The main objective of the present study was to synthesize potential inhibitor/activators of AChE and hCA I-II enzymes, which are thought to be directly related to Alzheimer's disease. Dithiodibenzothioate compounds were synthesized by thioesterification. Six different thiolate compounds produced were characterized by ¹H-, ¹³C-NMR, FT-IR, LC-MS/MS methods. HOMO-LUMO calculations and electronic properties of all synthesized compounds were comprehensively illuminated with a semi-empirical molecular orbital (SEMO) package for organic and inorganic systems using Austin Model 1 (AM1)-Hamiltonian as implemented in the VAMP module of Materials Studio. In addition, the inhibition effects of these compounds for AChE and hCA I-II in vitro conditions were investigated. It was revealed that TE-1, TE-2, TE-3, TE-4, TE-5, and TE-6 compounds inhibited the AChE under in vitro conditions. TE-1 compound activated the enzyme hCA I while TE-2, TE-3 TE-4 compounds inhibited it. TE-5 and TE-6, on the other hand, did not exhibit a regular inhibition profile. Similarly, TE-1 activated the hCA II enzyme whereas TE-2, TE-3, TE-4, and TE-5 compounds inhibited it. TE-6 compound did not have a consistent inhibition profile for hCA II. Docking studies were performed with the compounds against AChE and hCA I-II receptors using induced-fit docking method. Molecular Dynamics (MD) simulations for best effective three protein-ligand couple were conducted to explore the binding affinity of the considered compounds in semi-real in-silico conditions. Along with the MD results, TE-1-based protein complexes were found more stable than TE-5. Based on these studies, TE-1 compound could be considered as a potential drug candidate for AD.Communicated by Ramaswamy H. Sarma.

01 Feb 1994·Biological Mass Spectrometry

Identification of human urinary metabolites of isbufylline by high-performance liquid chromatography/thermospray mass spectrometry

Article

Author: Orenzo Agostini ; Antonio Triolo ; Fabio Bonelli

Analysis of urinary metabolites of isbufylline (1,3-dimethyl-7-(2-methylpropyl)xanthine) in healthy male volunteers after oral administration of a single dose of 320 mg was undertaken by high-performance liquid chromatography/mass spectrometry (HPLC/MS with thermospray ionization. Filtered urines were directed injected into the HPLC/MS system, equipped with a Lichrospher 100 RP 18 analytical column. The mobile phase was 0.1 M, pH 3.7 ammonium acetate in water and acetonitrile; the composition was varied linearly from 5% to 40% of the organic modifier in 40 min with a flow rate of 1 ml min-1. Three more chromatographic peaks appeared in urines from treated subjects as compared to untreated ones; their probable quasi-molecular ions were at m/z 253, 239 and 267 respectively, while the original drug, of 236 Da, was not present in appreciable quantity. The collisionally activated daughter ion spectra of the above ions allowed identification of 1,3-dimethyl-7-(3-hydroxy-2-methylpropyl)xanthine (D3OHMPX), 1-methyl-7-(2-hydroxy-2-methylpropyl)xanthine (M2OHMPX), and 1,3-dimethyl-(2-carboxypropyl)xanthine (D2CMPX), the first one being present as glucuronic acid conjugate.

01 Dec 1993·Pulmonary Pharmacology

Isbufylline, a Xanthine Derivative, Inhibits Bronchoconstrictor Responses Produced by Stimulation of Capsaicin-sensitive Sensory Nerves in Guinea-pig: 'In Vitro' and 'In Vivo' Evidence

Article

Author: L. Ballati ; S. Evangelista ; S. Manzini ; S. Meini

Isbufylline (1,3-dimethyl-7-isobutylxanthine) is a new xanthine derivative claimed to possess remarkable antibronchospastic properties coupled to reduced pro-convulsive side-effects. In guinea-pig bronchial preparations, isbufylline showed a differential and more pronounced, as compared to theophylline, relaxant activity on tonic bronchial contractions evoked by exogenous administration of equieffective concentrations of capsaicin (0.3 microM), neurokinin A (0.1 microM) and carbachol (0.3 microM) (in the presence of indomethacin 5 microM and thiorphan 10 microM). Isubfylline gave an IC50 of 21 (19-25, 95% confidence limits) microM on capsaicin-evoked contractile effects, and 36 (30-43) microM on carbachol-produced contractile effects, whilst it was almost ineffective in inhibiting neurokinin A-induced bronchospasm (IC50 not evaluable, > 100 microM). 'In vitro' studies were also performed using electrical field stimulation (EFS) to produce non-adrenergic non-cholinergic (NANC)- or cholinergic nerves-mediated contractions in guinea-pig isolated bronchi or trachea. Isbufylline (10-90 microM) produced a concentration-dependent inhibition of the NANC response (EFS: 20 Hz, supramaximal voltage, 0.5 ms pulse, width for 10 s) of bronchi (IC50 = 47 microM) without affecting the cholinergic contractile response in tracheal smooth muscle (EFS: 0.5 up to 32 Hz, supramaximal voltage, 0.5 ms pulse, for 15 s every min). The activity of isbufylline was also confirmed in anaesthetized guinea-pig showing a greater antibronchospastic activity towards capsaicin (8 nmol/kg i.v.) or vagal non-cholinergic (10 V, 1 ms, 20 Hz for 20 s) stimulation as compared to the inhibition exerted against acetylcholine (50 nmol/kg i.v.) or neurokinin A (1 nmol/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 2	-	Malesci Istituto Farmacobiologico SpA	-
Asthma	Phase 2	-	A. Menarini Industrie Farmaceutiche Riunite SRL	-
Asthma	Phase 2	IT	-	-

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