Defining the Structural Parameters That Confer Anticonvulsant Activity by the Site-by-Site Modification of (<i>R</i>)-<i>N</i>′-Benzyl 2-Amino-3-methylbutanamide

King, Amber M.; Ryck, Marc De; Kamiński, Rafał M.; Valade, Anne; Stables, James P.; Kohn, Harold

doi:10.1021/jm200760a

Cited by 14 publications

(13 citation statements)

References 40 publications

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“…1 The analytical data are consistent with the previously reported characterization. 35 Step 2: (S)-tert-butyl (3-methyl-1-oxo-1-phenylbutan-2yl)carbamate (11). According to general procedure TP2, phenyl magnesium bromide (1.5 eq., 1 M, 11.5 mL, 11.5 mmol) was reacted with the above described Weinreb amide of N-Boc-Lvaline 37 (1 eq., 2 g, 7.7 mmol) in THF (25 mL).…”

Section: -2-oxoethyl)carbamate (3)mentioning

confidence: 99%

Diastereoselective Synthesis of Nonplanar 3-Amino-1,2,4-oxadiazine Scaffold: Structure Revision of Alchornedine

et al. 2020

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Herein we report the diastereoselective synthesis of a 3-amino-1,2,4-oxadiazine (AOXD) scaffold. The presence of a NO bond in the ring prevents the planar geometry of the aromatic system and induces a strong decrease in the basicity of the guanidine moiety. While DIBAL-H appeared to be the most efficient reducing agent because it exhibited high diastereoselectivity, we observed various behaviors of the Mitsunobu reaction on the resulting β-aminoalcohol, leading to either inversion or retention of configuration depending on the steric hindrance in the vicinitude of the hydroxy group. The physicochemical properties (pKa, and log D) and hepatic stability of several AOXD derivatives were experimentally determined and found that the AOXD scaffold possesses promising properties for drug development. Moreover, we synthesized alchornedine, the only natural product with the AOXD scaffold. Based on a comparison of the analytical data, we found that the reported structure of alchornedine was incorrect and hypothesized a new one. were screened for the diastereoselective synthesis of chiral AOXDs and the relationship between chirality and NMR characteristics was highlighted. As a novel scaffold, the physicochemical properties of AOXD were also investigated. Finally, alchornedine was synthesized, and its spectra and analytical data were compared with those of the isolated compound previously reported. 14 RESULTS AND DISCUSSION As an initial experiment, achiral N-Boc-glycine was used as the starting material for exploring the synthesis of racemic AOXD (Scheme 1). N-Boc-glycine reacted with N, N'-carbonyl diimidazole (CDI) and N,O-dimethylhydroxylamine to form the corresponding Weinreb amide (2) in 99% yield. 18 The nucleophilic addition between 2 and 3,4-dichloro-phenyl magnesium bromide furnished ketone 3 in 86% yield, which was directly reduced by NaBH4, to yield alcohol 4 in 99% yield. As a key step in AOXD synthesis, the Mitsunobu reaction between alcohol 4 and N-hydroxyphthalimide (NHPI) was conducted to form the CON bond, affording the key intermediate, 5, in 94% yield. Then, phthaloyl and Boc protections were successively removed by hydrazine hydrate and HCl treatments, affording 6 and 7 in 94% and 96% yield, respectively. Finally, the cyclization reaction of 7 was carried out with BrCN, to afford racemic AOXD 8 and its 4-cyanated side product 9 in 81% and 17% yield, respectively (see SI section I). The presence of such a side product indicated that the nitrogen atom at position 4 (-HN-CH2-) in 8 is more nucleophilic toward BrCN than those at positions 3 and 2, respectively. X-ray crystallography confirmed the AOXD structure of 8 (Scheme 1), with a C=N double bond located between N 2 and C 3 , rather than C 3 and N 4 , likely because of the stabilization of p-π conjugation between the oxygen atom and the C=N double bond. Meanwhile, the bivalent character of the oxygen atom induced the expected non-planar geometry of AOXD, in which C 6 is located far out of the plane constituted by the N 2 =C 3-N 4 moiety. Moreover, the N...

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Section: -2-oxoethyl)carbamate (3)mentioning

confidence: 99%

Diastereoselective Synthesis of Nonplanar 3-Amino-1,2,4-oxadiazine Scaffold: Structure Revision of Alchornedine

et al. 2020

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“…Statistics have shown it to be a terrible menace affecting one percentage of global population (King et al, 2011;Chen et al, 2007). The anticonvulsants used to treat this condition are known as antiepileptic drugs and are among the most widely used drugs for the treatment of central nervous system disorders.…”

Section: Anticonvulsant Activitymentioning

confidence: 99%

Quinazoline pharmacophore in therapeutic medicine

Ajani

Aderohunmu

Umeokoro

et al. 2016

Bangladesh J Pharmacol

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This present study comprehensively expatiates the functionalized utilization of quinazoline scaffolds in drug development and furnishes latest updates in pharmacological appositeness of its derivatives in order to reveal novel pathways for therapeutic targets. It traverses numerous biological potentials of quinazoline in the contemporary time to allow researchers' unhindered access to the beneficial role of quinazoline in fighting infectious diseases for future drug discovery. This work provides broad overview of medicinal survey of quinazoline chemistry valuable in the discovery of more efficient clinical trials and to summarize the most promising molecular targets for drug design. Article Info

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“…The first focuses on the screening of thousands of newly-synthesized compounds in the hope of finding the most promising and efficacious agent [7][8][9]. The second method is based on structural transformation and chemical modification of the structure of widely used drugs with firmly established properties with respect to their impact on CNS in vivo [10][11][12]. The changes in chemical structure of currently available drugs are expected to enhance their desired properties.…”

Section: Introductionmentioning

confidence: 99%

Antinociceptive screening of various 1,2,4-triazole-3-thione derivatives in the hot-plate test in mice

Łuszczki

Pałka

Marzęda

et al. 2019

J Pre Clin Clin Res.

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Introduction. Despite the large number of analgesic drugs available currently, pain therapy is still a challenging issue for researchers and clinicians. The search for new drugs that could relieve patients from pain is not only justified, but also highly recommended. Objective.This study aimed to perform antinociceptive screening of 4 various 1,2,4-triazole-3-thione derivatives (TPB-2, TPB-4, TPF-32 and TPF-38) in the hot-plate test in mice, which is an experimental model allowing the testing of compounds alleviating acute thermal pain. Materials and method. Experimental verification of the antinociceptive effects of the tested compounds (administered intraperitoneally in a constant dose of 300 mg/kg) was performed in the hot-plate test in mice, by calculating maximum possible antinociceptive effects (MPAE in %) at 4 various pretreatment times (15, 30, 60 and 120 min.). Results. TPB-2 exerted strong antinociceptive effects with MPAE ranging between 18.54-35.43% in the hot-plate test. Similarly, TPF-32 exerted firmly established antinociceptive effects with MPAE ranging from 13.50-37.05%. In the case of TPB-4 and TPF-38, both compounds produced slight changes in MPAE in the hot-plate test in mice. These agents can be classified as virtually ineffective in the hot-plate test. Conclusions. The screening test revealed that TPB-2 and TPF-32 exerted a clear-cut antinociceptive effect in the hot-plate test in mice. If the results from this study were to be translated to clinical settings, both TPB-2 and TPF-32 might be beneficial drugs for pain relief in humans.

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Defining the Structural Parameters That Confer Anticonvulsant Activity by the Site-by-Site Modification of (R)-N′-Benzyl 2-Amino-3-methylbutanamide

Cited by 14 publications

References 40 publications

Diastereoselective Synthesis of Nonplanar 3-Amino-1,2,4-oxadiazine Scaffold: Structure Revision of Alchornedine

Diastereoselective Synthesis of Nonplanar 3-Amino-1,2,4-oxadiazine Scaffold: Structure Revision of Alchornedine

Quinazoline pharmacophore in therapeutic medicine

Antinociceptive screening of various 1,2,4-triazole-3-thione derivatives in the hot-plate test in mice

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