Synthesis of Certain 6-(Arylthio)uracils and Related Derivatives as Potential Antiviral Agents

GPR84, a Gi protein-coupled receptor that is activated by medium-chain (hydroxy)fatty acids, appears to play an important role in inflammation, immunity, and cancer. Recently, 6-octylaminouracil (4) has been reported to act as an agonist at GPR84. Here, we describe the synthesis of 69 derivatives and analogs of 4, 66 of which represent new compounds. They were evaluated in (a) cyclic adenosine monophosphate accumulation and (b) β-arrestin assays in human GPR84-expressing cells. Potent nonbiased as well as G protein-biased agonists were developed, e.g., 6-hexylamino-2,4(1H,3H)-pyrimidinedione (20, PSB-1584, EC50 5.0 nM (a), 3.2 nM (b), bias factor: 0) and 6-((p-chloro- and p-bromo-phenylethyl)amino)-2,4(1H,3H)-pyrimidinedione (47, PSB-16434, EC50 7.1 nM (a), 520 nM (b), bias factor: 1.9 = 79-fold Gi pathway-selective; 48, PSB-17365, EC50 2.5 nM (a), 100 nM (b), bias factor 1.3 = 20-fold selective), which were selective versus other free fatty acid-activated receptors. Compounds 20 and 48 were found to be metabolically stable upon incubation with human liver microsomes. A pharmacophore model was created on the basis of structurally diverse lipidlike GPR84 agonists.

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“…Compounds 13 and 69 , have previously been described. Compound 5 was synthesized according to a reported synthetic procedure .…”

Section: Experimental Sectionmentioning

confidence: 99%

6-(Ar)Alkylamino-Substituted Uracil Derivatives: Lipid Mimetics with Potent Activity at the Orphan G Protein-Coupled Receptor 84 (GPR84)

et al. 2018

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“…Several pyrimidine and pyrimidine-related drugs are currently employed for the treatment of various diseases. Numerous pyrimidine-based derivatives have been developed as antiviral agents against human immunodeficiency viruses (HIV) [1][2][3][4][5], hepatitis B viruses (HBV) [6,7], hepatitis C viruses (HCV) [8] and herpes simplex viruses (HSV) [9,10]. In addition, several pyrimidine derivatives have long been utilized as potent anticancer drugs [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

“…1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) and its related analogues [26][27][28][29] were discovered as potent and selectively active agents against HIV-1 infections. In continuation of our ongoing interest in the pharmacological and structural properties of pyrimidine and uracil derivatives [3,4,17,18,[30][31][32][33][34][35], we synthesized the title compound as the more lipophilic 5-propyl HEPT analog for evaluation as a potential chemotherapeutic agent [36].…”

Section: Introductionmentioning

confidence: 99%

Molecular structure, vibrational spectra, NBO, Fukui function, HOMO-LUMO analysis and molecular docking study of 6-[(2-methylphenyl)sulfanyl]-5-propylpyrimidine-2,4(1H,3H)-dione

AlRabiah

Muthu²,

Al-Omary

et al. 2017

Maced. J. Chem. Chem. Eng.

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Theoretical and experimental FT-IR and FT-Raman vibrational spectral analysis of 6-[(2-methylphenyl)sulfanyl]-5-propylpyrimidine-2,4(1H,3H)-dione have been recorded in the region 4000-400 cm-1 and 4000-100 cm-1 insolid phase. The molecular geometrical parameters, bond length, bond angle and vibrational wave numbers, harmonic vibrational frequency were investigated using the density functional theory B3LYP method with the 6-311++G(d,p) basis set. The stability of the molecule has been investigated using the natural bond orbital (NBO) analysis. The electronic properties such as HOMO-LUMO energies were determined by the time-dependent DFT approach. The thermodynamical properties and the first order hyperpolarizability and molecular electrostatic potential (MEP) of the title compound were also studied. The electron density-based local reactivity descriptors such as the Fukui functions were calculated to explain the chemical selectivity or reactivity site in the molecule. The molecule orbital contributions were investigated using the total density of states (TDOS), the sum of 𝛼 and 𝛽 electron density of states (𝛼𝛽DOS). The molecular docking (ligand-protein) simulations have been performed using the SWISSDOCK server. The full fitness (FF) score and hydrogen bonding interaction and binding affinity values revealed that title compound can act as potential inhibitor against HIV-1 protease.

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