1,721,121 research outputs found
Synthesis and antiviral evaluation of 1-[(2-Phenoxyethyl)oxymethyl] and 6-(3,5-Dimethoxybenzyl) analogues of HIV drugs emivirine and TNK-651
No full textNovel 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 EFVR (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
Synthesis and anti-HIV-1 activity of new fluoro-HEPT analogues: an investigation on fluoro versus hydroxy substituents
No full textCoupling of 6-benzyl-5-hydroxymethyluracil (1) with formaldehyde acetals followed by fluorination using (diethylamino)sulfur trifluoride (DAST) afforded 1-alkenyloxymethyl and 1-propargyloxymethyl 5-fluoromethyl-6-benzyluracils 3a-c. 6-(3,5-Dimethylbenzyl)-5-ethyl-1-[(2-fluoroethoxy)methyl]pyrimidine-2,4(1H,3H)-dione (6) was synthesized by fluorination of the corresponding hydroxy derivative 5. Sonogoshira reaction was performed on 6-(3,5-dimethylbenzyl)-5-ethyl-1-(4-iodobenzyl)uracil (7) with propargyl alcohol to afford 8 which was fluorinated to give the fluoro propargyl derivative 9. Compound 7 was synthesized by N1-alkylation of the corresponding uracil. Significant activity was found against HIV-1 except for compounds with 5-hydroxymethyl and 5-fluoromethyl substituents
Novel Synthesis and Anti-HIV-1 Activity of 2-Arylthio-6-benzyl-2,3-dihydro-1H-pyrimidin-4-ones (Aryl S-DABOs)
No full textThe synthesis and the anti-HIV-1 activity of a series of 2-arylthio-6-benzyl-2,3-dihydro-1H-pyrimidin-4-ones (aryl S-DABOs) are reported. These compounds were synthesized via a coupling reaction of the corresponding 6-benzyl-2-thiouracils with aryl iodides in the presence of neocuproine hydrate, copper(I) iodide, and sodium tert-butoxide. Target compounds showed moderate activity against HIV-1
Synthesis and Anti-HIV-1 activity of novel new MKC-442 analogues containing alkenyl chains or reactive functionalities in the 6-benzyl group
No full textIn an effort to obtain more insight into the anti-HIV efficacy of MKC-442 analogues (1-(alkoxymethyl)-6-benzyluracils), a new series of compounds was synthesized and evaluated for inhibition of HIV-1 replication. The modifications include a reactive center such as an aldehyde or an epoxide substituted at the benzyl group. It was believed that such reactive groups could improve the activity against HIV for the Y181C mutant by forming a covalent bond to the mercapto group in cysteine in the hydrophobic pocket. Unfortunately, only moderate activities were found in cell-based assays for such compounds against wild-type HIV and no activity against the Y181C mutant. However, higher activities were found for a corresponding oxime and the precursor molecules with butenyl and allyloxy substituents in the benzyl group. A few amino-DABO and S-DABO analogues were also synthesized, but they were found inactive against HIV
Synthesis and Anti-HIV-1 Activity of 1-Substiuted 6-(3-Cyanobenzoyl) and [(3-Cyanophenyl)fluoromethyl]-5-ethyl-uracils
No full text-Substiuted 6-(3-cyanobenzoyl) and [(3-cyanophenyl)fluoromethyl]-5-ethyl-uracils were synthesized and evaluated in cell-based assays against HIV-1 wild-type and its clinically relevant non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants. Some of the synthesized compounds showed activity against HIV-1 wild-type in the same range as Emivirine (MKC-442). 3-{[3-(Allyloxymethyl)-5-ethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]fluoromethyl}-benzonitrile 11b showed moderate activity against the Y181C HIV-1 mutant strain
Synthesis of some novel 2,6-disubstituted pyridazin-3-ones as TMC120 analogues
No full textDifferent analogues of TMC120 derived from pyridazin-3(2H)-one rings were synthesized by coupling of 3,6-dichloropyridazine with arylacetonitriles, phenols and/or aniline derivative followed by hydrolysis and alkylation with different benzyl bromide derivatives
Synthesis and anti-HIV-l activity of 1,3-phenylene bis-uracil analogues of MKC-442
No full textReaction of 1,3-phenylenediacetonitrile with the zinc organometallic reagent of ethyl 2-bromobutyrate afforded the 1,3-phenylene-bis(acetoacetate) 2 which was used as the starting material for the synthesis of 1,3-phenylene-bis[6-(2-thiouracil)] 4. Desulphurization of 4 gave the corresponding bis-uracil 6, which after silylation was N-1 alkylated with bis(allyoxy)methane using TMS-triflate as the catalyst or with chloromethyl ethyl ether to give the MKC-442 analogues 7 and 9. The amino-DABO and S-DABO derivatives 11, 12a,b and 14 were also synthesized. The anti-HIV-1 activity test showed that when MKCM42 analogues were constructed with 1,3-phenylene in all cases they were detrimental to have activity against HIV-1
Synthesis and anti-HIV-1 activity of new MKC-442 analogues with an alkynyl-substituted 6-benzyl group
No full textSynthesis and antiviral activities are reported of a series of 6-(3-alkynyl benzyl)-substituted analogues of MKC-442 (6-benzyl-1-(ethoxymethyl)-5-isopropyluracil), a highly potent agent against HIV. The 3-alkynyl group is assumed to give a better stacking of the substituted benzyl group to reverse transcriptase (RT) and this was believed to improve antiviral activity against HIV-1. The bromo derivatives, 5-alkyl-6-(3-bromo-benzyl)-1-ethoxymethyl derivatives 7a, b and 5-alkyl-6-(3-bromobenzyl)-1-allyloxymethyl derivatives 9a, b, showed activity against HIV on the same level as their corresponding analogues 10a-d with a 3-trimethylsilylalkynylbenzyl substituent and their desilylated analogues 11a-d. However, they all showed activity against HIV-1 wild type in the range of more than 10fold lower than the one of MKC-442. Moderate activity against Y181C and Y181C + K103N mutated strains was also observed and, in some cases, they were marginally better than those found for MKC-442. A few amino-DABO and S-DABO analogues were also synthesized but they were found to be inactive against HIV
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