A novel lead for specific anti-HIV-1 agents: 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine

Abstract

Sir:As a result of the clinical efficacy of 3'-azido-3'-deoxythymidine (AZT, retrovir) in the treatment of AIDS (acquired immunodeficiency syndrome) ,1-3 a large number of nucleoside including acyclonucleosides,1"20 (1) Yarchoan, R.; Weinhold, K. J.; Lyerly, H. K.; Gelmann, E.; Blum, R. M.; Shearer, G. M.; Mitsuya, H.; Collins, J. M.; Myers, C. E.; Klecker, R. W.; Markham, P. D.; Durack, D. T.; Lehrman, S. N.; Barry, D. W.; Fischl, M. A.; Gallo, R. C.; Bolognesi, D. P.; Broder, S. Lancet 1986, i, 575-580. (2) Fischl, M. A.; Richman, D. D.; Grieco, M. H.; Gottieb, M. S.; Volberding, P. A.; Laskin, 0. L.; Leedom, J. M.; Groopman, J. E.; Mildvan, D.; Schooley, R. T.; Jackson, G. G.; Durack, D. T.; King, D.; the AZT Collaborative Working Group N. Engl. (36) Pauwels, R.; De Clercq, E.; Desmyter, J.; Balzarini, J.; Goubau, P.; Herdewijn, P.; Vanderhaeghe, H.; Vandeputte, M.

Differential inhibitory effects of TIBO derivatives on different strains of simian immunodeficiency virus

“…For HEPT and its derivative E-EPU [5-ethyl-l-ethoxymethyl-6-(phenylthio)uracil] (Fig. 1), see Miyasaka et aL (1989) and Baba et aL (1991). Stock solutions of all compounds were prepared in DMSO.…”

Human immunodeficiency virus type 1 (HIV-1) strains selected for resistance against the HIV-1-specific [2',5'-bis-O-(tert-butyldimethylsilyl)-3'-spiro- 5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)]-beta-D-pentofurano syl (TSAO) nucleoside analogues retain sensitivity to HIV-1-specific nonnucleoside inhibitors.

“…A number of different structural classes of nonnucleoside analogues-i.e., 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine (HEPT) (1)(2)(3)(4)(5), tetrahydroimidazo [4,5,1-jk] [1,4]benzodiazepin-2(1H)-one and -thione (TIBO) (6,7), nevirapine (8,9), pyridinones (10,11), bis(heteroaryl)piperazine (12), and a-anilinophenylacetamide (13)-have recently been identified as potent and highly specific inhibitors of human immunodeficiency virus type 1 (HIV-1) replication. It has been demonstrated for the HIV-1-specific nonnucleoside derivatives that they interact with a site of HIV-1 reverse transcriptase (RT) that is clearly distinct from the substrate binding site (8,10,(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

Crystal structure of 6-(phenylsulfanyl)-5-propylpyrimidine-2,4(1H,3H)- dione, C13H14N2O2S

“…The chemotherapeutic efficacy of uracil and pyrimidine derivatives is related to their ability to inhibit vital enzymes responsible for DNA biosynthesis such as dihydrofolate reductase (DHFR), thymidylate synthetase (TSase), thymidine phosphorylase (TPase) and reverse transcriptase (RTase). Pyrimidine-2,4-diones and their related derivatives have long been known for their diverse chemotherapeutic activities including antiviral activity against HIV [1][2][3][4][5] and HSV viruses [6]. In addition, potent anticancer [7][8][9][10] and antimicrobial activities [11,12] was observed for several pyrimidine-2,4-diones.…”