5-(thien-2-yl) uracil analogs: 5-(5-methylthien-2-yl)-2′-deoxyuridine, 5-(5-thien-2-yl)-2′-deoxyuridine,and 5-(5-bromothien-2-yl)-2′-deoxyuridine

Crystal structures of 5-(5-methylthien-2-yl)-2-deoxyuridine (I), 5-(5-thien-2-yl)-2-deoxyuridine (II) and 5-(5-bromothien-2-yl)-2-deoxyuridine (III) have been obtained from data collected on a four-circle Enraf-Nonius diffractometer (CAD-4 system). Space group, unit/cell parameters and finalR indices are:I, monoclinic,P2₁,a=9.105(2),b=20.819(2),c=7.932(2) Å, =98.79(2)°,R=5.7%;II, monoclinic,P2₁,a=8.720(4),b=20.793(4),c=7.884(4) Å, =95.06(2)°,R=5.8%;III, monoclinic,P2₁,a=9.260(2),b=41.655(7),c=7.926(2) Å, =97.996(13)°,R=9.4%. Structural properties of the title compounds are compared with those of 5-(5-chlorothien-2-yl)-2-deoxyuridine (IV) previously reported in order to explain their affinity for HSV-1 thymidine kinase and their eventual interaction with viral DNA polymerase. The main structural features observed are the coplanarity of the uracil and thienyl cycles stabilized by a S–O intramolecular interaction and the formation of dimeric intermolecular H bonds between two uracil moieties.     

Synthesis and stability evaluation of novel peptidomimetic Caspase-1 inhibitors for topical application

During our search for topically-active Caspase-1 inhibitors, we identified a novel class of potent inhibitors based on a 1,3,5-trisubstituted uracil motif equipped with an l-aspartate semi-aldehyde derived warhead. In the literature, the majority of Caspase-1 inhibitors possessing the same warhead have been designed and evaluated for oral administration as the ethyl acetal pro-drug form. For our topical program, the pro-drug acetal form was not fully hydrolysed in the skin and was unstable in many of our standard topical excipients, therefore, we were obliged to focus on the actual hemiacetal drug form of the molecule during our drug discovery program. Our work focuses on both the synthesis and achiral and chiral stability of the final drug molecules in topical excipients.     

A convenient method for N-1 arylation of uracil derivatives

1-(4-Nitrophenyl)- and 1-(2,4-dinitrophenyl)uracil derivatives have been obtained by direct arylation of uracil and its 5-substituted derivatives using 1-fluoro-4-nitrobenzene or 1-fluoro-2,4-dinitrobenzene in the presence of a base. The application of the newly obtained uracil derivatives in further synthesis is also presented.     

A Novel Photoproduct of Uracil in Phosphate-Buffered Saline

Under UV irradiation the photoreaction of pyrimidine bases in aqueous solution hasdisclosed three mpes of reactions, namely: (a) nucleophilic addition ofwateT, ethanol, orhydrogen cyanide at the 5,6-double bond; (b) dimerization by addition at the samedouble bond; (c) ring cleavage. It has been reported' that the presence of phosphatesaltered the course of the photolysis process of pyrimidine bases and derivatives under theirradiation of low pressure mercury lamp (LPML, 254 "m), but the role…     

The Benzoylation of 6-Methyluracil and 5-Nitro-6-methyluracil

6-Methyluracil and 5-nitro-6-methyluracil react with variable molar quantities of benzoyl chloride in acetonitrile-pyridine at room temperature to give I-N, 3-N-dibenzoyl-6-methyluracil 3b and l-N-benzoyl-5-nitro-6-methyluracil 4b. The reactive rates of debenzoylation of 3b and 4b were investigated.     

Complexes of Uracil (2,4-Dihydroxypyrimidine) Derivatives

Equilibrium studies have been carried out on complex formation of M²⁺ ions (M=Co, Ni, and Zn) with L = thymine, 6-chloromethyluracil, 5-hydroxymethyluracil, uracil, 6-methyluracil, and 6-umpm (dimethyl 6-uracilmethylphosphonate) in aqueous solution, at 25 ^∘;C and an ionic strength of I=0.1 mol⋅L⁻¹ (KNO₃). Potentiometric results indicate the formation of ML species (coordination via N3) for Co(II) and Ni(II) as well as a hydroxo complex MLH₋₁—with a deprotonated water of the inner coordination sphere. Titrations of Zn(II) confirmed both the existence of ML and MLH₋₁ species with 6-chloromethyluracil as well as 5-hydroxymethyluracil, whereas for uracil, thymine, and 6-methyluracil the only species accepted pH-metrically was MLH₋₁. For all the ligands under study the complexation with Zn(II) was reinvestigated by means of ion-selective electrodes (ISE). The role of substituents is discussed.     

Synthesis and Evaluation of Some Uracil Nucleosides as Promising Anti-Herpes Simplex Virus 1 Agents

Since herpes simplex virus type 1 (HSV-1) infection is so widespread, several antiviral drugs have been developed to treat it, among which are uracil nucleosides. However, there are major problems with the current medications such as severe side-effects and drug resistance. Here we present some newly synthesized cyclic and acyclic uracil nucleosides that showed very promising activity against HSV-1 compared to acyclovir.     

Effects of the ionization in the tautomerism of uracil: A reaction electronic flux perspective

The one‐step tautomerization processes of uracil and its radical cation and radical anion have been investigated in the light of the reaction force and reaction electronic flux (REF) formalisms. The relative energies of the different tautomers as well as the corresponding tautomerization barriers have been obtained through the use of the G4 high‐level ab initio method and by means of B3LYP/6‐311+G(3df,2p)//B3LYP/6‐311+G(d, p) calculations. Systematically, the enol radical cations are more stable in relative terms than the neutral, due to the higher ionization energy of the diketo forms with respect to the enolic ones. Conversely, the enol radical anions, with the only exception of the 2‐keto‐N1 anion, are found to be less stable than the neutral. The effects of the ionization are also sizable on the tautomerization barriers although this effect also depends on the particular tautomerization process. The reaction force analysis shows that all reactions are mainly activated through structural rearrangements that initiate the electronic activity. This electronic activity is monitored along the reaction coordinate through the REF that obeys a delicate balance between the acid and basic character of the atoms involved in the hydrogen transfer. © 2015 Wiley Periodicals, Inc.     

Heterocyclization of Amidophenacylation Products of Uracil

When uracil is reacted with benzoylamino(chloro)acetophenone, we obtain two amidophenacylation products depending on the condensation conditions. The first product contains an amidophenacyl moiety at the N¹ center, and in the second product two such moieties are located at the N¹ and N³ centers of the uracil. Treatment of these accessible uracil derivatives with phosphorus oxychloride, thionyl chloride, or phosphorus pentasulfide leads to cyclization of the amidophenacyl side group, which is used to synthesize a number of modified pyrimidine bases with 2,5-diphenyloxazole or 2,5-diphenylthiazole residues.     

Eight new crystal structures of 5‐(hydroxymethyl)uracil, 5‐carboxyuracil and 5‐carboxy‐2‐thiouracil: insights into the hydrogen‐bonded networks and the predominant conformations of the C5‐bound residues

In order to examine the preferred hydrogen‐bonding pattern of various uracil derivatives, namely 5‐(hydroxymethyl)uracil, 5‐carboxyuracil and 5‐carboxy‐2‐thiouracil, and for a conformational study, crystallization experiments yielded eight different structures: 5‐(hydroxymethyl)uracil, C₅H₆N₂O₃, (I), 5‐carboxyuracil–N,N‐dimethylformamide (1/1), C₅H₄N₂O₄·C₃H₇NO, (II), 5‐carboxyuracil–dimethyl sulfoxide (1/1), C₅H₄N₂O₄·C₂H₆OS, (III), 5‐carboxyuracil–N,N‐dimethylacetamide (1/1), C₅H₄N₂O₄·C₄H₉NO, (IV), 5‐carboxy‐2‐thiouracil–N,N‐dimethylformamide (1/1), C₅H₄N₂O₃S·C₃H₇NO, (V), 5‐carboxy‐2‐thiouracil–dimethyl sulfoxide (1/1), C₅H₄N₂O₃S·C₂H₆OS, (VI), 5‐carboxy‐2‐thiouracil–1,4‐dioxane (2/3), 2C₅H₄N₂O₃S·3C₆H₁₂O₃, (VII), and 5‐carboxy‐2‐thiouracil, C₁₀H₈N₄O₆S₂, (VIII). While the six solvated structures, i.e. (II)–(VII), contain intramolecular S(6) O—H…O hydrogen‐bond motifs between the carboxy and carbonyl groups, the usually favoured R₂²(8) pattern between two carboxy groups is formed in the solvent‐free structure, i.e. (VIII). Further R₂²(8) hydrogen‐bond motifs involving either two N—H…O or two N—H…S hydrogen bonds were observed in three crystal structures, namely (I), (IV) and (VIII). In all eight structures, the residue at the ring 5‐position shows a coplanar arrangement with respect to the pyrimidine ring which is in agreement with a search of the Cambridge Structural Database for six‐membered cyclic compounds containing a carboxy group. The search confirmed that coplanarity between the carboxy group and the cyclic residue is strongly favoured.