Synthesis and Anti-HIV-1 Activity of Novel MKC-442 Analogues Containing Alkenyl Chains or Reactive Functionalities in the 6-Benzyl Group

Summary. In an effort to obtain more insight into the anti-HIV efficacy of MKC-442 analogues (1-(alkoxymethyl)-6-benzyluracils), a new series of compounds was synthesized and evaluated for inhibition of HIV-1 replication. The modifications include a reactive center such as an aldehyde or an epoxide substituted at the benzyl group. It was believed that such reactive groups could improve the activity against HIV for the Y181C mutant by forming a covalent bond to the mercapto group in cysteine in the hydrophobic pocket. Unfortunately, only moderate activities were found in cell-based assays for such compounds against wild-type HIV and no activity against the Y181C mutant. However, higher activities were found for a corresponding oxime and the precursor molecules with butenyl and allyloxy substituents in the benzyl group. A few amino-DABO and S-DABO analogues were also synthesized, but they were found inactive against HIV. On leave from Chemistry Department, Faculty of Education Kafr El-Sheikh branch, Tanta University, Kafr El-Sheikh, Egypt A research Center Funded by the Danish National Research Foundation for Studies on Nucleic Acid Chemical Biology     

New Emivirine (MKC-442) Analogues Containing a Tetrahydronaphthalene at C-6 and their Anti-HIV Activity

Summary. An 5-ethyl-2-thiouracil derivative with a 6-(tetrahydronaphthalen-1-yl)methyl substituent was synthesized by condensation of thiourea with an adequate β-ketoester which in turn was synthesized in a single step from (tetrahydronaphthalen-1-yl)acetonitrile. The latter starting material was also used to synthesize an analogously substituted tetrahydronaphthalen-1-yl substituted uracil with a locked conformation. Only the non-nucleoside derivatives prepared from the desulfurized substituted 2-thiouracil showed moderate activity against HIV whereas a corresponding non-nucleoside derivative was devoid of activity against HIV.     

Anti-HIV Active Naphthyl Analogues of HEPT and DABO

Summary.  5-Isopropyl-6-naphthyl uracil and 5-isopropyl-6-naphthyl-2-thiouracil were alkylated to give N-1-(ethoxymethyl and methylthiomethyl) uracil and S²-cyclohexyl-thiouracil, respectively. 5-Ethyl-6-naphthyl uracil and 5-ethyl-6-naphthyl-2-thiouracil afforded N-1-(ethoxymethyl, methoxy-methyl, methylthiomethyl, acetoxyethoxy methyl and hydroxyethoxy methyl) uracil and S²-((2,2- diethoxyethyl), methoxycarbonylmethyl, ethoxycarbonylpropyl, methylthiomethyl, ethoxymethyl, methyl and cyclohexyl)-thiouracil upon alkylation. Received September 25, 2001. Accepted (revised) December 3, 2001     

Synthesis and Anti-HIV-1 Activity of Novel MKC-442 Analogues Containing Alkenyl Chains or Reactive Functionalities in the 6-Benzyl Group

In an effort to obtain more insight into the anti-HIV efficacy of MKC-442 analogues (1-(alkoxymethyl)-6-benzyluracils), a new series of compounds was synthesized and evaluated for inhibition of HIV-1 replication. The modifications include a reactive center such as an aldehyde or an epoxide substituted at the benzyl group. It was believed that such reactive groups could improve the activity against HIV for the Y181C mutant by forming a covalent bond to the mercapto group in cysteine in the hydrophobic pocket. Unfortunately, only moderate activities were found in cell-based assays for such compounds against wild-type HIV and no activity against the Y181C mutant. However, higher activities were found for a corresponding oxime and the precursor molecules with butenyl and allyloxy substituents in the benzyl group. A few amino-DABO and S-DABO analogues were also synthesized, but they were found inactive against HIV.     

Nonnucleoside HIV-1 Reverse Transcriptase Inhibitors, Part 4[1]. Synthesis and Anti-HIV Activity of N-1-β-Carbonyl-6-naphthyl-methyl Analogues of HEPT

Summary.  A series of 6-naphthylmethyl substituted HEPT analogues bearing a β-carbonyl and a terminal phenyl ring or ester groups on the N-1 side chain of uracil were synthesized, and the in vitro anti-HIV activity was evaluated. Most of these HEPTs were considerably less potent and selective or inactive, only a few compounds showed moderate or high activity against HIV-1. The results demonstrated that the anti-HIV-1 activity of 6-naphthylmethyl substituted HEPT analogues was diminished or eliminated when the β-oxygen of N-1 side chain was replaced by a carbonyl group.     

On the Synthesis of 2-Acetyl-4-aryl-6H-1,3,4-thiadiazin-5-ones by Reaction of Nitrilimines with α-Mercapto Alkanoic Acids

Summary.  N′-Arylacetonitrilimines were generated from acetohydrazonyl chlorides and reacted with mercaptoalkanoic acids forming 4-aryl-5-oxo-3-thiahexanoic acids. These were cyclized by reaction with dicyclohexyl carbodiimide yielding 2-acetyl-4-aryl-6H-1,3,4-thiadiazin-5-ones. Received November 13, 2001. Accepted January 9, 2002     

Synthesis of a New Series of Imidazo-[1,5-a]pyrido[2,3-e]pyrazines as Potential Ligands for the GABA Receptor Complex

Summary.  Starting from 2-chloro-3-nitropyridine, 2-isopropyl-1,4-dihydropyrido[2,3-b]pyrazin-2(3H),3-dione was synthesized. This compound was reacted with potassium tert-butoxide and diethyl chlorophosphate to afford an intermediate dihydropyrido[2,3-b]pyrazin-2-ylphosphate derivative which in turn furnished the desired 1,2,4-oxadiazolylimidazo[1,5-a]pyrido[2,3-e]pyrazine derivatives with 5-alkyl-3-isocyanomethyl-1,2,4-oxadiazoles in the presence of additional tert-butoxide. The title compounds are potential ligands for the γ-aminobutyric acid A/benzodiazepine receptor complex. Received November 26, 2001. Accepted December 3, 2001     

Synthesis of 5-(6-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-4-amino-1,2,4-triazole-3-thione and its Reactions with Polyfunctional Electrophiles

Summary.  In the reaction of 5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-1,3,4-oxadiazole-2-thione with hydrazine hydrate, 5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-4-amino-1,2,4-triazole-3-thione was formed. The reactions of the latter with ethyl bromoacetate and chloroacetonitrile in the presence of triethylamine proceeded under formation of the corresponding S-alkylated derivatives, whereas from its reaction with ω-bromoacetophenone and ethyl 4-chloroacetoacetate triazolothiadiazines were obtained. Treatment of the title compound with ethyl 2-chloroacetoacetate led to the formation of 5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-4-N-acetylamino-(3-ethoxy-carbonylmethylthio)-1,2,4-triazole. Performing of the latter reaction without basic catalyst gave a triazolothiadiazine. Treatment of the S-alkylated derivatives with sodium methoxide resulted in triazolothiadiazines via a cyclocondensation reaction. Received November 20, 2000. Accepted January 15, 2001     

Novel High Energy Intermediate Analogues with Triazasterol-related Structures as Inhibitors of the Ergosterol Biosynthesis V [1]. Synthesis of Hexahydro-5H-imidazo[1'', 2'': 1,2]pyrimido-[4,3-a]isoquinolines and 1-Alkyl Analogues Representing New 8,13,15-Triazasteroids

Summary. The synthesis of 1,2,6,10b,11,12-hexahydro-5H-imidazo[1,2:1,2]pyrimido[4,3-a]isoquinolines representing new types of 8,13,15-triazasteroids is described. The tetracyclic title compounds were prepared from 4-(2-hydroxyalkylamino)tetrahydro-2H-pyrimidoisoquinolines, which furnish after conversion to the corresponding bromoalkylamino compounds and base-catalyzed intramolecular nucleophilic displacement cyclization of the latter the desired 1-substituted 8,13,15-triazasteroids with aromatic ring A. The structures of the compounds were proved and assigned on the basis of homo- and heteronuclear correlated 1D and 2D NMR experiments. The title compounds represent triaza-analogues of selected high energy intermediates (HEI) of steroidal substrates formed during the enzymatic transformation of squalene into ergosterol and are designed to act as inhibitory mimicries of HEIs and potential antimycotics.Received March 4, 2003; accepted March 7, 2003 Published online June 23, 2003