Emivirine
(Synonyms: MKC-442) 目录号 : GC64484Emivirine (MKC-442) 是有效的非核苷逆转录酶的抑制剂 (NNRTIs),对dTTP 和 dGTP 依赖性 DNA 或 RNA 聚合酶活性的 Ki 值分别为 0.20 和 0.01 μM。Emivirine 具有有效且选择性的抗 HIV-1 活性。
Cas No.:149950-60-7
Sample solution is provided at 25 µL, 10mM.
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Emivirine (MKC-442) is a non-nucleoside reverse transcriptase inhibitors (NNRTIs) with Ki values of 0.20 and 0.01 μM for dTTP- and dGTP-dependent DNA or RNA polymerase activity, respectively. Emivirine displays potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity[1][2].
Emivirine (EMV) is also specific for HIV-1 RT and was without effect on HIV-2[2].Emivirine (EMV) has no obvious toxicity for human healthy cells[2].
Tthe approximate lethal oral dose of Emivirine (EMV) for rats was ≥3 g/kg for males and 2.5 g/kg for females[2].
[1]. Panita Decha, et al. Theoretical studies on the molecular basis of HIV-1RT/NNRTIs interactions. J Enzyme Inhib Med Chem. 2011 Feb;26(1):29-36.
[2]. G M Szczech, et al. Safety assessment, in vitro and in vivo, and pharmacokinetics of emivirine, a potent and selective nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1. Antimicrob Agents Chemother. 2000 Jan;44(1):123-30.
Cas No. | 149950-60-7 | SDF | Download SDF |
别名 | MKC-442 | ||
分子式 | C17H22N2O3 | 分子量 | 302.37 |
溶解度 | 储存条件 | Store at -20°C | |
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1 mg | 5 mg | 10 mg | |
1 mM | 3.3072 mL | 16.536 mL | 33.0721 mL |
5 mM | 0.6614 mL | 3.3072 mL | 6.6144 mL |
10 mM | 0.3307 mL | 1.6536 mL | 3.3072 mL |
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Synthesis and Antiviral Evaluation of 1-[(2-Phenoxyethyl)oxymethyl] and 6-(3,5-Dimethoxybenzyl) Analogues of HIV Drugs Emivirine and TNK-651
Drug Res (Stuttg) 2016 Apr;66(4):181-8.PMID:26313923DOI:10.1055/s-0035-1559683.
Novel Emivirine analogues 6a, b were synthesized by reacting chloromethyl ethyl ether with 5-ethyl/isopropyl-6-(3,5-dimethoxybenzyl)uracils 5e, f. On the other hand, A series of new TNK-651 analogues 10a-f substituted at N-1 with phenoxyethoxymethyl moiety was prepared on treatment of the corresponding uracils 5a-f with bis(phenoxyethoxy)methane (9). The newly synthesized non-nucleosides were tested for antiviral activity against wild type HIV-1 IIIB as well as the resistant strains N119 (Y181C), A17 (K103N+Y181C), and the triple mutant EFV(R) (K103R+V179D+P225H) in MT-4 cells. Most of the tested compounds showed good activities. Among them 6-(3,5-dimethylbenzyl)-5-ethyl-1-[(2-phenoxyethyl)oxymethyl]uracil (10c) and 6-(3,5-dimethylbenzyl)-5-isopropyl-1-[(2-phenoxyethyl)oxymethyl]uracil (10d) that showed inhibitory potency higher than Emivirine against both wild type HIV-1 and the tested mutant strains, as well as higher activity than efavirenz against EFV(R).
Synthesis and antiviral evaluation of 6-(trifluoromethylbenzyl) and 6-(fluorobenzyl) analogues of HIV drugs Emivirine and GCA-186
Arch Pharm (Weinheim) 2008 Jan;341(1):9-19.PMID:18161905DOI:10.1002/ardp.200700113.
The present study describes the synthesis and antiviral evaluation of a series of novel 6-(3-trifluoromethylbenzyl) and 6-(fluorobenzyl) analogues of the HIV drugs Emivirine and GCA-186. The objective was to investigate whether the fluoro or trifluoromethyl substituents could lead to an improved antiviral activity against HIV-1 wild type and mutants resistant to non-nucleoside RT inhibitors. The biological test results showed that the most of theses compounds showed good activity against wild type HIV-1. Among them, compound 1-(ethoxymethyl)-6-(3-fluorobenzyl)-5-isopropyluracil (9i) showed the largest inhibitory potency (EC(50) = 0.02 microM), resulting equally potent than Emivirine against wild type HIV-1. Furthermore, compound 9i showed marginal better activity against resistant mutants than Emivirine. The key steps in the synthesis of the target compounds were either reaction of an appropriate beta-keto ester with thiourea or a cross-coupling reaction of 6-chloro-2,4-dimethoxypyrimidines with benzylic Grignard reagents.
Design of MKC-442 (Emivirine) analogues with improved activity against drug-resistant HIV mutants
J Med Chem 1999 Nov 4;42(22):4500-5.PMID:10579814DOI:10.1021/jm990192c.
Two analogues of the nonnucleoside inhibitor of HIV-1 RT, MKC-442 (Emivirine), containing different C6 substituents have been designed to be less susceptible to the commonly found drug-resistance mutation of Tyr181Cys. Compound TNK-6123 had a C6 thiocyclohexyl group designed to have more flexibility in adapting to the mutated drug-binding site. GCA-186 had additional 3',5'-dimethyl substituents aimed at forming close contacts with the conserved residue Trp229. Both compounds showed approximately 30-fold greater inhibitory effect than MKC-442 to the Tyr181Cys mutant virus as well as to the clinically important Lys103Asn virus. X-ray crystallographic structure determination of complexes with HIV-1 RT confirmed the predicted binding modes. These strategies might be used to improve the resilience of other NNRTI series against common drug-resistance mutations.
Synthesis of furoannelated analogues of Emivirine (MKC-442)
Arch Pharm (Weinheim) 2004 Mar;337(3):148-51.PMID:15038059DOI:10.1002/ardp.200300815.
Furoannelated analogues 1-alkoxymethyl-7-phenyl-5, 7-dihydro-1H-furo[3, 4-d]-pyrimidine-2, 4-diones of Emivirine (3a, b) were synthesized from the primary alcohols 1-alkoxymethyl-6-benzyl-5-hydroxymethyl-1H-pyrimidine-2, 4-dione (5a, b) using a radical ring closure reaction with Pb(OAc)(4). These analogues are conformationally restricted in order to fix the aromatic substituent of Emivirine in nearly the same position as it is in the case when the complex of Emivirine is bound to HIV-1 RT. However, the anti HIV-1 activities of 3a, b were considerably lower than those of the lead Emivirine.
Multiple pathways in the synthesis of new annelated analogues of 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (Emivirine)
Org Biomol Chem 2003 Aug 21;1(16):2908-18.PMID:12968341DOI:10.1039/b303658h.
Condensation of 3-(3,5-dimethylphenyl)-2-oxocyclopentanecarboxamide (11) with oxalyl chloride and condensation of ethyl 2-benzylamino-5-methyl-3-phenylcyclopent-1-enecarboxylate (17a) with trimethylsilyl isothiocyanate gave 7-(3,5-dimethylphenyl)-6,7-dihydro-5H-cyclopenta[e][1,3]oxazine-2,4-dione (12) and 1-benzyl-5-methyl-7-phenyl-2-thioxo-1,2,3,5,6,7- hexahydrocyclopentapyrimidin-4-one (18a), respectively. Acid catalyzed ring-closure of 6-(4-methyl-1-phenylpent-3-enyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (26) and radical mediated ring-closure of 1,3-bis(benzyloxymethyl)-5-bromo-6-(1-phenylbut-3-enyl)-1H-pyrimidine-2,4- dione (32a) gave 5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-1H-quinazoline-2,4- dione (28) and 1,3-bis(benzyloxymethyl)-5-methyl-7-phenyl-1,5,6,7- tetrahydrocyclopentapyrimidine-2,4-dione (33), respectively. Annelated Emivirine analogues 7-(3,5-dimethylphenyl)-1- ethoxymethyl-1,5,6,7-tetrahydrocyclopentapyrimidine-2,4-dione (4), 1-ethoxymethyl-5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-1H-quinazoline- 2,4-dione (5) and 1-ethoxymethyl-5-methyl-7-phenyl-1,5,6,7- tetrahydrocyclopentapyrimidine-2,4-dione (6) were obtained in few steps from 12, 28 and 18a/33, respectively. These new analogues can be considered as conformationally locaTed analogues of Emivirine. However, the compounds 4 6 showed lower activities against HIV-1 than Emivirine and it is concluded that the locked conformation disfavours activity against HIV-1.