Synthesis and anti‐HIV‐1 and anti‐HCMV Activity of 1‐Substituted 3‐(3,5‐Dimethylbenzyl)uracil Derivatives.

Abstract

3-(3,5-Dimethylbenzyl)uracil (3) was treated with alkyl halides in the presence of alkali to give 1-substituted congeners. Condensation of 3 with alcohols using the Mitsunobu reaction was also employed as an alternative method. The anti-HIV-1 activity of 1-substituted analogues of 3-(3,5-dimethylbenzyl)uracil was evaluated according to previously established procedures. It appeared that the nitrogen of the 1-cyanomethyl group is important for anti-HIV-1 activity, suggesting interaction with the amino acid residue of HIV-1 reverse transcriptase. 1-Arylmethyl derivatives also showed good anti-HIV-1 activity; and that of 2-and 4-picolyl derivatives was particularly excellent. These results were confirmed by Docking Studies using the program, Glide ligand docking jobs, which suggests hydrogen bonding between amide N-H of Lys 101 and nitrogen of the cyanomethyl and picolyl group.

Synthesis of 1-benzyl-3-(3,5-dimethylbenzyl)Uracil Derivatives with Potential Anti-HIV Activity

“…Then, compound 1 was treated with benzyl bromide to give the corresponding 1-benzylated congeners ( 2 ) in 55% yield as previously reported by Ichikawa et al [10]. This result indicates that the electron-withdrawing chlorine atom facilitates the dissociation of N 1 -H to produce an intermediary uracil-1-anion [7]. Compound 2 was condensed with 3,5-dimethylbenzyl alcohol using the Mitsunobu reaction [11] to afford 3-(3,5-dimethylbenzyl) congener ( 3a ).…”

“…Based on the estimation that the hydrogen bond accepting nitrogen of the cyanomethyl group might be related to the strong anti-HIV-1 activity, the introduction of 2-picolyl group or 4-picolyl group at N 1 -position of the uracil analogue has been investigated and resulted in further elevation of anti-HIV-1 activity. These results were confirmed by a computing science method, in which the docking energy of a substrate on HIV-1 RT has been calculated [7].…”

“…We have previously demonstrated that some novel 1,3-disubstituted uracils selectively inhibit HIV-1 replication in cell cultures [6,7]. In this report, hydrogen bonding interaction (H-bond) between ligand and amide group of Lys 101 residue as well as the hydrophobic interaction is important for the binding of uracil derivatives to HIV-1 RT.…”

Design, synthesis, and anti-HIV-1 activity of 1-aromatic methyl-substituted 3-(3,5-dimethylbenzyl)uracil and N-3,5-dimethylbenzyl-substituted urea derivatives

“…Therefore, we have actively investigated the development of an anti-HIV-1 agent using the structure-activity relationship (SAR) studies of 1,3-disubstituted and 1,3,6-trisubstituted uracils. [12][13][14][15] We have demonstrated that the 3,5-dimethylbenzyl group at the 3-position of the uracil skeleton plays an important role in the enhancement of anti-HIV-1 activity; notably, substitution at the 1-position (e.g. with a benzyl, cyanomethyl, or 4-picolyl group) of 3- (3,5dimethylbenzyl)uracil to obtain 1a-c resulted in good antiviral activity against HIV-1.…”

Design, synthesis, and anti-HIV-1 activity of 1-substituted 3-(3,5-dimethylbenzyl)triazine derivatives

“…We also continued the search for an anti-HIV-1 agent using the structure–activity relationships of the 1,3-disubstituted and 1,3,6-trisubstituted uracils. 11–16 We have demonstrated that the 3,5-dimethylbenzyl group at the N 3 -position and the amino group at the C6-position of the uracil skeleton play an important role in enhancing the anti-HIV-1 activity. Notably, substitution at the 1-position (with a benzyl or 4-picolyl group) of 6-amino-3-(3,5-dimethylbenzyl)uracil to obtain 1a–b (Table 1) yielded satisfactory anti-HIV-1 activity, with EC 50 values of 0.07 ± 0.01 µM and 0.03 ± 0.03 µM, respectively.…”