Design, synthesis and preliminary pharmacological evaluation of rigid analogues of the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP)

Guandalini, Luca; Martini, Elisabetta; Gualtieri, Fulvio; Romanelli, Maria Novella; Varani, Katia

doi:10.3998/ark.5550190.0005.525

Cited by 13 publications

(5 citation statements)

References 21 publications

(29 reference statements)

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“…Scheme summarizes the preparation of three more indole-modified analogues. Compounds 29f and 29g utilized ethyl indole-2-carboxylate 8 for their indole starting material, while 29j utilized azaindole ester 23j synthesized according to procedures described in the literature. , Each were N -alkylated under basic conditions and saponified to give intermediate acids 24f , 24g , and 24j . Final coupling reactions with piperidine 16 provided the final compounds.…”

Section: Resultsmentioning

confidence: 99%

Optimization of Novel Indole-2-carboxamide Inhibitors of Neurotropic Alphavirus Replication

et al. 2013

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Neurotropic alphaviruses, which include western equine encephalitis virus (WEEV) and Fort Morgan virus, are mosquito-borne pathogens that infect the central nervous system causing acute and potentially fatal encephalitis. We previously reported a novel series of indole-2-carboxamides as alphavirus replication inhibitors, one of which conferred protection against neuroadapted Sindbis virus infection in mice. We describe here further development of this series resulting in 10-fold improvement in potency in a WEEV replicon assay and up to 40-fold increases in half-lives in mouse liver microsomes. Using a rhodamine123 uptake assay in MDR1-MDCKII cells we were able to identify structural modifications that markedly reduce recognition by P-glycoprotein, the key efflux transporter at the blood brain barrier. In a preliminary mouse PK study we were able to demonstrate that two new analogs could achieve higher and/or longer plasma drug exposures than our previous lead, and that one compound achieved measurable drug levels in the brain.

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Section: Resultsmentioning

confidence: 99%

Optimization of Novel Indole-2-carboxamide Inhibitors of Neurotropic Alphavirus Replication

et al. 2013

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“…This tetrahydro-pyrazinoindole compound was found to be a partial agonist at MT 1 receptors and possessed no intrinsic activity at MT 2 receptors. It is noteworthy that the treatment of pyrazinoindole 7 (R = H) with MeI gave the corresponding N -dimethyliodonium salt which was found to displace [ 3 H]-cytisine from the nicotinic binding sites on rat cerebral cortex and was revealed to be a nicotinic agonist ligand [ 29 ].…”

Section: Pyrazinoindoles A: Synthesis and Biological Propertiesmentioning

confidence: 99%

Synthesis and Biological Activities of Pyrazino[1,2-a]indole and Pyrazino[1,2-a]indol-1-one Derivatives

et al. 2021

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This review concerns the synthesis and biological activities of pyrazino[1,2-a]indoles and pyrazino[1,2-a]indol-1-ones reported since 1997 and the discovery of biological activity of pyrazinoindole derivatives. In the first part, we first presented the synthetic routes that have been reported from a methodological point of view to access the pyrazinoindole unit according to cyclization reactions using or not using metal catalysts. Then, syntheses and neuropsychiatric, auto-immune, anti-infectious and anti-cancer properties of pyrazinoindoles were detailed. In the second part, we first reported the main accesses to pyrazinoindol-1-one substrates according to Michael reactions, metal-catalyzed and metal-free cyclization reactions. The syntheses and anti-cancer, anti-infectious, anti-allergenic and neuropsychiatric properties of pyrazinoindolones were next described and discussed.

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“…For example, the Bartoli reaction uses nitrobenzenes and vinyl Grignard reagents, and when applied to azaindole synthesis, this method requires a large excess of vinyl Grignard and only affords 4-azaindole and 6-azaindole in generally low yields [57]. Furthermore, reactions such as the Hemetsberger-knittel synthesis are limited to few isomers-6-azaindole and 7-azaindole, respectively-and, additionally, can only afford azaindole structures in low to moderate yields [58,59].…”

Section: Scheme 4 Synthesis Of Quinazolinones Via An Acceptorless Coupling Of O-aminobenzamidesmentioning

confidence: 99%

Advances in Green Catalysis for the Synthesis of Medicinally Relevant N-Heterocycles

et al. 2021

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N-heterocycles, both saturated and unsaturated, are ubiquitous biologically active molecules that are extremely appealing scaffolds in drug discovery programs. Although classical synthetic methods have been developed to access many relevant N-heterocyclic scaffolds, representing well-established and reliable routes, some do not meet the needs of sustainability. In this context, several advances have been made towards the sustainable synthesis of N-heterocycles. This review focuses on the most recent examples from the last five years of catalytic synthesis of several heterocyclic compounds of medicinal relevance. Thus, the synthesis of isoindoloquinazolines, quinazolines and azaindoles, among others, are covered. The synthetic methods selected include the use of homogeneous and heterogeneous catalysts and the use of alternative and sustainable methods such as, for example, metal-catalyzed acceptorless coupling and one-pot reactions. The green aspects of the individual synthetic approaches are highlighted, and the scope of each methodology is described.

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Design, synthesis and preliminary pharmacological evaluation of rigid analogues of the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP)

Cited by 13 publications

References 21 publications

Optimization of Novel Indole-2-carboxamide Inhibitors of Neurotropic Alphavirus Replication

Optimization of Novel Indole-2-carboxamide Inhibitors of Neurotropic Alphavirus Replication

Synthesis and Biological Activities of Pyrazino[1,2-a]indole and Pyrazino[1,2-a]indol-1-one Derivatives

Advances in Green Catalysis for the Synthesis of Medicinally Relevant N-Heterocycles

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