Synthesis and pharmacological evaluation of piperidine derivatives with various heterocyclic rings at the 4-position.

Takai, Haruki; Obase, Hiroyuki; Nakamizo, Nobuhiro; Teranishi, Masayuki; Kubo, Kazuhiro; Shuto, Katsuichi; Hashimoto, Tamotsu

doi:10.1248/cpb.33.1104

Cited by 17 publications

(13 citation statements)

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“…For installation of the sulfamide, we turned to new chemistry developed in our lab, which involves treatment of a 5′-aminonucleoside with sulfamide (NH 2 SO 2 NH 2 ), inspired by a side-reaction reported by Takai and co-workers. 49 In the present synthesis this was achieved by conversion of the 5′-alcohol in 39 to azide 40 . The azide was reduced by catalytic hydrogenation to provide a crude amine that was not isolated, but treated directly with sulfamide in dioxane at 90 °C to cleanly afford 41 in 87% yield.…”

Section: Resultsmentioning

confidence: 97%

Synthesis and Pharmacokinetic Evaluation of Siderophore Biosynthesis Inhibitors for Mycobacterium tuberculosis

et al. 2015

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MbtA catalyzes the first committed biosynthetic step of the mycobactins, which are important virulence factors associated with iron acquisition in Mycobacterium tuberculosis. MbtA is a validated therapeutic target for antitubercular drug development. 5′-O-[N-(salicyl)sulfamoyl]adenosine (1) is a bisubstrate inhibitor of MbtA and exhibits exceptionally potent biochemical and antitubercular activity. However, 1 suffers from sub-optimal drug disposition properties resulting in a short half-life (t1/2), low exposure (AUC), and low bioavailability (F). Four strategies were pursued to address these liabilities including the synthesis of prodrugs, increasing the pKa of the acyl-sulfonyl moiety, modulation of the lipophilicity, and strategic introduction of fluorine into 1. Complete pharmacokinetic (PK) analysis of all compounds was performed. The most successful modifications involved fluorination of the nucleoside that provided substantial improvements in t1/2 and AUC. Increasing the pKa of the acyl-sulfonyl linker yielded incremental enhancements while modulation of the lipophilicity and prodrug approaches led to substantially poorer PK parameters.

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Section: Resultsmentioning

confidence: 97%

Synthesis and Pharmacokinetic Evaluation of Siderophore Biosynthesis Inhibitors for Mycobacterium tuberculosis

et al. 2015

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“…On the other hand, reduction of 17 with LiAH 4 afforded the intermediate compound 19, subsequent cyclization of which with different reagents followed by removal of the Bn group led to the desired compounds 20 and 21. 13,14 Reductive amination of N-Boc-4-piperidone with 1,2,3,4-tetrahydroquinoline and subsequent removal of the Boc group gave compound 22. Treatment of salicylaldehyde with 4-amino-1-benzylpiperidine afforded 23, subsequent cyclization with CDI then hydrogenation of the benzyl group led to compound 24.…”

Section: Resultsmentioning

confidence: 99%

“…Treatment of salicylaldehyde with 4-amino-1-benzylpiperidine afforded 23, subsequent cyclization with CDI then hydrogenation of the benzyl group led to compound 24. 14 For the synthesis of 27 and 28, reductive amination of 2-nitrobenzaldehyde with 4-amino-1-benzylpiperidine and hydrogenation afforded the desired intermediate compound 26, while subsequent cyclization with different reagents followed by removal of the benzyl group resulted in the desired compounds 27 and 28. 14 Compounds 30 and 31 were synthesized in the same manner as ring opening of isatoic anhydride with 4-amino-1-benzylpiperidine and followed by cyclization and removal of the benzyl group.…”

Section: Resultsmentioning

confidence: 99%

“…14 For the synthesis of 27 and 28, reductive amination of 2-nitrobenzaldehyde with 4-amino-1-benzylpiperidine and hydrogenation afforded the desired intermediate compound 26, while subsequent cyclization with different reagents followed by removal of the benzyl group resulted in the desired compounds 27 and 28. 14 Compounds 30 and 31 were synthesized in the same manner as ring opening of isatoic anhydride with 4-amino-1-benzylpiperidine and followed by cyclization and removal of the benzyl group. 14,15 The activities of Type III and Type IV compounds are presented in Table 3.…”

Section: Resultsmentioning

confidence: 99%

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Diphenylbutylpiperidine-based cell autophagy inducers: Design, synthesis and SAR studies

et al. 2011

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“…One of the most corner stone principles in our research group is based on searching for new anticancer drugs 1,2 where the search for new anticancer drugs is never ending task with the aim to obtain products with lower toxicity and more selectivity towards tumor cells. Benzotriazine and its derivatives possess a diverse range of biological activities of pharmacological activities including antimicrobial, 3 antiinflammatory 4 , anti-depressant 5 , anti-ulcer 6 , antidiarrhoeal 7 , anaesthetics 8 , anticancer 9 . Some current commercial benzotriazinone anticancer drugs such as α-hydroxylatedbenzotriazinone 10 , N-Arylbenzotriazinones 11,12 , Tirapazamine(1,2,4-benzotriazin-3-amine,1,4-dioxide) 13 and 4-[(4-Oxobenzotriazin-3(4H)-yl)methyl]benzoic acid 14 show the possibility to reduce recombinant human cancer cells growth in culture.…”

Section: -Introductionmentioning

confidence: 99%

Synthesis, Molecular Docking and Biological Evaluation of Some New Benzotriazines

Rayes

Ali

Fathalla

et al. 2019

Proceedings of the 23rd International Electronic Conference on Synthetic Organic Chemistry

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Methyl 2-(4-oxobenzotriazin-3(4H)-yl) alkanoates4a-c proved to be important intermediates for the preparation of some biologically interesting compounds containing the benzotriazinone ring system. Esters 4a-c were prepared by direct diazotization of methyl anthranilate followed by addition of amino acid esters hydrochloride in a one-pot strategy. An equivocal synthesis of methyl 2-(4oxobenzotriazin-3(4H)-yl) acetate 4a was achieved by alkylation of benzotriazin-4(3H)one with methyl chloroacetate on the basis of chemoselective reaction of heterocyclic amide with electrophiles. A series of N-alkyl-2-(4-oxobenzotriazin-3(4H)-yl) alkanamides7-8(a-h) and methyl 2-(2-(4oxobenzotriazin-3(4H)-yl)alkanamido)alkanoates (dipeptides) 9-10(a-d) were prepared via azide coupling from 4a-b. Esters 4a-b were converted into the corresponding hydrazides followed by condensation with aldehydes; 4-methoxybenzaldehyde, 4-dimethylamino benzaldehyde and arabinose to afford the corresponding hydrazone derivatives11-13. All the synthesized compounds were subjected to the molecular docking using MOE 2008-10 software as agonist for; E. coli Fab-H receptor and Vitamin D receptor for antibacterial and anticancer evaluation, respectively. The most pronounced strong binding affinity towards the target E. coli Fab-H receptor were compounds 7a, 11a, 11b,10a,10cand 12b. On the other hand, the most pronounced strong binding affinity towards the target Vitamin D receptor were compounds 3, 9c, 11a and 10d. The in vitro antibacterial activity of highest binding affinity docked compounds were tested against E. coli, Staphylococcus aureus and Salmonella spp. All the tested compounds gave effective positive results against E. coli with inhibitory zone of about 1.1 cm, while were inactive against Staphylococcus aureus and Salmonella spp. The in vitro cytotoxic activity of the highest binding affinity docked compounds were tested against human liver carcinoma cell line (HepG2) cancer cell lines. Many compounds showed potent cytotoxic activity with low IC 50 values, especially for 3(6.525µM) and 11a (10.97 µM), while for standard drug doxorubicin (5.8 µM).

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Synthesis and pharmacological evaluation of piperidine derivatives with various heterocyclic rings at the 4-position.

Cited by 17 publications

References 0 publications

Synthesis and Pharmacokinetic Evaluation of Siderophore Biosynthesis Inhibitors for Mycobacterium tuberculosis

Synthesis and Pharmacokinetic Evaluation of Siderophore Biosynthesis Inhibitors for Mycobacterium tuberculosis

Diphenylbutylpiperidine-based cell autophagy inducers: Design, synthesis and SAR studies

Synthesis, Molecular Docking and Biological Evaluation of Some New Benzotriazines

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