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1.
Antiviral Res ; 167: 6-12, 2019 07.
Article in English | MEDLINE | ID: mdl-30849420

ABSTRACT

We report the design, synthesis, and biological evaluation of a class of 1H-pyrido[2,1-b][1,3]benzothiazol-1-ones originated from compound 1, previously identified as anti-flavivirus agent. Some of the new compounds showed activity in low µM range with reasonable selectivity against Dengue 2, Yellow fever (Bolivia strain), and West Nile viruses. One of the most interesting molecules, compound 16, showed broad antiviral activity against additional flaviviruses such as Dengue 1, 3 and 4, Zika, Japanese encephalitis, several strains of Yellow fever, and tick-borne encephalitis viruses. Compound 16 did not exert any effect on alphaviruses and phleboviruses and its activity was maintained in YFV infected cells from different species. The activity of 16 appears specific for flavivirus with respect to other virus families, suggesting, but not proving, that it might be targeting a viral factor. We demonstrated that the antiviral effect of 16 is not related to reduced viral RNA synthesis or virion release. On the contrary, viral particles grown in the presence of 16 showed reduced infectivity, being unable to perform a second round of infection. The chemical class herein presented thus emerges as suitable to provide pan-flavivirus inhibitors.


Subject(s)
Antiviral Agents , Flaviviridae/drug effects , Oxazocines , Pyridines , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Dengue Virus/drug effects , Encephalitis Viruses, Tick-Borne/drug effects , Humans , Oxazocines/chemical synthesis , Oxazocines/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , RNA, Viral/drug effects , Virion/drug effects , Virus Replication/drug effects , West Nile virus/drug effects , Yellow fever virus/drug effects , Zika Virus/drug effects
2.
Bioorg Chem ; 86: 569-582, 2019 05.
Article in English | MEDLINE | ID: mdl-30782575

ABSTRACT

In order to investigate potential therapeutically agents, novel products of Biginelli reaction (4a-l) were synthesized and exposed to cytotoxic and caspase activities, angiogenesis, cell cycle distribution, gene and microRNA expression levels, lipophilicity assessment and docking study. Among the twelve novel compounds (4a-l) evaluated for the cytotoxic activity, five of them (4c, 4d, 4f, 4k and 4l) that showed excellent activity on the tested cell lines (HeLa, LS174 and A549) were selected for further evaluation. Interestingly, compound 4f has up to three times higher selectivity index (SI) towards cancer cells than cisplatin (on HeLa, LS174 and A549 SI = 18.2, 13.5 and 11.2, respectively). The obtained results from cell cycle distribution and caspase activity indicate that tested compounds (4c, 4d, 4f, 4k and 4l) promoted caspase-9 activation, implicated in the intrinsic pathway of apoptosis. Lipophilicity of 4a-l was determinate by using reversed-phase high-performance liquid chromatography.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Caspase 9/metabolism , Drug Discovery , MicroRNAs/antagonists & inhibitors , Molecular Docking Simulation , Neovascularization, Pathologic/drug therapy , A549 Cells , Aldehydes/chemical synthesis , Aldehydes/chemistry , Aldehydes/pharmacology , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Cell Proliferation/drug effects , Cells, Cultured , Cisplatin/chemistry , Cisplatin/pharmacology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Hydrophobic and Hydrophilic Interactions , MicroRNAs/genetics , Molecular Structure , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Oxazocines/chemical synthesis , Oxazocines/chemistry , Oxazocines/pharmacology , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Structure-Activity Relationship
3.
Org Lett ; 17(3): 418-21, 2015 Feb 06.
Article in English | MEDLINE | ID: mdl-25569027

ABSTRACT

Several benzoxazocenones have been found to exhibit novel cellular activities. In the present study, we report a gold(I)-catalyzed 8-endo-dig hydroalkoxylation reaction of alkynamides to access analogous oxazocenone scaffolds. This methodology provided an advanced intermediate, which was elaborated to a des-benzo analog of a bioactive benzoxazocenone.


Subject(s)
Alkynes/chemistry , Amides/chemistry , Gold/chemistry , Oxazocines/chemical synthesis , Aldehydes , Catalysis , Cyclization , Molecular Structure , Oxazocines/chemistry , Stereoisomerism
4.
Z Naturforsch C J Biosci ; 69(7-8): 283-90, 2014.
Article in English | MEDLINE | ID: mdl-25265848

ABSTRACT

A series of annulated 7-membered oxazepine and 8-membered oxazocine derivatives were synthesized by photoreaction of phthalimide derivatives and an alkene. The antimicrobial activities of the synthesized compounds were evaluated, and compounds 18 and 20 exhibited best antibacterial activity against Gram-positive bacteria. The relationships between structure (especially steric structure) and antimicrobial activities are discussed.


Subject(s)
Oxazepines/chemical synthesis , Oxazepines/pharmacology , Oxazocines/chemical synthesis , Oxazocines/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Structure-Activity Relationship , X-Ray Diffraction
5.
Chem Commun (Camb) ; 49(70): 7738-40, 2013 Sep 11.
Article in English | MEDLINE | ID: mdl-23877190

ABSTRACT

Five series of heterocycles with extraordinary structural diversity have been regiospecifically synthesized from the same Morita-Baylis-Hillman Acetates (MBHAs). All four potential electrophilic sites (α, ß, γ, δ) of MBHAs are proved to be reactive.


Subject(s)
Acetates/chemistry , Heterocyclic Compounds/chemistry , Indolizines/chemical synthesis , Indolizines/chemistry , Oxazocines/chemical synthesis , Oxazocines/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry
8.
J Med Chem ; 54(1): 289-301, 2011 Jan 13.
Article in English | MEDLINE | ID: mdl-21141896

ABSTRACT

Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.


Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/drug effects , Indoles/chemical synthesis , Oxazocines/chemical synthesis , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Biological Availability , Cell Line, Tumor , Crystallography, X-Ray , Dogs , Hepacivirus/enzymology , Hepacivirus/physiology , Humans , Indoles/pharmacokinetics , Indoles/pharmacology , Macaca mulatta , Mice , Mice, SCID , Mice, Transgenic , Models, Molecular , Molecular Structure , Oxazocines/pharmacokinetics , Oxazocines/pharmacology , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Viremia/drug therapy , Viremia/virology , Virus Replication/drug effects
9.
Chem Pharm Bull (Tokyo) ; 56(2): 176-80, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18239303

ABSTRACT

A scaleable synthetic route is described to obtain 2-(4-acetylpiperadin-1-yl)-6-[3,5-bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (1, KRP-103) as a neurokinin (NK)(1) antagonist. The key step in the synthesis is the intramolecular cyclization of N-[3,5-bis(trifluoromethyl)phenylmethyl]-N-(3-hydroxypropyl)-4-chloro-6-(2-methylphenyl)-2-methylthiopyrimidine-5-carboxamide (15) which was obtained by amide formation between 4-(2-methylphenyl)-2-methylthio-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (8) and 3-[3,5-bis(trifluoromethyl)phenylmethylamino]-1-propanol (3). Treatment of 15 with 1,8-diazabicyclo[5,4,0]undec-7-ene provided 6-[3,5-bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-2-methylthio-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (6). This intermediate (6) is transformed into the candidate compound (1) by two steps; oxidation, and substitution reaction of the resultant sulfone (7) with 1-acetylpiperazine. This synthetic method is free of chromatographic purification and is amenable to large scale synthesis.


Subject(s)
Neurokinin-1 Receptor Antagonists , Oxazocines/chemical synthesis , Chromatography, High Pressure Liquid , Cost-Benefit Analysis , Cyclization , Indicators and Reagents , Oxazocines/economics , Spectrometry, Mass, Electrospray Ionization , Spectrometry, Mass, Fast Atom Bombardment , Spectrophotometry, Ultraviolet
10.
Bioorg Med Chem ; 13(20): 5717-32, 2005 Oct 15.
Article in English | MEDLINE | ID: mdl-15993086

ABSTRACT

A series of novel bicyclic pyrimidine derivatives was prepared as part of a search for NK1 antagonist aimed at the treatment of urinary incontinence. Among them, 3g, a pyrimido[4,5-b][1,5]oxazocine derivative, bearing a 4-acetylpiperazinyl group and a 2-methylphenyl group, was shown to have potent NK1 antagonist activity with a K(B) value of 0.105 nM and markedly increased the effective bladder capacity of guinea pigs (59.4% at 0.3 mg/kg iv and 62.8% at 3 mg/kg id). Furthermore, the effect of 3g on bladder function appeared to differ from that of tolterodine, another classical anti-pollakiuria agent, as determined by the distention-induced rhythmic bladder contraction assay using a urethane-anesthetized guinea pig model. Compound 3g is expected to be a promising agent for the treatment of urinary incontinence.


Subject(s)
Neurokinin-1 Receptor Antagonists , Oxazocines/chemical synthesis , Oxazocines/pharmacology , Animals , Drug Evaluation, Preclinical , Guinea Pigs , Magnetic Resonance Spectroscopy , Muscle Contraction/drug effects , Oxazocines/chemistry , Spectrometry, Mass, Electrospray Ionization , Urinary Bladder/drug effects , Urinary Bladder/physiology
11.
Bioorg Med Chem Lett ; 15(5): 1479-84, 2005 Mar 01.
Article in English | MEDLINE | ID: mdl-15713411

ABSTRACT

Novel 9-substituted-7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,3-b]- and [2,3-b]-1,5-oxazocin-6-ones were designed and prepared as part of a search for NK1 antagonists. Structure-activity relationship studies indicated that the conformational restriction resulting from the incorporation of an oxazocine ring and the presence of a terminal heteroatom on the cyclic amino group at the C-9 position play important roles in NK1, receptor recognition.


Subject(s)
Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/pharmacology , Neurokinin-1 Receptor Antagonists , Oxazocines/chemical synthesis , Oxazocines/pharmacology , Animals , Drug Design , Guinea Pigs , Heterocyclic Compounds, 2-Ring/chemistry , Ileum/drug effects , Ileum/metabolism , Microsomes/drug effects , Microsomes/metabolism , Molecular Structure , Oxazocines/chemistry , Rats , Receptors, Neurokinin-1/metabolism , Structure-Activity Relationship , Urinary Bladder/drug effects , Urinary Bladder/physiology
12.
Bioorg Med Chem Lett ; 15(5): 1485-8, 2005 Mar 01.
Article in English | MEDLINE | ID: mdl-15713412

ABSTRACT

The structurally novel pyrimido[4,5-b][1,5]oxazocine derivative 3, a hybrid compound of pyrido[4,3-b]- and [2,3-b]-1,5-oxazocine (1 and 2, respectively), was designed and synthesized. We examined the atropisomeric property and the NK1 antagonist activity of 3. Compound 3 was found to possess both a feature of 1, free rotation about the biaryl bond, and a feature of 2, potent in vivo activity.


Subject(s)
Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacology , Neurokinin-1 Receptor Antagonists , Oxazocines/chemical synthesis , Oxazocines/pharmacology , Animals , Drug Evaluation, Preclinical , Guinea Pigs , Heterocyclic Compounds/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Oxazocines/chemistry , Structure-Activity Relationship , Urinary Bladder/drug effects , Urinary Bladder/physiology
13.
Bioorg Med Chem ; 12(10): 2653-69, 2004 May 15.
Article in English | MEDLINE | ID: mdl-15110847

ABSTRACT

Previously we reported on the synthesis and properties of a series of highly potent piperidinyl 2-subsituted-3-cyano-1-naphthamide NK1 antagonists that includes 3 and 4. Here we report our efforts to alleviate a troublesome atropisomeric property of those derivatives by introduction of a tethering bridge that, in addition, could be used to lock the resulting cyclic derivatives in a purported NK1 pharmacophore conformation. Using 3 as a starting point, the naphtho[2,1-b][1,5]oxazocine, 17, was found to contain the optimal ring tether size (8) for retaining NK1 activity, was more NK1 versus NK2 selective, and reduced the number of atropisomers from four to two. Cyclic derivatives 29 and 32, which exist as essentially single atropisomers in the purported pharmacophore conformation, were prepared in the closely related naphtho[1,2-f][1,4]oxazocine series as part of an effort to use mono methyl substitution of the tethering bridge as a conformation stabilizing factor. Both 29 and 32 were found to be less active as NK1 antagonists than the non-methylated parent 28 possibly due to methyl group destabilization of receptor interaction. We discuss the above findings in the context of a previously proposed NK1 pharmacophore model and present a further refinement of that model.


Subject(s)
Neurokinin-1 Receptor Antagonists , Oxazocines/chemistry , Oxazocines/pharmacology , Animals , Cell Line , Isomerism , Magnetic Resonance Spectroscopy , Mice , Molecular Conformation , Molecular Structure , Oxazocines/chemical synthesis
14.
Farmaco ; 52(12): 751-3, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9648281

ABSTRACT

We synthetized pyridobenzoxazocynone that differs in the enlarged eight-membered heterocyclic system from the basic structure of pyridobenzoxazepinones a known class of non-nucleoside HIV-1 reverse transcriptase inhibitors. Pyridobenzoxazocynone hydrochloride was found to inhibit HIV-1 reverse transcriptase activity. At concentration 0.35 microM the enzyme activity decreased by 64 +/- 14%. Higher concentrations of pyridobenzoxazocynone hydrochloride completely abolished the enzyme activity expressed as radioactivity of acid insoluble products. These results suggest that pyridobenzoxazocynones may represent a new class of HIV-1 reverse transcriptase inhibitors.


Subject(s)
HIV Reverse Transcriptase/antagonists & inhibitors , Oxazocines/chemical synthesis , Pyridines/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Gene Products, pol/antagonists & inhibitors , Humans , Molecular Structure , Oxazocines/pharmacology , Pyridines/pharmacology , Reverse Transcriptase Inhibitors/pharmacology
16.
J Med Chem ; 28(2): 225-33, 1985 Feb.
Article in English | MEDLINE | ID: mdl-3968687

ABSTRACT

During an investigation of the antiinflammatory properties of a number of tetracyclic derivatives of 6,8-dichlorodibenz[b,f]oxepin-10(11H)-one, the ring-expanded 1,3-dichloro-5H-dibenz[b,g]-1,4-oxazocine (9) was prepared and found to be considerable pharmacological interest. It was subsequently found that the corresponding ring-opened amino acid 66, a close analogue of the antiinflammatory agent fenclofenac, also possessed significant antiinflammatory activity, superior both to the dibenzoxazocine and to fenclofenac. These findings prompted extensive synthetic programs in both areas, and a number of derivatives in the amino acid series showed potencies considerably in excess of the standard compound. These phenylacetic acids, however, were significantly more ulcerogenic than fenclofenac whereas the corresponding dibenzoxazocines showed few signs of ulcerogenicity at doses up to 1 g/kg.


Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Oxazocines/chemical synthesis , Phenylacetates/chemical synthesis , Animals , Arthritis, Experimental/drug therapy , Female , Male , Oxazocines/therapeutic use , Phenylacetates/therapeutic use , Rats , Stomach/drug effects , Stomach Ulcer/chemically induced
18.
Pol J Pharmacol Pharm ; 32(5): 773-7, 1980.
Article in English | MEDLINE | ID: mdl-7196575

ABSTRACT

Anthelminthic activity of new esters of 3,4,5-trimethoxybenzoic acid containing rests of the title heterocyclic amines has been determined. 3-(Perhydroazepinyl)-propyl ester 6 acts on enchytraeids in vitro 56-fold stronger than piperazine adipate, 2-(perhydroazepinyl)-ethyl ester 5 is the most effective in a therapy of mice infested with nematodes.


Subject(s)
Anthelmintics/chemical synthesis , Azepines/chemical synthesis , Oxazocines/chemical synthesis , Animals , Anthelmintics/pharmacology , Anthelmintics/toxicity , Mice , Nematode Infections/drug therapy
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