ABSTRACT
In previous work, a novel pathway for the synthesis of ephedrine/pseudoephedrine and methamphetamine using the precursors benzaldehyde, nitroethane and dimethyl carbonate was investigated, and an impurity profile presented. This paper presents chiral and stable isotope ratios of ephedrine/pseudoephedrine and methamphetamine synthesised by this pathway. Based on the chiral profile and the more negative δ13C (avg. -33.2) and more positive δ2H values, it is possible to distinguish ephedrine/pseudoephedrine and methamphetamine prepared from this pathway from those of "fully synthetic", "semi-synthetic" or "natural" origin. The more positive δ2H values of methamphetamine from this pathway allowed for differentiation from methamphetamine produced from phenyl-2-propanone. It was noted, however, that the use of stable isotope profiling would likely be limited when a benzaldehyde source having a negative δ2H value was used as a precursor. Furthermore, the stable isotope values alone could not be used to differentiate from methamphetamine prepared by the Akabori-Momotani reaction, highlighting the need for combination with impurity profiling.
ABSTRACT
Glycogen Phosphorylase (GP) is a functionally active dimeric enzyme, which is a target for inhibition of the conversion of glycogen to glucose-1-phosphate. In this study we report the design and synthesis of 14 new pyridone derivatives, and seek to extend the SAR analysis of these compounds. The SAR revealed the minor influence of the amide group, importance of the pyridone ring both spatially around the pyridine ring and for possible π-stacking, and confirmed a preference for inclusion of 3,4-dichlorobenzyl moieties, as bookends to the pyridone scaffold. Upon exploring a dimer strategy as part of the SAR analysis, the first extended 2-oxo-dihydropyridinyl-3-yl amide nanomolar based inhibitors of GPa (IC50 = 230 and 260 nM) were identified.
Subject(s)
Amides/chemistry , Amides/pharmacology , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glycogen Phosphorylase/antagonists & inhibitors , Animals , Inhibitory Concentration 50 , Models, Molecular , Molecular Conformation , RabbitsABSTRACT
Glycogen phosphorylase (GP), which plays a crucial role in the conversion of glycogen to glucose-1-phosphate, is a target for therapeutic intervention in diabetes. In this study, we report the design and synthesis of 29 new derivatives of 2-oxo-1,2-dihydro pyridin-3-yl amides, as potential inhibitors of GP. The hit rate (45%) was high with 13 compounds inhibiting GPa (between 33% at 4.40 mM and an IC50 of 1.92 µM). Two lead compounds were identified as compounds exhibiting good GPa inhibition (IC50 = 2.1 and 1.92 µM). SAR analysis of these compounds revealed sensitivity of GPa to the length of the 2-oxo-1,2-dihydro pyridin-3-yl amide derivative and a preference for inclusion of a 3,4-dichlorobenzyl moiety.
Subject(s)
Acetamides/chemistry , Acetamides/pharmacology , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glycogen Phosphorylase/antagonists & inhibitors , Pyridones/chemistry , Pyridones/pharmacology , Acetamides/chemical synthesis , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Glycogen Phosphorylase/metabolism , Humans , Models, Molecular , Molecular Structure , Pyridones/chemical synthesis , Structure-Activity RelationshipABSTRACT
A series of morpholine substituted amino acids (phenylalanine, leucine, lysine and glutamic acid) was synthesized. A fragment-based screening approach was then used to evaluate a series of small heterocycles, including morpholine, oxazoline, dihydro-1,3-oxazine, tetrahydro-1,3-oxazepine, thiazoline, tetrahydro-1,3-pyrimidine, tetrahydro-1,3-diazepine and hexahydro-1H-benzimidazole, as potential inhibitors of Glycogen Phosphorylase a. Thiazoline 7 displayed an improved potency (IC50 of 25 µM) and had good LE and LELP values, as compared to heterocycles 1, 5, 9-13 and 19 (IC50 values of 1.1 mM-23.9 mM). A docking study using the crystal structure of human liver Glycogen Phosphorylase, provided insight into the interactions of heterocycles 5, 7, 9-13 and 19 with Glycogen Phosphorylase.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glycogen Phosphorylase/antagonists & inhibitors , Heterocyclic Compounds/pharmacology , Molecular Docking Simulation , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Glycogen Phosphorylase/metabolism , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Humans , Liver/enzymology , Structure-Activity RelationshipABSTRACT
The molecular structure of the title compound, C21H19Cl2N3O2, a potent glycogen phosphorylase a (GPa) inhibitor (IC50 of 6.3â µM), consists of four distinct conjugated π systems separated by rotatable C-C bonds at the methylene groups. Molecules are linked into dimers disposed about a crystallographic centre of symmetry through a cyclic N-H...O hydrogen-bonding motif [graph set R2(2)(10)]. These dimers are further connected along the crystallographic c axis by N-H...O hydrogen bonding between the amide groups [graph set C(4)]. A comparison of this structure with that of the monohydrate of the significantly less active analogue (S)-2-(3-benzylamino-2-oxo-1,2-dihydropyridin-1-yl)-N-(2-hydroxy-1-phenylethyl)acetamide (IC50 of 120â µM) is presented.
Subject(s)
Acetamides/chemistry , Benzylamines/chemistry , Enzyme Inhibitors/chemistry , Glycogen Phosphorylase/antagonists & inhibitors , Glycogen Phosphorylase/chemistry , Acetamides/pharmacology , Benzylamines/pharmacology , Crystallography, X-Ray , Enzyme Inhibitors/metabolism , Glycogen Phosphorylase/metabolism , Hydrogen Bonding , Molecular StructureABSTRACT
Methods for the cyclodehydration of N-(aminoalkyl)benzamides are few and employ harsh reaction conditions. We have found that the easily prepared phosphonium anhydrides 1 (Hendrickson reagent) or 2 can be used for cyclodehydration of N-(aminoalkyl)benzamides under very mild conditions (room temperature) to produce five-, six-, and seven-membered cyclic amidines. Good yields are obtained by employing a temporary trityl group protection strategy. Cyclic analogue 2 can be used when the product cyclic amidine is organic-soluble, thus producing water-soluble byproducts.
Subject(s)
Amidines/chemical synthesis , Anhydrides/chemistry , Benzamides/chemistry , Organophosphorus Compounds/chemistry , Amidines/chemistry , Cyclization , Dehydration , Molecular StructureABSTRACT
The development of leishmanicidal quinolines and their in vitro (promastigote and amastigote) and, where applicable, in vivo activities are reviewed. This survey provides a direct comparison of bioactivity across different species(e.g. L. donovani, L. amazonensis, L. chagasi, L infantum), and in different animal models (e.g. L. donovani Balb/c mice and L. donovani infected hamsters). The progress of selected quinolines through pre-clinical development and phase I/II trials, and the lead quinoline drugs sitamaquinine and Imiquimod, are discussed in conjunction with delivery systems and combination therapies.
Subject(s)
Antiprotozoal Agents/therapeutic use , Leishmaniasis/drug therapy , Quinolines/chemistry , Aminoquinolines/chemistry , Aminoquinolines/pharmacology , Aminoquinolines/therapeutic use , Animals , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Clinical Trials as Topic , Drug Evaluation, Preclinical , Humans , Imiquimod , Leishmania/drug effects , Primaquine/chemistry , Primaquine/pharmacology , Primaquine/therapeutic use , Quinolines/pharmacology , Quinolines/therapeutic use , Structure-Activity RelationshipABSTRACT
Glycogen phosphorylase (GP) plays a crucial role in the conversion of glycogen to glucose-1-phosphate (and in turn glucose) and is a promising target for therapeutic intervention in diabetes. In this study we synthesized new derivatives of 2-oxo-1,2-dihydropyridin-3-yl amides using a facile aminolysis reaction, in which different alkyl and aryl esters and amides are substituted at N-1 and C-3 of the heterocyclic ring. The in vitro inhibitory activity of compounds against glycogen phosphorylase was evaluated. From this series the most potent compound exhibits good GPa inhibition (IC(50)=6.3 microM). A preliminary study of these compounds showed that anti-GP activity was decreased by the incorporation of a C3-N carbonyl group and favored by increased lipophilicity.
Subject(s)
Amides/chemistry , Amides/pharmacology , Glycogen Phosphorylase/antagonists & inhibitors , Glycogen Phosphorylase/metabolism , Pyridones/chemistry , Pyridones/pharmacology , Amides/chemical synthesis , Amino Acid Sequence , Animals , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Sequence Data , Molecular Structure , Muscles/enzymology , Pyridones/chemical synthesis , Rabbits , Rats , Sequence Alignment , Structure-Activity RelationshipABSTRACT
The first solution state structural analysis (NMR) of the C-terminal sequence of human G(L) that binds to glycogen phosphorylase a (GPa), PEWPSYLGYEKLGPYY-NH(2) (1), showed it to be in a random coil conformation. This was supported by molecular dynamics simulation (modelled in solution) using NAMD 2.6. The conformational ambiguity of the peptide makes the structural arrangement of the peptide (and internal residues) strongly dependent on the environment. Thirteen tetra-peptide fragments of the C-terminal sequence, YEKLG-NH(2), and the corresponding tri- and di-peptide sequences were used in a fragment screen against GPa. Compound 2 (H-GPYY-NH(2)) did not give an IC(50) value, whereas PEWPSYLGYEKLGPYY-NH(2) (1) displayed an IC(50) of 34 microM against GPa. Truncated peptides derived from 1, (EKL-NH(2), EKLG-NH(2), and AcEKNH(2)) inhibited GPa (21%, 32%, 63%, respectively at 22 mM). These studies suggest key residues within the peptide chain have additional molecular interactions with GPa. The interaction of intra-sequence residues in combination with the terminal residues of PEWPSYLGYEKLGPYY with GPa may form the basis for the design of new inhibitors of GPa.
Subject(s)
Glycogen Phosphorylase/antagonists & inhibitors , Peptides/chemistry , Peptides/chemical synthesis , Circular Dichroism , Computer Simulation , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular StructureABSTRACT
Beta-hydroxy amides 6 and 7 were treated with triphenylphosphonium anhydride trifluoromethane sulfonate (3), or the cyclic analogue 4, to generate 2-oxazolines 5 and 8 under mild conditions. The reaction was optimised by examining the number of equivalents of reagents 3 or 4, or diisopropylethyl amine required to best effect cyclisation. The effects of altering the reaction temperature, reaction time, concentration, solvent, and addition rate also were investigated. However, it was found that use of a trityl group to block reaction at the hydroxyl or thiol group of the starting amides, and subsequent in situ detritylation, in the absence of base, led to greatly improved yields. Reagent 4 offered significant advantages in the purification of products and was used to dehydrate a range of trityl derivatives to form simple oxazolines, thiazolines, and a dihydro-1,3-oxazine, in high yield (85-99%), as well as a tetrahydro-1,3-oxazepine (31%).
Subject(s)
Oxazines/chemical synthesis , Oxazoles/chemical synthesis , Thiazoles/chemical synthesis , Anhydrides/chemistry , Organophosphorus Compounds/chemistryABSTRACT
Bis-phosphine oxides can be selectively reduced to bis-phosphine monoxides under exceptionally mild conditions using triflic anhydride and a thiol.
Subject(s)
Oxides/chemistry , Phosphines/chemistry , Magnetic Resonance Spectroscopy , Oxidation-ReductionABSTRACT
The structure of a polymer-supported version of the Hendrickson "POP" reagent, prepared by the reaction of polymer-supported triphenylphosphine oxide 1 with triflic anhydride, is established as an equilibrium mixture of polymer-supported triphenylphosphine ditriflate 3 (delta 79.4 ppm) and polymer-supported phosphonium anhydride 4 (delta 73.3 ppm). The (31)P NMR chemical shift reported previously for 3 is shown to be incorrect.
Subject(s)
Indicators and Reagents/chemistry , Organophosphorus Compounds/chemistry , Polymers/chemistryABSTRACT
The lipophilicity, permeability, solubility, polar surface area and 'rule-of-five' properties were assessed, using QikProp v2.5 (Schrödinger, Inc.) and ALOGPS 2.1 calculations, for 25 Hyphodermin derivatives. These compounds obeyed the 'rule-of-five', and the calculated physicochemical values were generally within desired limits. All compounds were tested against Glycogen Phosphorylase a (GPa). Four phenyl and benzyl substituted 2-oxo-hexahydro and tetrahydrobenzo[cd]indole carboxylic acids were identified as novel inhibitors of GPa with estimated IC(50) values in the range 0.8-1.3mM. Molecular modelling of these novel inhibitors was used to obtain the main structural features of this class of molecule for future structure-activity relationship studies.
Subject(s)
Furans/pharmacology , Glycogen Phosphorylase, Muscle Form/antagonists & inhibitors , Naphthalenes/pharmacology , Allosteric Regulation , Animals , Basidiomycota/chemistry , Basidiomycota/metabolism , Cell Membrane Permeability , Furans/chemistry , Glycogen Phosphorylase, Muscle Form/chemistry , Hydrogen Bonding , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Lipids/chemistry , Models, Molecular , Naphthalenes/chemistry , Rabbits , Solubility , Surface PropertiesABSTRACT
An efficient formal synthesis of (+/-)-hyphodermins A and D, metabolites of Hyphoderma radula, has been completed in 12 and 11 steps, respectively. The tricyclic carbon skeleton of enone 6 was rapidly assembled from diester 11 via an alpha brominationn-elimination sequence followed by anhydride formation. Regioselective reduction of the lactone group of enone 6 with LiAlH(t-BuO) 3 gave lactol 15. Lactol 15 was converted in two steps to (+/-)-hyphodermin D, without the need for complex protection-deprotection strategies. Lactol 15 was converted in three steps to (+/-)-hyphodermin A, via the key step of epoxidation of an enone in the presence of a THP lactol. A combination of NMR and ab initio studies suggests that the structures of hyphodermin C and D should be interchanged.
Subject(s)
Furans/chemical synthesis , Naphthalenes/chemical synthesis , Acetals/chemistry , Furans/chemistry , Methylation , Models, Molecular , Molecular Structure , Naphthalenes/chemistryABSTRACT
The title compound, C(13)H(18)N(2)O(4), crystallizes as discrete mol-ecules associated as N-Hâ¯O hydrogen-bonded dimers disposed about a crystallographic inversion centre. The structure is the first solid-state structure for a 3-acetyl-pyridone without C-4 to C-6 substituents. The amide subsituent at C-3 is coplanar with the pyridone ring, while the tert-butyl ester group is orthogonal to the pyridine ring. The amide and ester carbonyl O atoms are not involved in strong hydrogen bonding with only a number of intramolecular and intermolecular C-Hâ¯O inter-actions apparent in the structure.
ABSTRACT
An efficient formal synthesis of hyphodermin B 1, a metabolite of Hyphoderma radula, has been completed in 15% overall yield. The tricyclic carbon skeleton 3 was rapidly assembled from a novel vinyl enone via a Diels-Alder reaction, followed by dehydrogenation and anhydride formation. Selective reduction of anhydride 3 with LiAlH(t-BuO)3 gave hyphodermin B 1 in 99% yield. The structure of hyphodermin B 1 was confirmed by X-ray crystallographic analysis. The anhydride 3, bearing a gamma-carbonyl group, displayed unexpected reactivity with the anhydride carbonyl closest to the gamma-ketone being the most electrophilic site. This was confirmed by HF/6-31G calculations. In the presence of base, 3 underwent a rearrangement to the novel lactone 16.
Subject(s)
Furans/chemical synthesis , Ketones/chemistry , Naphthalenes/chemical synthesis , Polyporales/chemistry , Crystallography, X-Ray , Furans/chemistry , Models, Molecular , Molecular Structure , Naphthalenes/chemistry , StereoisomerismABSTRACT
Reaction of lithium enolates of simple ketones with (+/-)-phenyl vinyl sulfoxide has potential for the convergent construction of complex fused ring systems containing a bicyclo[n.2.0]alkan-1-ol. The formation of sulfinylbicyclo[4.2.0]octan-1-ols 1-3 from the lithium enolate of cyclohexanone with (+/-)-phenyl vinyl sulfoxide or (R)-(+)-p-tolyl vinyl sulfoxide 18 was used to probe the mode of this novel cyclization reaction. Using phenyl vinyl sulfoxide, variations in the reaction lighting and solvent were investigated, in conjunction with radical trapping (TEMPO) and isotope labeling (deuterium) experiments. Cyclization to form sulfinylbicyclooctanols 1-3 is likely to proceed via an intermediate that ring closes to the bicycloalkanol anion 11 and was presently favored by the use of solvents such as THF or DME.
ABSTRACT
Two novel dehydrating reagents and, based on a phosphonium anhydride and an oxyphosphonium triflate respectively, were prepared by reaction of the corresponding polymer-supported phosphine oxides with triflic anhydride. Reagent, based on the novel phosphorus heterocycle 1,1,3,3-tetraphenyl-2-oxa-1,3-diphospholanium bis(trifluoromethanesulfonate), was found to be a useful reagent for ester and amide formation. A wide range of coupling/dehydration-type reactions, such as ester, amide, anhydride, peptide, ether and nitrile formation, were performed in high yield using the more readily prepared polymer-supported triphenylphosphine ditriflate, which was easily recovered and re-used several times without loss of efficiency. With primary alcohols, both reagents and provide an alternative to the Mitsunobu reaction, where the use of azodicarboxylates and chromatography to remove the phosphine oxide by-product can be avoided. The use of 4-dimethylaminopyridine allowed the esterification of secondary alcohols with to proceed in high yield but with retention of configuration.