benzene ring. Depending on the bulky nature of the substituent at C4 position, 15



the molecular strain increases. Hence effective binding with the macromolecules would aid to relieve this strain. The methyl group at C9 or C10 position in the benzene ring does not significantly influence the binding interactions. In the case of compound 4g, where no substituents are present, such steric effects do not exist and hence week binding is observed. While in compound 4i, the chloro substitution at C2 position does not generate steric hindrance. Our data reveals that the interaction with the macromolecule exposes the buried tryptophan to the solvent environment and hence quenching of fluorescence occurs. The presence of iso-emissive point in compounds 4a-4d could be due to the equilibrium between the bound and free form of the macromolecule. The thermodynamic stabilization offered upon binding is revealed by the red shift in the emission spectrum from 350 nm to 376 nm. In the case of compounds 4e-4p, the binding interactions are revealed by hypochromic effect in the emission spectrum. Molecular Docking – In silico analysis to investigate the binding interactions of substituted benzo[e]pyrido/pyrazino/pyridazino[1,2-b][1,2,4]thiadiazine dioxides 4 with bovine serum albumin: To investigate the nature of binding interactions and the interacting residues, molecular docking was performed for all the synthesized substituted benzo[e]pyrido/pyrazino/pyridazino [1,2b]thiadiazine dioxides 4 with BSA. The docking method employed was followed as reported elsewhere.21 The observed change in the binding energies and the intermolecular energies during interactions are shown in Table 5.

16


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Table 5. The binding energy (∆GBE) and intermolecular energy (∆Gintermol) of the compounds 4a-p with BSA is given below. All the energies are reported in kcal/mol. Product

∆Gintermol

∆GBE

∆Gvdw_hb_desol

∆Gelec

4a

-4.34

-4.28

-0.06

4b

-4.39

-4.27

- 0.12

4c

-4.72

-4.58

-0.14

4d

-4.75

-4.75

0

4e

-4.36

-4.37

0.01

4f

-4.52

-4.38

-0.14

4g

-4.41

-4.29

-0.12

4h

-4.56

-4.41

-0.15

4i

-5.19

-5.12

-0.06

4j

-5.55

-5.60

0.05

4k

-5.42

-5.26

-0.16

4l

-6.96

-6.96

0.05

4m

-4.72

-4.62

-0.09

4n

-4.64

-4.44

-0.20

4o

-4.25

-3.93

-0.33

4p

-4.04

-4.03

-0.01

It could be observed that compounds 4l, 4j and 4k exhibit strong binding with BSA as compared to other analogues. The intermolecular energy contributions to the total energy are -6.96, -5.60, and -5.26 Kcal/mol respectively. The results are in good agreement with our experimental values given in Table 4. The strong binding of 4l could be attributed to the hydrogen bond interaction with Leu197, in addition to other non-covalent interactions with residues Arg194, Arg198, Ser201, Ala209, Leu210, Trp213, Leu480 and Val481. The best docked conformation of 4l is

17



Page 18 of 30

shown in Figure 4. The binding interactions of 4j and 4k are shown in supporting information. The observed results are in good agreement with the experimental binding studies.

Figure 4. Docked conformation of 4l with the crystal structure BSA (Pdb id: 4JK4). The structure of 4l is represented in ball and stick model. The dotted line indicates the hydrogen bonding interaction between 4l and BSA. These results indicated that benzo[e]pyrido/pyrazino/pyridazino [1,2-b]thiadiazine dioxide compounds possess significant anti-inflammatory activities and protein binding affinities for their applications as biomolecular probes. Further development of such compounds might be of interest to medicinal chemists.

Conclusion: In summary, we have developed the one-pot, telescopic approach for the chemoselective synthesis of substituted benzo[e]pyrido/pyrazino/pyridazino[1,2-b][1,2,4]thiadiazine dioxides. This

is

the

first

report

for

the

chemoselective

benzo[e]pyrido/pyrazino/pyridazino[1,2-b][1,2,4]thiadiazine

dioxides

synthesis

through

the

of [3+3]

approach under thermal condition. The salient features of this telescopic approach include milder 18


Page 19 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


reaction conditions, inexpensive reagents, high-atom economy, and clean reaction profile in a single

synthetic

operation.

The

biological

significance

of

the

synthesized

benzo[e]pyrido/pyrazino/pyridazino[1,2-b][1,2,4]thiadiazine dioxides was evaluated by their potency as anti-inflammatory agent and ability to bind macromolecules. Our investigations reveal benzo[e]pyrido/pyrazino/pyridazino[1,2-b][1,2,4]thiadiazine dioxides as potent candidates for biomolecular probes. The results suggested that these unique heterocyclic molecules might serve as interesting lead compounds for the drug discovery applications.

Experimental Section General Methods Unless otherwise indicated all common reagents and solvents were used as obtained from commercial suppliers without further purification. 1H NMR (400 MHz) and 13C NMR (100 MHz) were recorded on a Bruker DRX400 spectrometer. Chemical shifts are reported in ppm relative to the internal solvent peak. Coupling constants, J, are given in Hz. Multiplicities of peaks are given as: d (doublet), m (multiplet), s (singlet), and t (triplet). Mass spectra were recorded on a Perkin Elmer Calrus 600 GC-MS spectrometer. HRMS were recorded on a micrOTOF-Q II 10330 instrument. IR spectra were recorded on a Bomen DA8 3FTS spectrometer. All the starting materials such as 2-aminopyridine, 2-aminopyrazine, 2aminopyridazine and substituted 2-chloro benzene sulfonyl chlorides were purchased from either Sigma-Aldrich or Avra scientific limited. Representative

Procedure

for

the

Synthesis

of

2-chlorobenzo[e]pyrido[1,2-

b][1,2,4]thiadiazine 5,5-dioxides 4a. In a round bottomed flask, a mixture of 2-aminopyridine 1a (0.1 g, 1.06 mmol, 1.0 equiv), 2,4-dichloro benzene sulfonyl chloride 2a (0.260 g, 1.06 mmol, 19



1.0 equiv), and K2CO3 (0.292 g, 2.12 mmol, 2.0 equiv) was added to 5 mL of CH3CN. The reaction mixture was stirred under room temperature condition for 10 h. The progress of the reaction was monitored by TLC. After completion, to the same reaction mixture was added 5 mol% of CuI and refluxed for 3 h at 80 oC. After checking the progress of the reaction by TLC, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was washed with water and extracted with ethyl acetate (10 mL, twice). The combined organic layer was dried over anhydrous MgSO4. The combined filtrate was subjected to evaporation to obtain the crude compound, which was purified over silica gel column (60–120 mesh) using 5% ethyl acetate in hexane as eluent to obtain the corresponding 2chlorobenzo[e]pyrido[1,2-b][1,2,4]thiadiazine 5,5-dioxide 4a as the product.

2-Chlorobenzo[e]pyrido[1,2-b][1,2,4]thiadiazine 5,5-dioxides (4a). Yield = 0.238 g, 90%; Brown solid; mp:148-150 °C; 1H NMR (400MHz,CDCl3) δ 8.33 (d, J =5.2 Hz, 1H), 8.21(d, J = 8.4 Hz, 1H), 7.69-7.65 (m, 1H), 7.44-7.36 (m, 2H), 7.28 (d, J = 8.4 Hz, 1H), 6.79 (t, J = 6.4 Hz, 1H);

13C{1H}NMR

(100MHz, CDCl3) δ 143.1, 139.5, 138.1, 133.1,

132.2, 131.3, 130.6, 127.5, 127.0, 115.8, 113.6; HRMS (ESI, m/z) calcd for C11H8ClN2O2S: m/z 266.9995; Found 266. 9990 (M+H); IR (cm-1, KBr): 2920, 1598, 1531, 1458, 1357, 817, 765 9-Methylbenzo[e]pyrido[1,2-b][1,2,4]thiadiazine 5,5-dioxide (4b). Yield = 0.197 g, 80%; Brown solid; mp: 155-156°C; 1H NMR (400MHz, CDCl3) δ 8.28 (t, J = 6.3 Hz, 1H) 8.22 (d, J = 6.3 Hz, 1H), 7.43-7.39 (m, 3H), 7.09 (s, 1H), 6.57 (d, J = 6.4Hz, 1H), 2.26 (s, 3H); 13C{1H}NMR (100MHz, CDCl3) δ 154.6, 154.1, 138.7, 136.9, 131.7, 131.2, 130.8, 129.9, 125.6, 114.1, 114.0, 21.2; HRMS (ESI, m/z) calcd for C12H11N2O2S: m/z 247.0541; Found 247.0536 (M+H); IR (cm-1, KBr): 3215, 2814, 1600, 1236, 1033. 20


Page 20 of 30

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10-Methylbenzo[e]pyrido[1,2-b][1,2,4]thiadiazine 5,5-dioxide (4c). Yield = 0.206 g, 84%; Light brown solid; 1HNMR (400MHz, CDCl3) δ 8.24 (dd, J = 7.6, 1.6 Hz, 1H), 7.50-7.35 (m, 5H), 6.58 (t, J = 6.4Hz, 1H), 2.16 (s, 3H); 13C{1H}NMR (100MHz, CDCl3) δ 153.4, 139.9, 139.2, 131.4, 131.1, 130.3, 129.8, 128.6, 125.7, 110.5, 16.8; HRMS (ESI, m/z) calcd for C12H11N2O2S: m/z 247.0541; Found 247.0536 (M+H); IR (cm-1, KBr): 3228, 2918, 1585, 1251, 1037. 3-Chlorobenzo[e]pyrido[1,2-b][1,2,4]thiadiazine 5,5-dioxide (4d). Yield = 0.217 g, 82%; Brown solid; 1HNMR (400MHz, CDCl3) δ 7.95 (d, J = 7.2 Hz, 1H), 7.83 (d, J = 8 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.33-7.19 (m, 3H), 6.59 (t, J = 7.2 Hz, 1H); 13C{1H}NMR

(100MHz, CDCl3) δ 155.3, 142.7, 139.4, 139.3, 132.9, 132.1, 131.9, 131.1, 126.7,

115.6, 113.4; HRMS (ESI, m/z) calcd for C11H8ClN2O2S: m/z 266.9995; Found 266.9990 (M+H); IR (cm-1, KBr): 3257, 1550, 1166, 1051, 601. 1-Chloro-9-methylbenzo[e]pyrido[1,2-b][1,2,4]thiadiazine 5,5-dioxide (4e). Yield = 0.246 g, 88%; Yellow solid; 1HNMR (400MHz, CDCl3) δ 7.83 (d, J = 7.2 Hz, 1H), 7.77 (dd, J = 8.0, 1.6 Hz, 1H), 7.71 (dd, J = 7.2, 1.2 Hz, 1H), 7.19-7.15 (m, 1H), 6.97 (s, 1H), 6.41 (dd, J = 7.6 2.0 Hz, 1H), 2.24 (s, 3H); 13C{1H}NMR (100MHz, CDCl3) δ 148.5, 147.8, 141.3, 134.7, 130.7, 123.8, 123.7, 123.6, 122.2, 120.4, 114.6, 21.5; HRMS (ESI, m/z) calcd for C12H10ClN2O2S: m/z 281.0152; Found 281.0146 (M+H); IR (cm-1, KBr): 1643, 1506, 1180, 694. 1-Chloro-10-methylbenzo[e]pyrido[1,2-b][1,2,4]thiadiazine 5,5-dioxide (4f). Yield = 0.224 g, 80%; Brown solid; 1HNMR (400MHz, CDCl3) δ 8.18 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (dd, J = 8.4, 1.6 Hz, 1H), 7.52 (d, J = 6.8 Hz, 1H), 7.48 (d, J = 6.4Hz, 1H), 7.32 (t, J = 8.8 Hz, 1H), 6.61 (t, J = 6.8Hz, 1H), 2.16 (s, 3H); 13C{1H}NMR (100MHz, CDCl3) δ 154.6, 142.9, 140.5, 134.9, 133.2, 131.1, 130.6, 128.0, 127.6, 127.1, 111.8, 17.8; HRMS (ESI, m/z) calcd for 21



Page 22 of 30

C12H10ClN2O2S: m/z 281.0152; Found 281.0146 (M+H); IR (cm-1, KBr): 1591, 1251, 1089, 644. Benzo[e]pyrido[1,2-b][1,2,4]thiadiazine 5,5-dioxide (4g). Yield = 0.185 g, 80% ; Brown solid; mp: 256-258°C; 1HNMR (400MHz, CDCl3) δ 8.39 (d, J = 5.2 Hz, 1H), 8.29 (t, J = 5.2 Hz, 1H), 7.67-7.63 (m, 1H), 7.43-7.40 (m, 3H), 7.31(d, J = 9.2 Hz,1H);

13C{1H}NMR

(100MHz, CDCl3) δ 154.5, 141.9, 138.3, 138.2, 131.9, 131.1, 130.9,

130.1, 125.7, 114.5, 112.2; MS (GC-MS); 232; HRMS (EI, m/z) calcd for C11H8N2O2S: m/z 232.0306; Found 232.0326; IR (cm-1, KBr): 2692,1612, 1257, 1037 2-Chloro-10-methylbenzo[e]pyrido[1,2-b][1,2,4]thiadiazine 5,5-dioxide (4h). Yield = 0.238 g, 85%; Yellow solid; mp: 136-138 °C; 1HNMR (400MHz,CDCl3) δ 7.90 (d, J = 7.2Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.29 (dd, J = 8.8, 2 Hz,1H), 6.52 (t, J = 6.8, 7.2Hz, 1H), 2.37 (s, 3H);

13C{1H}NMR

(100MHz, CDCl3) δ 148.6, 145.4, 140.3,

133.9, 133.5, 127.4, 124.6, 122.9, 122.3, 119.5, 110.9, 18.4; HRMS (ESI, m/z) calcd for C12H10ClN2O2S: m/z 281.0152; Found 281.0146 (M+H); IR (cm-1, KBr): 1597, 1257, 1037, 650. 2-Chloro-9-methylbenzo[e]pyrido[1,2-b][1,2,4]thiadiazine 5,5-dioxide (4i). Yield = 0.230 g, 82 %; Brown solid; mp:144-146°C; 1H NMR (400MHz,CDCl3) δ 7.99 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.36 (t, J = 10.0, 2Hz, 1H), 6.94 (s, 1H), 6.54 (dd, J = 7.6, 1.6Hz, 1H), 2.39 (s, 3H);

13C{1H}NMR

(100MHz, CDCl3) δ 148.9,

147.8, 145.8, 140.5, 126.7, 124.3, 123.7, 123.0, 123.0, 119.4, 114.3, 21.6; HRMS (ESI, m/z) calcd for C12H10ClN2O2S: m/z 281.0152; Found 281.0146 (M+H); IR (cm-1, KBr): 2922, 1625, 1234, 1074, 646. 4-Chlorobenzo[e]pyrido[1,2-b][1,2,4]thiadiazine 5,5-dioxide (4j). 22


Page 23 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Yield = 0.213 g, 80%; Pale Yellow solid ; mp: 206-208°C; 1H NMR (400MHz, CDCl3) δ 7.91 (d, J = 7.6 Hz,1H), 7.44 (t, J = 8.4 Hz, 1H), 7.37-7.31 (m, 1H), 7.22-7.15 (m, 2H), 6.90 (d, J = 9.2 Hz, 1H), 6.47 (m, 1H); 13C{1H}NMR (100MHz, CDCl3) δ 148.0, 145.7, 135.6, 133.9, 131.4, 128.8, 126.6, 126.4, 125.4, 124.7, 111.2; HRMS (ESI, m/z) calcd for C11H8ClN2O2S: m/z 266.9995; Found 266.9990 (M+H); IR (cm-1, KBr): 2922, 1550, 1259, 1016, 644.. 4-Chloro-10-methylbenzo[e]pyrido[1,2-b][1,2,4]thiadiazine 5,5-dioxide (4k). Yield = 0.246 g, 88%; Yellow solid; mp:138-140°C; 1HNMR (400MHz, CDCl3) δ 7.94 (d, J = 7.2 Hz, 1H), 7.55-7.47 (m, 2H), 7.30 (d, J = 7.6, Hz, 1H), 7.15(d, J = 6.4 Hz, 1H), 6.50 (t, J = 7.2 Hz, 1H), 2.36 (s, 3H);

13C{1H}NMR

(100MHz, CDCl3) δ 146.8, 144.8, 132.7, 132.5,132.2,

127.5, 126.1, 125.1, 121.4, 118.9, 109.6; MS (GC-MS) 280; HRMS (ESI, m/z) calcd for C12H10ClN2O2S: m/z 281.0152; Found 281.0146 (M+H); IR (cm-1, KBr): 3109, 1544, 1257, 1064, 669. 4-Chloro-9-methylbenzo[e]pyrido[1,2-b][1,2,4]thiadiazine 5,5-dioxide (4l). Yield = 0.224 g, 80%; Yellow solid; mp:156-158°C; 1H NMR (400MHz, CDCl3) δ 7.93 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 8 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8 Hz, 1H), 6.79 (s, 1H), 6.42 (dd, J = 7.6, 1.6 Hz, 1H), 2.28 (s, 3H);

13C{1H}NMR

(100MHz, CDCl3) δ 148.1, 147.6,

146.2, 133.7, 128.8, 126.4, 125.8, 123.9, 122.8, 119.9, 114.1, 21.5; MS (GC-MS) 280; HRMS (ESI, m/z) calcd for C12H10ClN2O2S: m/z 281.0152; Found 281.0146 (M+H); IR (cm-1, KBr): 2920, 2850, 1546, 1261, 686 9-Chlorobenzo[e]pyrazino[1,2-b][1,2,4]thiadiazine 6,6-dioxide (4m) Yield = 0.226 g, 85%; Brown solid; 1H NMR (400MHz, CDCl3) δ 8.61 (s, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.23 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 2.4 Hz,1H), 7.42 (dd, J = 8.4, 1.6 Hz, 1H);

13C{1H}NMR

(100MHz, CDCl3) δ 139.5, 138.1, 135.6, 135.2, 134.0, 133.3, 132.3, 23



Page 24 of 30

131.4, 130.6, 127.5; MS (GC-MS) 266; HRMS (EI, m/z); calcd for C10H6ClN3O2S: m/z 266.9869; Found 266.9861; IR (cm-1, KBr) 1571,1166, 1037, 621. 7-Chlorobenzo[e]pyridazino[1,6-b][1,2,4]thiadiazine 10,10-dioxide (4n). Yield = 0.234 g, 88%; Brown solid; mp: 176-178°C; 1HNMR (400MHz ,CDCl3) δ 8.16-8.14 (m, 2H), 7.48(d, J = 1.6 Hz, 1H), 7.42-7.32 (m, 3H);

13C{1H}NMR

(100MHz, CDCl3) δ 154.9,

140.9, 138.8, 138.2, 133.4, 132.2, 131.2, 130.9, 130.2, 127.2; MS (GC-MS) 266; HRMS (EI, m/z); calcd for C10H6ClN3O2S: m/z 266.9869; Found 266.9866; IR (cm-1, KBr) 1610, 1020, 1097, 648. 9-Chlorobenzo[e]pyridazino[1,6-b][1,2,4]thiadiazine 10,10-dioxide (4o). Yield = 0.223 g, 84%; Brown solid; 1HNMR (400MHz, CDCl3) δ 8.16 (dd, J = 4.0, 1.6 Hz, 1H), 7.43-7.39 (m, 2H), 7.37-7.35 (m, 2H), 7.30-7.25 (m, 1H);

13C{1H}NMR

(100MHz, CDCl3) δ

154.6, 141.0, 137.0, 135.2, 132.2, 131.9, 131.3, 129.9, 127.9, 127.6; MS (GC-MS) 266; HRMS (EI, m/z); calcd for C10H6ClN3O2S: m/z 266.9869; Found 266.9870; IR (cm-1, KBr) 3045, 1618, 1190, 1026, 645. 6-Chlorobenzo[e]pyridazino[1,6-b][1,2,4]thiadiazine 10,10-dioxide (4p). Yield = 0.218 g, 82%; Brown solid; mp:194-196°C; 1H NMR (400MHz, CDCl3) δ 8.19-8.14 (m, 2H), 7.63 (d, J = 8Hz, 1H), 7.42-7.34 (m, 2H), 7.27 (s, 1H); 13C{1H}NMR (100MHz, CDCl3) δ 154.8, 141.5, 140.9, 135.2, 133.8, 132.1, 130.9, 130.7, 128.2, 127.3; MS (GC-MS) 266; HRMS (EI, m/z); calcd for C10H6ClN3O2S: m/z 266.9869; Found 266.9866; IR (cm-1, KBr) 2920, 1614, 1278, 1020, 621. 1-((2,4-dichlorophenyl)sulfonyl)pyridin-2(1H)-imine (3a). Yield = 0.272 g, 90%; Brown solid; mp:194-196°C; 1H NMR (400MHz, CDCl3) δ 7.99 (d, J = 6.4 Hz,1H), 7.86 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 2Hz, 1H), 7.34-7.30 (m, 2H), 7.07 (d, J = 9.2 24


Page 25 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Hz, 1H), 6.62-6.58 (m, 1H);

13C{1H}NMR

(100MHz, CDCl3) δ 148.8, 145.3, 140.6, 135.6,

126.9, 125.6, 124.9, 124.5, 123.0, 119.6, 111.3; MS (GC-MS) 303; IR (cm-1, KBr) 3273, 1649,1255, 1074, 644.

Acknowledgements The authors thank the Chancellor and Vice Chancellor of Vellore Institute of Technology for providing opportunity to carry out this study. Further the authors wish to thank the management of this institute for providing seed money as research grant. Kaushik Chanda thanks CSIR-Govt of India for funding through Grant no 01(2913)/17/EMR-II. Thanks are also to Central instrumentation facility VIT University for recording the spectra and sophisticated analytical instrumentation facility (SAIF), GU, for use of the single-crystal X-ray diffractometer. The authors are thankful to Prof Ranjit Thakuria of GU for solving the crystal structure. Supporting Information Available. The Supporting Information is available free of charge on the Publications website at. along with 1H, 13CNMR,

IR and HRMS spectra of compounds 4. Assays for the anti-inflammatory and BSA

binding assay for compounds 4, and X-ray data of compound 4l.

References 1. Jones, G. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., McKillop, A., Eds.; Pergamon: Oxford, 1996; Vol. 5, p 167. (b) Michael, J. P. Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep. 2005, 22, 627-646. 2. (a) Arranz, M. I.; Diaz, J. A.; Ingate, S. T.; Witrrouw, M.; Pannecouque, C.; Balzarini, J.; De Clercq, E.; Vega, S. Synthesis and anti-HIV activity of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]25



thiadiazines (TTDs): A new family of HIV-1 specific non-nucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem. 1999, 7, 2811− 2822. (b) Martinez, A.; Gil, C.; Abasolo, M. I.; Casto, A.; Bruno, A. M.; Perez, C.; Preto, C.; Otero, J. Benzothiadiazine dioxide dibenzyl derivatives as potent human cytomegalovirus inhibitors: Synthesis and comparative molecular field analysis. J. Med. Chem. 2000, 43, 3218− 3225. (3) (a) Pirotte, B.; Ouedraogo, R.; de Tullio, P.; Khelili, S.; Somers, F.; Boverie, S.; Dupont, L.; Fontaine, J.; Damas, J.; Lebrun, P. 3-Alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1,1Dioxides Structurally Related to Diazoxide and Pinacidil as Potassium Channel Openers Acting on Vascular Smooth Muscle Cells: Design, Synthesis, and Pharmacological Evaluation. J. Med. Chem. 2000, 43, 1456-1466. (b) de Tullio, P.; Servais, A. C.; Fillet, M.; Gillotin, F.; Somers, F.; Chiap, P.; Lebrun, P.; Pirotte, B. Hydroxylated Analogues of ATP-Sensitive Potassium Channel Openers Belonging to the Group of 6- and/or 7-Substituted 3-Isopropylamino-4H-1,2,4benzothiadiazine 1,1-Dioxides: Toward an Improvement in Sulfonylurea Receptor 1 Selectivity and Metabolism Stability. J. Med. Chem. 2011, 54, 8353-8361. (c) Pirotte, B.; de Tullio, P.; Florence, X.; Goffin, E.; Somers, F.; Boverie, S.; Lebrun, P. 1,4,2-Benzo/pyridodithiazine 1,1Dioxides Structurally Related to the ATP-Sensitive Potassium Channel Openers 1,2,4Benzo/pyridothiadiazine 1,1-Dioxides Exert a Myorelaxant Activity Linked to a Distinct Mechanism of Action. J. Med. Chem. 2013, 56, 3247-3256. (d) Francottea, P.; de Tullio, P.; Podonaa, T.; Dioufa, O.; Fraikin, P.; Lestage, P.; Danober, L.; Thomas, J. Y.; Caignard, D. H.; Pirotte, B. Synthesis and pharmacological evaluation of a second generation of pyridothiadiazine 1,1-dioxides acting as AMPA potentiators. Bioorg. Med. Chem. 2008, 16, 9948-9956. (e) Castro, S.; Peromingo, M. T.; Naesens, L.; Andrei, G.; Snoeck, R.; Balzarini, J.; Velazquez, S.; Camarasa, M.-J. 4 ́″-Benzoylureido TSAO derivatives as potent and selective non-nucleoside 26


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pyridazino - ACS Publications

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