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Nasser R. El-Brollosy Omar. A. Al-Deeb Ali A. El-Emam Erik B. Pedersen Paolo La Colla Gabriella Collu Giuseppina Sanna Roberta Loddo 《Archiv der Pharmazie》2009,342(11):663-670
Novel emivirine and TNK-651 analogues 5a – d were synthesized by reaction of chloromethyl ethyl ether and / or benzyl chloromethyl ether, respectively, with uracils having 5-ethyl and 6-(4-methylbenzyl) or 6-(3,4-dimethoxybenzyl) substituents. A series of new uracil non-nucleosides substituted at N-1 with cyclopropylmethyloxymethyl 9a – d , 2-phenylethyloxymethyl 9e – h , and 3-phenylprop-1-yloxymethyl 9i – l were prepared on treatment of the corresponding uracils with the appropriate acetals 8a – c . Some of the tested compounds showed good activity against HIV-1 wild type. Among them, 1-cyclopropylmethyloxymethyl-5-ethyl-6-(3,5-dimethylbenzyl)uracil 9c and 5-ethyl-6-(3,5-dimethylbenzyl)-1-(2-phenylethyloxymethyl)uracil 9g showed inhibitory potency equally to emivirine against HIV-1 wild type. Furthermore, compounds 9c and 9g showed marginal better activity against NNRTI resistant mutants than emivirine. 相似文献
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Molecular Modeling,Synthesis, and Anti‐HIV Activity of Novel Isoindolinedione Analogues as Potent Non‐nucleoside Reverse Transcriptase Inhibitors
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Different isoindolinedione derivatives bearing imine, amide, thioamide, and sulfonamide linkages have been designed in silico using discovery studio software (BIOVIA, San Diego, CA, USA), synthesized, and evaluated for their anti‐HIV activity. SAR studies revealed that the linkages in these molecules did affect their anti‐HIV activity and the molecules having sulfonamide linkages were the most potent HIV‐RT inhibitors as the S=O bonds of the sulfonamide moiety interacted with Lys103 (NH or carbonyl or both) and Pro236; the NH part of the sulfonamide linkage formed bond with carbonyl of Lys101. blood–brain barrier (BBB) plots were also studied, and it was found that all the designed molecules have potential to cross BBB, a very vital criteria for anti‐HIV drugs. In vitro screening was performed using HIV‐1 strain IIIB in MT‐4 cells using the MTT assay, and it was seen that some of these molecules were effective inhibitors of HIV‐1 replication at nanomolar concentration with selectivity indices ranging from 33.75 to 73.33 under in vitro conditions. Some of these molecules have shown good anti‐HIV activity at 3–4 nm concentrations. These derivatives have potential to be developed as lead molecules effective against HIV‐1. Novel isoindolinedione derivatives as probable NNRTIs have been synthesized and characterized. Some of these molecules have shown good anti‐HIV activity at 3–4 nm concentrations. 相似文献
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