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

Abstract

The excellent activity of 6-amino-3-(3,5-dimethylbenzyl)-1-(4-aminobenzyl)uracil (EC50: 0.010 ± 0.006 µM, SI: >1923) may serve as the basis for conducting further investigations on the behavior of this class of compounds against drug-resistant mutants.

Synthesis and Evaluation of Novel Cyclopropane Nucleoside as Potential Tube Formation Agents

“…[6][7][8]15) Secondary alcohols 3a-d were treated with 2,6-dichloropurine and underwent the Mitsunobu reaction [15][16][17][18] in the presence of PPh 3 and diisopropyl azodicarboxylate (DIAD) to give 9-cyclopropylmethyl-2,6-dichloropurine congeners 4a-d in 29-49% yield. Then, 4c was subsequently treated with methanolic ammonia to obtain the desired product 2c in 67% yield.…”

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

“…21,22 The 1-substituted 6-methylthiotriazine derivatives (3) and 1-substituted 6aminotriazine analogs (4) were essentially synthesized by alkylation at the 1-position of the triazine skeleton of the intermediate (2), using our previously reported method, as shown in Scheme 1. [14][15][16] First, compound (2) was allowed to react with the appropriate alkyl halides (e.g. 4-nitrobenzyl bromide, 4-picolyl chloride, or 4-fluorobenzyl bromide) to yield the corresponding 1-alkylated products (3), 35-98% of which was treated with methanolic ammonia to give the Table 2.…”

“…(EC 50 ¼ 0.010 AE 0.006 mM), compared to the unsubstituted compound 1a (EC 50 ¼ 0.07 AE 0.01 mM) ( Table 1). 16 In contrast, three types of 6-methylthiolated derivatives (3a-c) exhibited considerably less anti-HIV-1 activity than their 6-amino counterparts (4a-c); for example, 3a (N 1 -benzyl-6-methylthiotriazine) was approximately 16 times less potent (EC 50 ¼ 3.0 AE 1.0 mM, SI ¼ 15) than its N 1 -benzyl-6-aminotriazine analog, 4a (EC 50 ¼ 0.19 AE 0.02 mM, SI > 526). The 6-(4-picolyl), 6-(2-picolyl), and 6-(3-picolyl) derivatives 4l-n showed moderate anti-HIV-1 activity with EC 50 values from 0.34 mM to 1.2 mM.…”

“…14,15 Furthermore, N 1 -4aminobenzyl-C6-aminouracil derivatives (1c, Table 1) exhibited superior activities, with EC 50 values of 0.010 AE 0.006 mM. 16 In an ongoing effort to discover potential NNRTIs with high anti-HIV-1 activity and low cytotoxicity, we designed 22 structurally relevant, novel classes of 1-substituted 3-(3,5-dimethylbenzyl)triazine analogs (3a-c, 4a-p, and 5, Table 2), and 3-(4-fluorobenzyl)-1-(4methoxybenzyl)triazine derivatives (6a-b, Table 2) by replacing the uracil skeleton with a triazine moiety, by means of using the biological isostere principle, [17][18][19] as shown in Figure 2. Moreover, it has been confirmed that emivirine bound to HIV-1 RT at the nevirapinebinding site in the X-ray co-crystal structure; 20 thus, preliminary structure-activity relationship studies and molecular modeling analyses using two types of prospective ligands (4c and 5, Table 2) were also performed to explore the major interactions between the nevirapine-binding site in HIV-1 RT and 4c or 5.…”

“…10 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][12][13][14][15][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 AE 0.01 mM and 0.03 AE 0.03 mM, respectively.…”