Microwave-assisted synthesis of 3-aminobenzo[b]thiophene scaffolds for the preparation of kinase inhibitors

Bagley, Mark C.; Dwyer, Jessica E.; Molina, Maria D. Beltran; Rand, Alexander W.; Rand, Hayley L.; Tomkinson, Nicholas C. O.

doi:10.1039/c5ob00819k

Cited by 21 publications

(10 citation statements)

References 72 publications

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“…For the synthesis of the benzothiophene derivative 32 (Scheme 3), aldehyde 31 [33, 34] was submitted to the reductive amination reaction, which upon acidic Boc deprotection, led to the preparation of the desired final compound 32 . Five-membered heterocycles 37 and 38 were prepared starting from arylhydrazide 33 .…”

Section: Resultsmentioning

confidence: 99%

Antimalarial agents against both sexual and asexual parasites stages: structure-activity relationships and biological studies of the Malaria Box compound 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine (MMV019918) and analogues

Vallone¹,

D’Alessandro²,

Brogi³

et al. 2018

European Journal of Medicinal Chemistry

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Therapies addressing multiple stages of Plasmodium falciparum life cycle are highly desirable for implementing malaria elimination strategies. MMV019918 (1, 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine) was selected from the MMV Malaria Box for its dual activity against both asexual stages and gametocytes. In-depth structure-activity relationship studies and cytotoxicity evaluation led to the selection of 25 for further biological investigation. The potential transmission blocking activity of 25 versus P. falciparum was confirmed through the standard membrane-feeding assay. Both 1 and 25 significantly prolonged atrioventricular conduction time in Langendorff-isolated rat hearts, and showed inhibitory activity of Ba current through Ca1.2 channels. An in silico target-fishing study suggested the enzyme phosphoethanolamine methyltransferase (PfPMT) as a potential target. However, compound activity against PfPMT did not track with the antiplasmodial activity, suggesting the latter activity relies on a different molecular target. Nevertheless, 25 showed interesting activity against PfPMT, which could be an important starting point for the identification of more potent inhibitors active against both sexual and asexual stages of the parasite.

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Section: Resultsmentioning

confidence: 99%

Antimalarial agents against both sexual and asexual parasites stages: structure-activity relationships and biological studies of the Malaria Box compound 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine (MMV019918) and analogues

Vallone¹,

D’Alessandro²,

Brogi³

et al. 2018

European Journal of Medicinal Chemistry

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“…Towards the synthesis of PF-3644022, cross-coupling of a 2-chloroquinoline with a 3-pyridinylboronic acid provided the desired biaryl target but the pyridine moiety and the chloroquinoline precursor both proved incompatible with the subsequent Yamazaki cyanation of a 6-nitroquinoline, en route to the benzothiophene ring. Thus, although a relatively early-stage Suzuki-Miyaura coupling would appear incompatible with this cyanation method, alternative strategies for the incorporation of the 3-aminobenzo[ b ]thiophene moiety could be envisaged and thus incorporated with this transformation [ 58 ]. Towards the synthesis of a 3-aminopyrazole MK2 inhibitor, bearing a 1-[(6-indolyl)phenyl] substituent, the Suzuki-Miyaura cross-coupling reaction established one biaryl linkage, but the unprotected indole group interfered with the subsequent NBS bromination required to set up the second Suzuki-Miyaura coupling.…”

Section: Discussionmentioning

confidence: 99%

Microwave-Assisted Synthesis of a MK2 Inhibitor by Suzuki-Miyaura Coupling for Study in Werner Syndrome Cells

et al. 2015

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Microwave-assisted Suzuki-Miyaura cross-coupling reactions have been employed towards the synthesis of three different MAPKAPK2 (MK2) inhibitors to study accelerated aging in Werner syndrome (WS) cells, including the cross-coupling of a 2-chloroquinoline with a 3-pyridinylboronic acid, the coupling of an aryl bromide with an indolylboronic acid and the reaction of a 3-amino-4-bromopyrazole with 4-carbamoylphenylboronic acid. In all of these processes, the Suzuki-Miyaura reaction was fast and relatively efficient using a palladium catalyst under microwave irradiation. The process was incorporated into a rapid 3-step microwave-assisted method for the synthesis of a MK2 inhibitor involving 3-aminopyrazole formation, pyrazole C-4 bromination using N-bromosuccinimide (NBS), and Suzuki-Miyaura cross-coupling of the pyrazolyl bromide with 4-carbamoylphenylboronic acid to give the target 4-arylpyrazole in 35% overall yield, suitable for study in WS cells.

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“…Thioesters 2 a , [28] 2 b , [29] 5 c , [30] 6 a , [8b] 6 b , [31] 7 n , [32] 8 , [7] 11 , [33] 12 , [34] as well as aminothieno,– [2,–3b] pyridines 15 a , [35] 15 b [19b] and 2‐Methoxy‐3‐nitropyridine 3 [36] have already been prepared in the literature by other methods.…”

Section: Methodsmentioning

confidence: 99%

“…Methyl 3‐aminothieno [2,3– b ] pyridine‐2‐carboxylate (15 b) [19b] . Yellow solid (396 mg, 95 %); m.p.…”

Section: Methodsmentioning

confidence: 99%

“…Yellow solid (396 mg, 95 %); m.p. 190 – 191 °C (lit – 191 °C [19b] ); 1 H NMR (700 MHz, DMSO‐d 6 ) δ=8.68 (dd, J =4.6, 1.6 Hz, 1H), 8.54 (dd, J =8.1, 1.6 Hz, 1H), 7.46 (dd, J =8.1, 4.6 Hz, 1H), 7.30 (brs, 2H), 3.80 (s, 3H); 13 C NMR (75 MHz, DMSO‐d 6 ) δ=164.8, 159.7, 150.7, 147.8, 131.5, 125.6, 119.4, 93.3, 51.4; HRMS (ESI): m/z calcd for C 9 H 9 N 2 O 2 S + : 209.0379 [M+H] + ; found: 209.0384.…”

Section: Methodsmentioning

confidence: 99%

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Xanthates as Thiol Surrogates for Nucleophilic Substitution with Aryl Halides

et al. 2021

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We herein report an unprecedented xanthate‐based protocol for the preparation of aryl‐alkyl thioethers. Heating xanthates with aryl halides and namely cesium carbonate in methanol provides the target thioethers in generally good yields within short reaction times. This method allows one to avoid contact with odorous thiols and also to introduce substituents of which the corresponding thiols are virtually unavailable or inconvenient in use.

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Microwave-assisted synthesis of 3-aminobenzo[b]thiophene scaffolds for the preparation of kinase inhibitors

Cited by 21 publications

References 72 publications

Antimalarial agents against both sexual and asexual parasites stages: structure-activity relationships and biological studies of the Malaria Box compound 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine (MMV019918) and analogues

Antimalarial agents against both sexual and asexual parasites stages: structure-activity relationships and biological studies of the Malaria Box compound 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine (MMV019918) and analogues

Microwave-Assisted Synthesis of a MK2 Inhibitor by Suzuki-Miyaura Coupling for Study in Werner Syndrome Cells

Xanthates as Thiol Surrogates for Nucleophilic Substitution with Aryl Halides

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