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1.
Molecules ; 26(22)2021 Nov 21.
Article in English | MEDLINE | ID: mdl-34834123

ABSTRACT

Spontaneous S-alkylation of methimazole (1) with 1,2-dichloroethane (DCE) into 1,2-bis[(1-methyl-1H-imidazole-2-yl)thio]ethane (2), that we have described recently, opened the question about its formation pathway(s). Results of the synthetic, NMR spectroscopic, crystallographic and computational studies suggest that, under given conditions, 2 is obtained by direct attack of 1 on the chloroethyl derivative 2-[(chloroethyl)thio]-1-methyl-1H-imidazole (3), rather than through the isolated stable thiiranium ion isomer, i.e., 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium chloride (4a, orthorhombic, space group Pnma), or in analogy with similar reactions, through postulated, but unproven intermediate thiiranium ion 5. Furthermore, in the reaction with 1, 4a prefers isomerization to the N-chloroethyl derivative, 1-chloroethyl-2,3-dihydro-3-methyl-1H-imidazole-2-thione (7), rather than alkylation to 2, while 7 further reacts with 1 to form 3-methyl-1-[(1-methyl-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8, monoclinic, space group P 21/c). Additionally, during the isomerization of 3, the postulated intermediate thiiranium ion 5 was not detected by chromatographic and spectroscopic methods, nor by trapping with AgBF4. However, trapping resulted in the formation of the silver complex of compound 3, i.e., bis-{2-[(chloroethyl)thio]-1-methyl-1H-imidazole}-silver(I)tetrafluoroborate (6, monoclinic, space group P 21/c), which cyclized upon heating at 80 °C to 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium tetrafluoroborate (4b, monoclinic, space group P 21/c). Finally, we observed thermal isomerization of both 2 and 2,3-dihydro-3-methyl-1-[(1-methyl-1H-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8), into 1,2-bis(2,3-dihydro-3-methyl-1H-imidazole-2-thione-1-yl)ethane (9), which confirmed their structures.


Subject(s)
Ethylene Dichlorides/chemistry , Methimazole/chemistry , Alkylation , Crystallography, X-Ray/methods , Magnetic Resonance Spectroscopy/methods , Silver/chemistry
2.
Eur J Pharm Biopharm ; 80(2): 402-9, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22019530

ABSTRACT

In this study, we evaluated the usefulness of biorelevant in vitro data and of canine data in forecasting early exposure after the administration of two phases of a BCS Class II compound, i.e., doxazosin base (DB) and its mesylate salt (DM). DB, DM, and doxazosin hydrochloride (DH) were prepared and characterized. In vitro data were collected in various media, including human aspirates. Solubilities of DB and DM in human gastric fluid were forecasted by data in fasted state simulating gastric fluid containing physiological components (FaSSGF-V2) but not by data in HCl(pH 1.8). Unlike data in FaSSGF-V2, dissolution of DB and DM tablets in HCl(pH 1.6) is rapid. Dissolution of DB tablet in FaSSGF-V2 is incomplete and conversion to DH seems to occur. Differences between DB and DM in dissolution in the small intestine are overestimated in the absence of physiological solubilizers. Using the in vitro data and previously described modeling procedures, the cumulative doxazosin profile in plasma was simulated and the 0-2h profile was used for evaluating early exposure. Individual cumulative doxazosin profiles in plasma, after single DM tablet administrations to 24 adults, were constructed from corresponding actual plasma profiles. Compared with in vitro DM data in pure aqueous buffers, DM data in biorelevant media led to better prediction of early exposure. Based on intersubject variability in early exposure after DM administration and simulated profiles, the administered phase, DB or DM, does not have a significant impact on early exposure. Partial AUCs were used for evaluating early exposure after DB and DM administration in 4 dogs. Early exposure was significantly higher after administration of DM to dogs. Dogs are not appropriate for evaluating differences in early exposure after DB and DM administrations.


Subject(s)
Doxazosin/pharmacokinetics , Drug Design , Gastric Juice/metabolism , Adult , Animals , Area Under Curve , Dogs , Doxazosin/administration & dosage , Doxazosin/chemistry , Female , Humans , In Vitro Techniques , Salts , Solubility , Species Specificity , Tablets
3.
Bioorg Med Chem Lett ; 21(2): 853-6, 2011 Jan 15.
Article in English | MEDLINE | ID: mdl-21185182

ABSTRACT

A series of novel ureas and thioureas of 3-decladinosyl-3-hydroxy 15-membered azalides, were discovered, structurally characterized and biologically evaluated. They have shown good antibacterial activity against selected Gram-positive and Gram-negative bacterial strains. These include N″ substituted 9a-(N'-carbamoyl-γ-aminopropyl)- (6a,c), 9a-(N'-thiocarbamoyl-γ-aminopropyl)- (7a,e), 9a-[N'-(ß-cyanoethyl)-N'-(carbamoyl-γ-aminopropyl)]- (9a-c, 9g) 9a-[N'-(ß-cyanoethyl)-N'-(thiocarbamoyl-γ-aminopropyl)]-derivatives (10d-f) of 5-O-desosaminyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythronolide A (3). Among the synthesized compounds thiourea 7a and urea 9b have shown substantially improved activity comparable to azithromycin (1) and significantly better activity than the 3-decladinosyl-azithromycin (2) and the parent 3-cladinosyl analogues against efflux-mediated resistant S. pneumoniae.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Streptococcus pneumoniae/drug effects , Thiourea/chemistry , Thiourea/pharmacology , Urea/chemistry , Urea/pharmacology , Bacteria/drug effects , Bacterial Infections/drug therapy , Drug Resistance, Bacterial , Humans , Microbial Sensitivity Tests , Models, Molecular , Pneumococcal Infections/drug therapy
4.
Bioorg Med Chem Lett ; 20(11): 3244-9, 2010 Jun 01.
Article in English | MEDLINE | ID: mdl-20462754

ABSTRACT

Fifteen-membered 8a-aza-8a-homoerythromycins derived from either erythromycin or clarithromycin have been acylated to form 4''-O-propenoyl derivative. These functionalized analogues underwent Michael reaction with primary or secondary amines to afford novel 8a-aza-8a-homoerythromycin-4''-(3-substituted-amino)propionates. This preparative sequence was adapted so that analogues could be made by parallel synthesis. Among them, 4-quinolone derivatives show particularly good antibacterial potency against macrolide resistant bacteria, comparable or better than azithromycin and telithromycin.


Subject(s)
Anti-Bacterial Agents/pharmacology , Erythromycin/analogs & derivatives , Anti-Bacterial Agents/chemistry , Bacteria/classification , Bacteria/drug effects , Erythromycin/pharmacology , Microbial Sensitivity Tests
5.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 5): o1098-9, 2010 Apr 17.
Article in English | MEDLINE | ID: mdl-21579151

ABSTRACT

There are two independent mol-ecules per asymmetric unit of the title compound, C(26)H(23)N(2)O(3)PS. Their superposition shows that they differ in the conformation of the CH(3)CO- group and the benzene rings from the triphenyl-phospho-rane group. In the crystal structure, independent mol-ecules are inter-conected by strong N-H⋯O hydrogen bonds, forming infinite chains along the a axis.

6.
J Pharm Biomed Anal ; 50(1): 68-72, 2009 Aug 15.
Article in English | MEDLINE | ID: mdl-19410412

ABSTRACT

Successful use of LC-NMR and LC-MS for rapid identification of an impurity in a novel antifungal drug icofungipen has been demonstrated. Complementary information obtained from the two methods made it possible to determine the structure of A1 prior to its isolation and purification. Stop-flow LC-NMR ((1)H and DQFCOSY), LC-MS and LC-MS/MS spectra have shown that A1 is structurally related to icofungipen. It was later isolated and prepared synthetically and its structure was corroborated by high-resolution NMR spectroscopy.


Subject(s)
Antifungal Agents/chemistry , Chromatography, Liquid/methods , Cycloleucine/analogs & derivatives , Magnetic Resonance Spectroscopy/methods , Mass Spectrometry/methods , Cycloleucine/chemistry
7.
Eur J Med Chem ; 44(9): 3459-70, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19303171

ABSTRACT

The new ureas and thioureas of 15-membered azalides, N''-substituted 9a-(N'-carbamoyl-gamma-aminopropyl) (4), 9a-(N'-thiocarbamoyl-gamma-aminopropyl) (6), 9a-[N'-(beta-cyanoethyl)-N'-(carbamoyl-gamma-aminopropyl)] (8) and 9a-[N'-(beta-cyanoethyl)-N'-(thiocarbamoyl-gamma-aminopropyl)] (10) of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (2), were synthesized and structurally characterized by NMR and IR spectroscopic methods and mass spectrometry. The new compounds were evaluated in vitro against a panel of erythromycin susceptible and erythromycin-resistant gram-positive and gram-negative bacterial strains. These compounds displayed an excellent overall antibacterial in vitro activity against erythromycin sensitive gram-positive strains, Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and good against negative strains, Moraxella catarrhalis and Haemophilus influenzae. In addition, several ureas with naphthyl substituents (4f, 4g, 4h) showed better activity in comparison to azithromycin against inducible resistant S. pyogenes. Ureas with naphthyl substituents 4g, 4h and thiourea 8h displayed moderate activity against constitutively resistant S. pneumoniae.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Erythromycin/analogs & derivatives , Thiourea/pharmacology , Urea/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Drug Stability , Erythromycin/chemical synthesis , Erythromycin/chemistry , Erythromycin/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Thiourea/chemical synthesis , Thiourea/chemistry , Urea/chemical synthesis , Urea/chemistry
8.
Eur J Med Chem ; 42(2): 138-45, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17011079

ABSTRACT

Novel hybrid compounds 6a-6d, conjugates of 15-membered azalides and sulfonamides, i.e. unsubstituted, 4-aryl- and 4-heteroaryl-aminosulfonyl derivatives of 9a-[N'-(phenylcarbamoyl)]-9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A were synthesized and characterized by IR, one- and two-dimensional NMR spectroscopies and MALDI-TOF and MS/MS mass spectrometry. The new compounds were evaluated in vitro against a panel of sensitive and resistant Gram-positive and Gram-negative bacterial strains. 9a-{N'-[4-(Aminosulfonyl)phenyl]carbamoyl}--(6a) and 9a-{N'-[4-(phenylaminosulfonyl)phenyl]carbamoyl}--(6b) derivatives showed improvements in activity against inducible resistant Streptococcus pyogenes in comparison with macrolide antibiotic azithromycin and starting material 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (2). In addition, the synthesized azithromycin-sulfonamide conjugates 6a-6d showed good antibacterial activity against sensitive S. pyogenes and Streptococcus pneumoniae strains. The kinetics of degradation in the artificial gastric juice showed that the most active compounds, 6a and 6b, exhibited azithromycin like stability. The cleavage of the cladinose sugar was found to be the main decomposition pathway leading to inactive 7a and 7b, prepared also as analytical standards by the alternative synthetic route together with 7c and 7d.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Azithromycin/analogs & derivatives , Azithromycin/chemical synthesis , Drug Resistance, Bacterial , Streptococcus pyogenes/drug effects , Sulfonamides/chemical synthesis , Acetaldehyde/analogs & derivatives , Anti-Bacterial Agents/pharmacology , Azithromycin/pharmacology , Drug Stability , Hydrolysis , Magnetic Resonance Spectroscopy , Spectrophotometry, Infrared , Structure-Activity Relationship , Sulfonamides/pharmacology , Tandem Mass Spectrometry
9.
J Pharm Pharmacol ; 58(11): 1475-82, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17132210

ABSTRACT

The biopharmaceutical properties of an in-house developed new crystal modification of torasemide (Torasemide N) were investigated in comparison with the most well known crystal modification form of torasemide (Torasemide I) in order to classify the drug according to the Biopharmaceutics Classification System (BCS), and to evaluate the data in line with current US Food and Drug Administration (FDA) guidance (with biowaiver provision for Class I drugs) to determine if the biowaiver provision could be improved. The solubility profiles of Torasemide I and Torasemide N were determined, and tablets prepared from both forms of the drug were studied for in-vitro release characteristics in media recommended by the current FDA guidance for biowaiver of generic products, and in other media considered more appropriate for the purpose than the ones recommended by the FDA. Two separate bioequivalence studies in healthy humans (following oral administration) were performed with two test products (both prepared from Torasemide I) against a single reference product (prepared from Torasemide N). The absorption profiles of the drug from the tablets were determined by deconvolution for comparison with the in-vitro release profiles to determine the appropriateness of some dissolution media for predicting in-vivo performance and to determine the comparative rate and extent of absorption. The drug was absorbed from the tested products quickly and almost completely (about 95% within 3.5 h of administration). However, one test product failed to meet the bioequivalence criteria and had a significant initial lower absorption rate profile compared with the reference product (P< or =0.05), whereas the other product was bioequivalent and had a similar absorption profile to the reference product. A dissolution medium at pH 5.0, in which torasemide has minimum solubility, was found to be more discriminatory than the media recommended by the FDA. Torasemide has been classified as a Class I drug according to the BCS up to a maximum dose of 40 mg and the data suggest that the current FDA guidance could be improved by giving more emphasis to selection of appropriate dissolution media than is given in its current form for approving biowaiver to generic products of Class I drugs.


Subject(s)
Drugs, Generic/classification , Sulfonamides/classification , United States Food and Drug Administration/standards , Area Under Curve , Biological Availability , Crystallization , Drug Approval , Drugs, Generic/chemistry , Drugs, Generic/pharmacokinetics , Guidelines as Topic/standards , Humans , Hydrogen-Ion Concentration , Molecular Structure , Reference Standards , Sodium Potassium Chloride Symporter Inhibitors/chemistry , Sodium Potassium Chloride Symporter Inhibitors/classification , Sodium Potassium Chloride Symporter Inhibitors/pharmacokinetics , Solubility , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Tablets , Therapeutic Equivalency , Torsemide , United States , United States Food and Drug Administration/legislation & jurisprudence
10.
Acta Crystallogr C ; 61(Pt 11): o648-51, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16272600

ABSTRACT

The structures of the three title isomers, namely 4-(2-methylanilino)pyridine-3-sulfonamide, (I), 4-(3-methylanilino)pyridine-3-sulfonamide, (II), and 4-(4-methylanilino)pyridine-3-sulfonamide, (III), all C(12)H(13)N(3)O(2)S, differ in their hydrogen-bonding arrangements. In all three molecules, the conformation of the 4-aminopyridine-3-sulfonamide moiety is conserved by an intramolecular N-H...O hydrogen bond and a C-H...O interaction. In the supramolecular structures of all three isomers, similar C(6) chains are formed via intermolecular N-H...N hydrogen bonds. N-H...O hydrogen bonds lead to C(4) chains in (I), and to R(2)(2)(8) centrosymmetric dimers in (II) and (III). In each isomer, the overall effect of all hydrogen bonds is to form layer structures.


Subject(s)
Sulfonamides/chemistry , Crystallization , Crystallography, X-Ray , Hydrogen Bonding , Sulfonamides/chemical synthesis
11.
J Antibiot (Tokyo) ; 58(6): 380-9, 2005 Jun.
Article in English | MEDLINE | ID: mdl-16156514

ABSTRACT

Three series of the novel sulfonylurea derivatives of 15-membered azalides, i.e. 9a-N-[N'-(aryl)sulfonylcarbamoyl] (4a-4f, 5a-5f), 9a-N-{N'-[(aryl)sulfonylcarbamoyl-gamma-aminopropyl]} (10a-10f, 11a, 11c) and 9a-N-{N'-(beta-cyanoethyl)-N'-[(aryl)sulfonylcarabamoyl-gamma-aminopropyl]} (14a-14f, 15a, 15b, 15f) derivatives of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (2) and 5-O-desosaminyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythronolide A (3) were prepared and their structures elucidated by NMR and IR spectroscopic methods and mass spectrometry. Minimal inhibitory concentration (MIC) of these compounds was determined on a panel of sensitive and resistant Gram-positive and Gram-negative bacterial strains. Several compounds of the series of 9a-N-[N'-(aryl)sulfonylcarbamoyl] derivatives that showed significant improvements in activity against inducible resistant Streptococcus pyogenes strain were suggested for further optimization.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Aza Compounds/chemical synthesis , Aza Compounds/pharmacology , Sulfonylurea Compounds/chemical synthesis , Sulfonylurea Compounds/pharmacology , Bacteria/drug effects , Drug Resistance, Bacterial , Indicators and Reagents , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, Infrared , Streptococcus pyogenes/drug effects , Structure-Activity Relationship
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