Synthesis and anti‐HIV‐1 activity of 1,5‐dialkyl‐6‐(arylselenenyl)uracils and ‐2‐thiouracils

Abstract

The 1,5‐dialkyl‐6‐(arylselenenyl)uracils 10a‐h and ‐2‐thiouracils 10i‐p have been synthesized as potential anti‐HIV‐1 agents. Cyclization of N‐alkyl‐N'‐[3,3‐di(methylthio)‐2‐alkylacryloyl]ureas 6a‐d and ‐thioureas 6e‐h in acetic acid either containing a catalytic amount of methanesulfonic acid at 80°or containing 1 equivalent of methanesulfonic acid at room temperature afforded 1,5‐dialkyl‐6‐(methylthio)uracils 7a‐d in 84–96% yields and 1,5‐dialkyl‐5,6‐dihydro‐6,6‐di(methylthio)‐2‐thiouracils 11a‐d in 88–99% yields, respectively. Oxidation of 7a‐d and 11a‐d with either 3‐chloroperoxybenzoic acid in benzene or aqueous sodium periodate solution in methanol gave 1,5‐dialkyl‐6‐(methylsulfonyl)uracils 8a‐d in 88–98% yields and 1,5‐dialkyl‐6‐(methylsulfinyl)‐2‐thiouracils 12a‐d in 57–73% yields, respectively, which were subsequently treated with arylselenol 9a‐b in ethanolic sodium hydroxide solution to afford 10a‐p in 6099% yields. Of these compounds, 6‐[(3,5‐dimethylphenyl)selenenyl]‐5‐isopropyl‐1‐(3‐phenylpropyl)uracil (10h) inhibited HIV‐1 replication in MT‐4 cells at a 50% effective concentration (EC50) of 0.0006 μM with a selective index of 44833, which is 7.7‐fold more potent than AZT.

Synthesis and Anti-HIV-1 Activity of a Series of 1-Alkoxy-5-alkyl-6-(arylthio)uracils

“…The 6-((3,5-dimethylphenyl)thio) derivative 18 was the most inhibitory to HIV-1 replication with an EC 50 value of 0.064 µM and a selectivity index (SI, ratio of 50% cytotoxic concentration (CC 50 ) to EC 50 ) of 516. However, modification at the 2-or 4-position of the C-6-(phenylthio) ring with a methyl group diminished, or destroyed, the anti-HIV-1 activity; the 6-((2-methylphenyl)thio) derivative 15 was found to be moderately active, and the 6-((4-methylphenyl)thio) Since it has been confirmed that the two methyl groups at the 3-and 5-positions of the C-6-(phenylthio) ring contributed to the maximum activity in these 1-alkoxy-5isopropyl-6-(arylthio)uracils 14-25 as shown previously in the HEPT analogs, [22][23][24][25] we selected a ((3,5-dimethylphenyl)thio) group as the C-6 substituent for the following target compounds 26-49.…”

“…Overall, structure-activity relationships in these 1-alkoxy-5-alkyl-6-(arylthio)uracils are in good agreement with those established in HEPT analogs. 20,[22][23][24][25] When the anti-HIV-1 activity of the most potent compound 18 was compared with that of AZT, DDC, DDI, and HEPT, 18 was 14-fold less potent than AZT, but 3-, 44-, and 130-fold more potent than DDC, DDI, and HEPT, respectively. The inhibitory effect of compound 18 on the replication of HIV-1 (HTLV-III B ) in human peripheral blood mononuclear cells (PBMCs) was evaluated as previously described, 10,17 and the results are shown in Table 5 along with that of AZT.…”

“…14,16 Since the discovery of HEPT as a novel lead for specific anti-HIV-1 agents, a number of HEPT analogs have been synthesized to increase its potency. [17][18][19][20][21][22][23][24][25] Several of these compounds such as 6-((3,5-dimethylphenyl)thio)-1-(ethoxymethyl)-5-ethyluracil and 6-(3,5dimethylbenzyl)-1-(ethoxymethyl)-5-isopropyluracil inhibit HIV-1 replication in the nanomolar concentration range. From synthetic studies of HEPT analogs, it has been found that the presence of the 2′-oxygen atom in the acyclic chain of HEPT is not essential for anti-HIV-1 activity.…”

“…From synthetic studies of HEPT analogs, it has been found that the presence of the 2′-oxygen atom in the acyclic chain of HEPT is not essential for anti-HIV-1 activity. [23][24][25] This result prompted us to synthesize the 1-alkoxy analogs of HEPT to examine the effect of an oxygen atom adjacent to the uracil base on anti-HIV-1 activity since a number of acyclic N-O linked nucleosides show potent and selective antiherpesvirus activity. [26][27][28][29][30] In addition, the N-O linkage of these 1-alkoxy analogs is expected to be chemically and metabolically stable on the basis of a recent report.…”

The Flourishing Syntheses of Non-Nucleoside Reverse Transcriptase Inhibitors

“…49 The alkylation at C-6 using lithiation is dependent on the substituent at N-1, and derivatives with N-1 alkoxy substituents could not be lithiated at C-6. 50,51 The position of the oxygen in the ethoxymethyl substituent at N-1 of the HEPT analogues may thus stabilize the 6-lithiated intermediates. Analogues with different substituents at N-1 have been made by removing the N-1 ethoxymethyl substituent, followed by benzylation at N-3, alkylation at N-1, and finally removal of the N-3 benzyl protection.…”