- 2-Arylthio-5-iodo pyrimidine derivatives as non-nucleoside HBV polymerase inhibitors
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In this study, a series of 2-arylthio-5-iodo pyrimidine derivatives, as non-nucleoside hepatitis B virus inhibitors, were evaluated and firstly reported as potential anti-HBV agents. To probe the mechanism of active agents, DHBV polymerase was isolated and a non-radioisotopic assay was established for measuring HBV polymerase. The biological results demonstrated that 2-arylthio-5-iodo pyrimidine derivatives targeted HBV polymerase. In addition, pharmacophore models were constructed for future optimization of lead compounds. Further study will be performed for the development of non-nucleoside anti-HBV agents.
- Wang, Jie,Zhang, Liang,Zhao, Jianxiong,Zhang, Yu,Liu, Qingchuan,Tian, Chao,Zhang, Zhili,Liu, Junyi,Wang, Xiaowei
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p. 1573 - 1578
(2018/02/21)
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- 5-Iodo-2-arylalkylthio-6-aryl pyrimidin-4(3H)-ones as non-nucleoside anti-HBV agents
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A series of 5-iodo-2-arylalkylthio-6-aryl pyrimidin-4(3H)-ones, which can be considered as S-DABO derivatives, have been synthesized and their antiviral effect on extracellular HBV DNA was evaluated using the HepAD38 cell system. Compounds 6d1 and 6e3 exhibited more potent anti-HBV activity than lamivudine with EC50 values of 0.376 μM and 0.469 μM, respectively. In addition, inhibition of intracellular HBV DNA, pgRNA, HBeAg and HBsAg of compounds 6d1 and 6e3 was examined to initially infer the action mechanism. RT-PCR analysis of pgRNA demonstrated that these new S-DABO analogues could not interfere with HBV transcription. TRFIA analysis revealed that compounds 6d1 and 6e3 effectively reduced the secretion of HBeAg. These results demonstrated that 5-iodo-2-arylalkylthio-6-aryl pyrimidin-4(3H)-ones possess anti-HBV abilities and could be used as potential agents against HBV infection with an additional merit of low cytotoxicity.
- Zhang, Yu,Sun, Xuefeng,Fan, Ningning,Zhao, Jianxiong,Tu, Jing,Chen, Xiangmei,Liu, Junyi,Wang, Xiaowei
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p. 1438 - 1443
(2015/08/18)
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- Synthesis and biological evaluation of novel 2-Arylalkylthio-5-iodine-6- substituted-benzyl-pyrimidine-4(3H)-ones as Potent HIV-1 Non-Nucleoside reverse transcriptase inhibitors
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A novel series of 2-arylalkylthio-5-iodine-6-substitutedbenzyl-pyrimidine- 4(3H)- ones (S-DABOs) 8a-x had been synthesized via an efficient method. Their biological activity against HIV virus and RT assay were evaluated. Some compounds, especially 8h, 8l and 8n, displayed promising activity against HIV-1 RT with IC50 values in a range of 0.41 μM to 0.71 iM, which were much better than that of nevirapine. Molecular modeling studies revealed that the binding mode would be affected via forming an additional hydrogen bond by incorporating an oxygen atom on the C-2 side chain. The biological activity was in accordance with the docking results.
- Zhang, Liang,Tang, Xiaowan,Cao, Yuanyuan,Wu, Shaotong,Zhang, Yu,Zhao, Jianxiong,Guo, Ying,Tian, Chao,Zhang, Zhili,Liu, Junyi,Wang, Xiaowei
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p. 7104 - 7121
(2014/07/08)
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- Design, synthesis, and biological evaluation of 1-[(2-benzyloxyl/alkoxyl) methyl]-5-halo-6-aryluracils as potent HIV-1 non-nucleoside reverse transcriptase inhibitors with an improved drug resistance profile
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Because the emergence of drug-resistant mutants has limited the efficacy of non-nucleoside reverse transcriptase inhibitors (NNRTIs), it is essential to develop new antivirals with better drug resistance and pharmacokinetic profiles. Here we designed and synthesized a series of 1-[(2-benzyloxyl/alkoxyl)methyl]- 5-halo-6-aryluracils, the HEPT analogues, and evaluated their biological activity using nevirapine and 18 (TNK-651) as reference compounds. Most of these compounds, especially 6b, 7b, 9b, 11b, and 7c, exhibited highly potent anti-HIV-1 activity against both wild-type and NNRTI-resistant HIV-1 strains. Compound 7b, which had the highest selectivity index (SI = 38 215), is more potent than nevirapine and 18. These results suggest that the introduction of a halogen at the C-5 position may contribute to the effectiveness of these compounds against RTI-resistant variants. In addition, meta substituents on the C-6 aromatic moiety could significantly enhance activity against NNRTI-resistant HIV-1 strains. These compounds can be further developed as next-generation NNRTIs with an improved antiviral efficacy and drug-resistance profile.
- Wang, Xiaowei,Zhang, Jianfang,Huang, Yang,Wang, Ruiping,Zhang, Liang,Qiao, Kang,Li, Li,Liu, Chang,Ouyang, Yabo,Xu, Weisi,Zhang, Zhili,Zhang, Liangren,Shao, Yiming,Jiang, Shibo,Ma, Liying,Liu, Junyi
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p. 2242 - 2250
(2012/05/20)
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- Synthesis and biological evaluation of novel C5 halogen-functionalized S-DABO as potent HIV-1 non-nucleoside reverse transcriptase inhibitors
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A series of novel S-DABO analogues (4a1-5a12) have been synthesized by an efficient method and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). The biological testing results clearly indicated that the substitution of halogen at the C5 position of pyrimidine ring could increase the anti-HIV-1 RT activity. The most active compounds showed activity in the low micromole range with IC50 values (IC50 0.18-3.03 μM) comparable to nevirapine (IC50 4.12 μM). The docking showed that a new halogen bond was formed between halogen and carbonyl of TYR188 in the HIV-I RT.
- Qin, Hua,Liu, Chang,Guo, Ying,Wang, Ruiping,Zhang, Jianfang,Ma, Liying,Zhang, Zhili,Wang, Xiaowei,Cui, Yuxin,Liu, Junyi
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scheme or table
p. 3231 - 3237
(2010/07/05)
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- Synthesis and biological evaluation of novel 2-arylalkylthio-4-amino-6-benzyl pyrimidines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors
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Novel 2-aryalkylthio-4-amino-6-benzylpyrimidines (3a-i), which can be considered as S-DABO and TMC-125 analogue hybrid molecules, have been designed and synthesized as inhibitors of HIV-1 RT. The results clearly indicated that the changes at the N3/C4 position of pyrimidine ring could affect the hydrogen bonds strength and number between N3/C4 and the Lys101 residue which are indispensable for anti-HIV-1 RT activity. The biological activity results are also in accordance with the docking study.
- Qin, Hua,Liu, Chang,Zhang, Jianfang,Guo, Ying,Zhang, Siwei,Zhang, Zhili,Wang, Xiaowei,Zhang, Liangren,Liu, Junyi
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scheme or table
p. 3003 - 3005
(2010/08/05)
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- Does the 2-methylthiomethyl substituent really confer high anti-HIV-1 activity to S-DABOs?
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S-DABO derivatives containing the methylthiomethyl (MTM) group have been synthesized and tested for anti-HIV-1 activity in cell-based assay (MTT and p24 assays) and for their capability to target the HIV-1 reverse transcriptase in enzyme assays. Data of experiments lead to the conclusion that the introduction of a 2-MTM-thio side chain is not sufficient per se to significantly increase S-DABO's potency. Nevertheless, potent MTM-S-DABOs can be obtained by introducing a 2,6-difluorophenylmethyl moiety as a C-6 substituent.
- Sbardella, Gianluca,Mai, Antonello,Artico, Marino,Massa, Silvio,Marceddu, Tiziana,Vargiu, Laura,Marongiu, Maria Elena,La Colla, Paolo
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- Synthesis and Anti-HIV-1 Activity of Thio Analogues of Dihydroalkoxybenzyloxopyrimidines
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Various thio analogues of dihydroalkoxybenzyloxopyrimidines (DABOs), a new class of nonnucleoside reverse transcriptase inhibitors, were found to selectively inhibit the HIV-1 multiplication in vitro.Among the C-5 H-substituted 6-benzyl-3,4-dihydro-4-oxopyrimidines, the introduction of alkylthio or cycloalkylthio substituents at C-2 of the pyrimidine ring led to derivatives (S-DABOs) which were up to 10-fold more potent than the alkoxy or cycloalkyloxy counterparts.The further introduction of a methyl group at the 3'-position of the benzyl portion of 2-(alkylthio)-6-benzyluracils reduced the cytotoxicity leading to more selective compounds.Among C-5 methyl-substituted S-DABOs, numerous derivatives showed EC50 values as low as 0.6 μM and lacked cytotoxicity at doses as high as 300 μM.In the C-5 double methyl-substituted series, a more pronounced cytotoxicity was observed and the further introduction of a methyl at the 3'-position in the benzylidene group resulted in total loss of antiviral activity.S-DABOs, namely 2-(alkylthio)-6-benzyl-3,4-dihydro-4-oxopyrimidines, were synthesized by reacting proper methyl (phenylacetyl)acetates or their 2-methyl compounds with thiourea to afford 6-benzyl-4-oxo-1,2,3,4-tetrahydro-2-thiaoxopyrimidines or the related 5-methyl derivatives.Treatment of the latter derivatives with alkyl or cycloalkyl halides in alkaline medium gave the required title compounds.
- Mai, Antonello,Artico, Marino,Sbardella, Gianluca,Massa, Silvio,Loi, Anna Giulia,et al.
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p. 3258 - 3263
(2007/10/03)
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- Tetrahydropyrimidine derivatives
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The invention provides a fungicidal composition comprising a carrier and, as active ingredient, certain tetrahydropyrimidine derivatives of the general formula STR1 or an acid-addition salt or metal salt complex thereof, in which n is 0, 1, 2 or 3; R represents an optionally substituted alkyl, aryl or aralkyl group; R1 represents a hydrogen atom or an optionally substituted alkyl or aralkyl group; R2 represents an optionally substituted aryl group; p is 0 or 1; X represents a group --NR3 -- or --NR3 --NR3 -- where each R3 independently represents a hydrogen atom or an optionally substituted alkyl, aryl or aralkyl group or R1 and (X)p --A--R2 together represent a group --(CR4 R5)q --N(A--R2)-- where q is 2 or 3 and each of R4 and R5 is independently selected from a group consisting of hydrogen atoms and optionally substituted alkyl groups; and A represents a group --(CR6 R7)m -- where m is 0, 1, 2, 3 or 4 and each of R6 and R7 is independently selected from a group consisting of hydrogen atoms and optionally substituted alkyl groups.
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