Because the emergence of drug-resistant mutants has limited the efficacy of non-nucleoside reverse transcriptase inhibitors (NNRTIs), it is essential to develop new antivirals with better drug resistance and pharmacokinetic profiles. Here we designed and synthesized a series of 1-[(2-benzyloxyl/alkoxyl)methyl]-5-halo-6-aryluracils, the HEPT analogues, and evaluated their biological activity using nevirapine and 18 (TNK-651) as reference compounds. Most of these compounds, especially 6b, 7b, 9b, 11b, and 7c, exhibited highly potent anti-HIV-1 activity against both wild-type and NNRTI-resistant HIV-1 strains. Compound 7b, which had the highest selectivity index (SI = 38 215), is more potent than nevirapine and 18. These results suggest that the introduction of a halogen at the C-5 position may contribute to the effectiveness of these compounds against RTI-resistant variants. In addition, meta substituents on the C-6 aromatic moiety could significantly enhance activity against NNRTI-resistant HIV-1 strains. These compounds can be further developed as next-generation NNRTIs with an improved antiviral efficacy and drug-resistance profile.

A series of novel S-DABO analogues (4a1-5a12) have been synthesized by an efficient method and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). The biological testing results clearly indicated that the substitution of halogen at the C5 position of pyrimidine ring could increase the anti-HIV-1 RT activity. The most active compounds showed activity in the low micromole range with IC(50) values (IC(50) 0.18-3.03 microM) comparable to nevirapine (IC(50) 4.12 microM). The docking showed that a new halogen bond was formed between halogen and carbonyl of TYR188 in the HIV-I RT.

A new practical approach to prepare 1,3-(diethoxymethyl)-5-N,N-dimethylamino-6-methyluracil (5) has been realized from 6-methyluracil (1). Compound 5 is a key intermediate material in the synthesis of HIV-1 RT and methionine synthase inhibitors. 6-Methyluracil (1) reacted with HNO3-P2O5 giving 5-nitro-6-methyluracil (2), which alkylated at N-1,N-3 through reaction with ethoxymethyl chloride to give 3. Compound 3 was then reduced through treatment with HCOONH4-Pd/C and the derived C-5 amino group reacted with CH3I to convert into compound 5 in good yield.

A simple method for synthesis of tetracycline Mannich bases by C-2 reacting with primary and secondary amine was reported. Secondary Mannich base was obtained by primary amine reacting with tetracycline hydrochloride in methanol and water. Tertiary Mannich base was obtained by the reaction of secondary amine and tetracycline in t-butanol. The structures of synthesized ten of tetracyline analogs 4～13 had been identified.