Synthesis, characterization, monoamine oxidase inhibition, molecular docking and dynamic simulations of novel 2,1-benzothiazine-2,2-dioxide derivatives

Ahmad, S.; Zaib, Sumera; Jalil, Saquib; Shafiq, Muhammad; Ahmad, Matloob; Sultan, Sadia; Iqbal, Mazhar; Aslam, Sana; Iqbal, Jamshed

doi:10.1016/j.bioorg.2018.04.012

Cited by 18 publications

(12 citation statements)

References 49 publications

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“…Multiple publications identified two aromatic moieties linked by a short bridging element as mutual MAO scaffold. 8,[12][13][14][15][16] Due to their high stability under physiological conditions, amides were used as linkers in our series. Aromatic moieties bearing different substituents were chosen to elucidate electronic and steric effects on the binding affinities towards both MAO isoforms.…”

Section: Introductionmentioning

confidence: 99%

<p>Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs</p>

Hagenow¹,

Hagenow²,

Grau³

et al. 2020

DDDT

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Background: Ligands consisting of two aryl moieties connected via a short spacer were shown to be potent inhibitors of monoamine oxidases (MAO) A and B, which are known as suitable targets in treatment of neurological diseases. Based on this general blueprint, we synthesized a series of 66 small aromatic amide derivatives as novel MAO A/B inhibitors. Methods: The compounds were synthesized, purified and structurally confirmed by spectroscopic methods. Fluorimetric enzymological assays were performed to determine MAO A/B inhibition properties. Mode and reversibility of inhibition was determined for the most potent MAO B inhibitor. Docking poses and pharmacophore models were generated to confirm the in vitro results. Results: N-(2,4-Dinitrophenyl)benzo[d][1,3]dioxole-5-carboxamide (55, ST-2043) was found to be a reversible competitive moderately selective MAO B inhibitor (IC 50 = 56 nM, K i = 6.3 nM), while N-(2,4-dinitrophenyl)benzamide (7, ST-2023) showed higher preference for MAO A (IC 50 = 126 nM). Computational analysis confirmed in vitro binding properties, where the anilides examined possessed high surface complementarity to MAO A/B active sites. Conclusion: The small molecule anilides with different substitution patterns were identified as potent MAO A/B inhibitors, which were active in nanomolar concentrations ranges. These small and easily accessible molecules are promising motifs, especially for newly designed multitargeted ligands taking advantage of these fragments.

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Section: Introductionmentioning

confidence: 99%

<p>Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs</p>

Hagenow¹,

Hagenow²,

Grau³

et al. 2020

DDDT

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“…This is exemplified by chromones 3-5, which are at least an order of magnitude more potent MAO-B inhibitors compared to 14b. Molecular docking is considered to be a useful tool for predicting potential binding orientations and interactions of ligands in the MAO active site [51][52][53]. Based on the crystal structures of MAO-B in complex with reversible inhibitors, it may be expected that chromane-2,4-diones will bind to the active site with the chromane-2,4-dione moiety in proximity to the FAD, the most polar region.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and evaluation of chromone derivatives as inhibitors of monoamine oxidase

Mpitimpiti

Petzer

et al. 2019

Mol Divers

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Based on reports that chromone compounds are good potency inhibitors of monoamine oxidase (MAO), the present study evaluates the effect of substitution with flexible side chains on the 3 position on MAO inhibition potency. Fifteen chromone derivatives were synthesised by reacting aromatic and aliphatic amines and alcohols with chromone 3-carboxylic acid in the presence of carbonyldiimidazole (CDI). This yielded chromane-2,4-dione and ester chromone derivatives. Generally, the esters exhibited weak MAO inhibition, while the chromane-2,4-dione derivatives showed promise as selective MAO-B inhibitors with IC 50 values in the micromolar range. Compound 14b, 3-[(benzylamino)methylidene]-3,4-dihydro-2H-1-benzopyran-2,4-dione, was the most potent MAO-B inhibitor with an IC 50 value of 638 µM. This compound was shown to be a reversible and competitive MAO-B inhibitor with a K i of 94 µM. In conclusion, the effect of chain elongation and introduction of flexible substituents on position 3 of chromone were explored and the results showed that aminomethylidene substitution is preferable over ester substitution. Good potency MAO-B inhibitors may act as leads for the design and development of therapy for Parkinson's disease where these agents reduce the central metabolism of dopamine.

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“…[35] Entry NH-CSICr precursor The synthesis of diversely substituted 1H-benzo[c][1,2] thiazin-4(3H)-one 2,2-dioxides III (Figure 2) follows a well and simple three-step protocol proposed by Lombardino in the seventies, [44] consisting of the CSICr of a N-alkyl-N-(methylsulfonyl)anthranilate, obtained from the reaction of an anthranilate and methanesulfonyl chloride, followed by Nalkylation of the resulting intermediate. This procedure has been used later by other authors without significant modifications, under conventional conditions [43,[45][46][47][48][49][50][51][52][53][54][55][56] or solid-phase, a very appropriate method for the combinatorial synthesis of heterocyclic compound libraries, albeit in low chemical yields. [57] Scheme 15.…”

Section: Entrymentioning

confidence: 99%

“…Target ligands 167 were easily prepared in two steps starting from 159 precursors as shown in Scheme 41. Thus, intramolecular CSICr of ethyl 2‐( N ‐methylmethylsulfonamido)benzoate ( 159 a ) and 2‐( N ‐benzylmethylsulfonamido)benzoate ( 159 d ), promoted by sodium hydride in DMF, gave methyl‐1 H ‐benzo[c][1,2] thiazin‐4(3 H )‐one 2,2‐dioxide ( 95 b ) and benzyl‐1 H ‐benzo[c][1,2]thiazin‐4(3 H )‐one 2,2‐dioxide ( 95 g ), respectively (Scheme 41, unreported yields) [55] . Next, Et 3 N‐catalyzed intermolecular CSICr of intermediates 95 a , b with substituted benzaldehydes, afforded adducts that reacted in situ with malononitrile to provide racemic 2‐amino‐6‐methy(benzyl)‐4‐phenyl‐4,6‐dihydrobenzo[ c ]pyrano[2,3‐ e ][1,2]thiazine‐3‐carbonitrile 5,5‐dioxides ( 167 a , b ) (Scheme 41) in good yields.…”

Section: Csicr From Selected Authors and Laboratoriesmentioning

confidence: 99%

“…CSICr described by Tomita et al [47] dioxide (95 g), respectively (Scheme 41, unreported yields). [55] Next, Et (Figure 4), as a dual, almost equally equipotent monoamine oxidases A and B inhibitors. [56] Shemchuk and co-workers have reported related chemistry leading to similar compounds of type 167 in good chemical yields (Scheme 41), by three-component catalyzed reaction of 1-ethyl-1H-benzo[c][1,2]thiazin-4(3H)-one 2,2-dioxide (95 c) (Scheme 34) with substituted benzaldehydes [82] or cyclopropyl (cyclopentane, cyclohexane) carbaldehydes, and malononitrile, or ethyl cyanoacetate, in the presence of triethylamine at rt, in ethanol, [83] to compounds 169 and 170 ( Figure 4).…”

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confidence: 99%

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Updating the CSIC Reaction (2003–2020)

Dobrydnev

Marco‐Contelles

2021

Eur J Org Chem

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Herein, we have updated the progress and developments of the Carbanion-mediated Sulfonate (or Sulfonamide) Intermolecular Coupling, and Intramolecular Cyclization, abbreviated as CSIC reaction (CSICr), in the last seventeen years from the seminal review published in 2003 in this same Journal. CSICr has proven to be a useful and versatile synthetic tool, efficiently providing a number of open-chain [alkane(sulfonamide)sulfonates] or cylic (sultams and sultones) synthetic intermediates or final products of high value in organic and medicinal chemistry.

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Synthesis, characterization, monoamine oxidase inhibition, molecular docking and dynamic simulations of novel 2,1-benzothiazine-2,2-dioxide derivatives

Cited by 18 publications

References 49 publications

<p>Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs</p>

<p>Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs</p>

Synthesis and evaluation of chromone derivatives as inhibitors of monoamine oxidase

Updating the CSIC Reaction (2003–2020)

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