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1.
Eur J Med Chem ; 58: 84-97, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23108363

ABSTRACT

Alzheimer's disease (AD) onset and progression are associated with the dysregulation of multiple and complex physiological processes and a successful therapeutic approach should therefore address more than one target. Two new chemical entities, the easily accessible heterocyclic scaffolds 1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (benzotriazinone I) and 2-phenyl-6H-[1,2,4]triazino[5,6,1-jk]carbazol-6-one (triazafluoranthenone II), were explored for their multitarget-directed inhibition of beta-amyloid (Aß) fibrillization and acetyl- (AChE) and/or butyryl- (BChE) cholinesterase, three valuable targets for AD therapy. Introduction of appropriate amine substituents at positions 6 and 5 on scaffold I and II, respectively, allowed the preparation of a series of compounds that were tested as Aß(1-40) aggregation and cholinesterase inhibitors. Potent inhibitors of Aß self-aggregation were discovered and among them benzotriazinone 7 exhibited an outstanding IC(50) equal to 0.37 µM. Compounds bearing a basic amine linked to the heterocyclic scaffold through a linear alkyl chain of varying length also afforded good ChE inhibitors. In particular, benzotriazinone 24 and triazafluoranthenone 38 were endowed with an interesting multiple activity, the former displaying IC(50) values of 1.4, 1.5 and 1.9 µM on Aß aggregation and AChE and BChE inhibition, respectively, and the latter showing IC(50) values of 1.4 and an outstanding 0.025 µM in the Aß aggregation and BChE inhibition, respectively. Benzotriazinone 24 and triazafluoranthenone 29, selected owing to their suitable aqueous solubility and Aß aggregation inhibition, were submitted to a time course kinetic assay followed with thioflavin T (ThT) spectrofluorimetry, circular dichroism (CD) and transmission electron microscopy (TEM). Experimental data indicated that 24 acted at a low concentration ratio (10 µM 24 vs. 50 µM Aß), stabilizing the unstructured Aß peptide and inhibiting fibrillogenesis, and that 29 also acted as fibrillization inhibitor, but likely enhancing and stabilizing the ß-sheet arrangement of Aß to yield protofibrillar species as detected by TEM.


Subject(s)
Acetylcholinesterase/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Drug Design , Peptide Fragments/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Butyrylcholinesterase/blood , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Electrophorus , Horses , Molecular Structure , Peptide Fragments/metabolism , Structure-Activity Relationship
2.
Beilstein J Org Chem ; 8: 308-12, 2012.
Article in English | MEDLINE | ID: mdl-22423299

ABSTRACT

A core 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-4-one scaffold is elaborated at C-3(Me) by base-mediated aldol condensation to give new 3-alkenyl-4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-4-ones, which are masked forms related to the acylpyridone natural products.

3.
Org Biomol Chem ; 10(7): 1339-48, 2012 Feb 21.
Article in English | MEDLINE | ID: mdl-22218496

ABSTRACT

Regioselective nucleophilic addition of bisnucleophiles 1,2-benzenediamine, 2-amino-benzenethiol, and N-phenyl-1,2-benzenediamine to 1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (1) at C6 followed by intramolecular cyclocondensation at the C7 carbonyl afforded highly coloured tetracenes 1,3-diphenyl-1,6-dihydro-[1,2,4]triazino[5,6-b]phenazin-4-ium 4-methylbenzenesulfonate (12), 1,3-diphenyl-1H-[1,2,4]triazino[6,5-b]phenothiazine (14) and 1,3,11-triphenyl-1,6-dihydro-[1,2,4]triazino[5,6-b]phenazin-11-ium 4-methylbenzenesulfonate (15), respectively. Neutralization of the latter with alkali gave the free base 1,3,11-triphenyl-1H-[1,2,4]triazino[5,6-b]phenazin-11-ium-6-ide (16). Furthermore, the benzotriazinone 1 reacts with dimethyl malonate to give 6-(methoxycarbonyl)-7-oxo-1,3-diphenyl-7H-benzofuro[5,6-e][1,2,4]triazin-1-ium-4-ide (17) in 74% yield, while with S(4)N(4) [5,6-c]-thiadiazolo-7-oxo-1,3-diphenyl-1,2,4-benzotriazine (22) was formed in 15% yield. The free bases 16 and 17 display negative solvatochromism, which supports charge separated ground states similar to those of zwitterionic biscyanines, and DFT calculations at the UB3LYP/6-31G(d) level afford ΔE(ST) values of -13.6 and -18.7 kcal mol(-1), respectively that strongly favour the singlet ground state. All ring systems described are new and fully characterized.

4.
J Org Chem ; 76(14): 5793-802, 2011 Jul 15.
Article in English | MEDLINE | ID: mdl-21639125

ABSTRACT

Silver(I) fluoride (AgF)-mediated intramolecular nonoxidative and oxidative palladium-catalyzed cyclizations of 1,3-diphenyl- and 8-iodo-1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-ones 6a (R = H) and 7a (R = I) afford a new 'alkaloid like' ring system 2-phenyl-6H-[1,2,4]triazino[5,6,1-jk]carbazol-6-one 8a (triazafluoranthenone) in 86 and 100% yields, respectively. Furthermore, these cyclization protocols were used to prepare triazafluoranthenone analogues 8b-e bearing dialkylamino, methoxy, and phenylsulfanyl substituents at C-5, which were also independently synthesized from triazafluoranthenone 8a by regioselective nucleophilic addition. Similar AgF-mediated intramolecular nonoxidative and oxidative palladium-catalyzed cyclizations of 8,10-dihydro-1-iodo-10-phenylphenazin-2(7H)-ones 13 gave the new 'alkaloid like' ring system 8H-indolo[1,2,3-mn]phenazin-8-one 14 in 80 and 18% yields, respectively.


Subject(s)
Aza Compounds/chemistry , Fluorides/chemistry , Organometallic Compounds/chemistry , Palladium/chemistry , Silver Compounds/chemistry , Catalysis , Cyclization , Molecular Structure , Oxidation-Reduction , Stereoisomerism
5.
Org Biomol Chem ; 9(9): 3122-5, 2011 May 07.
Article in English | MEDLINE | ID: mdl-21409274

ABSTRACT

Stille and Suzuki-Miyaura reactions of 7-iodo-1,3-diphenyl-1,4-dihydro-1,2,4-benzotriazin-4-yl are presented as rare examples of cross-coupling reactions with stable organic radicals. Both the Stille and Suzuki-Miyaura reactions are in most cases high yielding but the latter are cleaner while the former are faster and are accompanied by 1,3-diphenyl-1,2,4-benzotriazin-7(H)-one as by-product. A range of 7-aryl and 7-heteroaryl-1,2,4-benzotriazinyls have been synthesized and characterized using standard spectroscopic and spectrometric means.

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