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We report a study of the influence of Lewis acids upon the regioselectivity of ring opening of quinolinic[2,3]anhydrides to provide 2-(isopropoxycarbonyl)-nicotinic acids. In the presence of stoichiometric amounts of indium trifluoromethanesulfonate or lanthanum trifluoromethanesulfonate, the desired 2-position ester was generated with greater than 95:5 regioselectivity. This methodology was also applied to 6-methyl-[2,3]-quinoline to provide similar results.

A series of novel 1′-substituted analogues of 4-aza-7,9-dideazaadenosine C-nucleoside are prepared and tested in antiviral assays.

The conversions proceed via mono ester (II) by either nucleophilic or electrophilic alkylation to produce a broad spectrum of amino acid biosteres.

A novel synthetic methodology for the hydroxymethyl substituted acyclic acetal functionality was developed, The rationally designed phosphonate analogue 3 of ganciclovir monophosphate was highly active against human cytomegalovirus.

The synthesis of 9-[(2R,5R)-2,5-dihydro-5-(phosphonomethoxy)-2-furanyl]-2,6-diaminopurine ( 2 ) is described. This compound exhibited good inhibitory activity against HIV replication in MT-4 cells.

Regiospecific synthesis of alkylated A ring of arotinoids has been achieved by using Me3Al-TMSOSO2CF3 as a key reagent for conversion of carbonyl to a geminal dimethyl functionality.

Aromatic analogues of sialic acid ( 2 and 3 ) have been synthesized as potential influenza neuraminidase inhibitors. Whereas compound 2 exhibited good neuraminidase inhibitory activity, compound 3 , possessing the glycerol side chain at the C 5 position, was not a neuraminidase inhibitor.

Carbocyclic analogues as transition state mechanism based inhibitors of 3-deoxy-D-manno-2-octulosonate-8-phosphate synthase were designed, synthesized, and evaluated for their biological activity.

1,4,5,6-Tetrahydropyridazine derivative 15 and its C-5 epimer 19, which possessed side chains similar to GS4071, were synthesized via a hetero Diels-Alder reaction, and evaluated as influenza neuraminidase inhibitors. Compounds 15 and 19 exhibited a microM range of influenza neuraminidase inhibitory activity.

The total synthesis for the determination of the absolute stereochemistry of a GS 4104 metabolite 3 is described. In addition, the influenza neuraminidase inhibitory activity of 3 and related intermediates are reported.

GS-9148 (2'-Fd4AP, 4) has been identified as a nucleoside phosphonate reverse transcriptase (RT) inhibitor with activity against wild-type HIV (EC(50)=12 microM). Unlike many clinical RT inhibitors, relevant reverse transcriptase mutants (M184V, K65R, 6-TAMs) maintain a susceptibility to 2'-Fd4AP that is similar to wild-type virus. The 2'-fluorine group was rationally designed into the molecule to improve the selectivity profile and in preliminary studies using HepG2 cells, compound 4 showed no measurable effect on mitochondrial DNA content indicating a low potential for mitochondrial toxicity.

A novel class of tri-cyclic HIV integrase inhibitors were designed based on conformational analysis of 1,6-naphthyridine carboxamide compound L-870810 and docking the designed inhibitor into the active site of our integrase enzyme model. The efficient syntheses of pyrroloquinoline tri-cyclic analogs are described. The SAR studies resulted in the identification of a lead compound that is more potent and more soluble than L-870810.

This communication details both the syntheses and biological evaluation of a novel class of HIV-1 integrase inhibitors. When the quinoline moiety is replaced with the quinoxoline moiety, the antiviral activity is significantly compromised. Similarly, introduction of imidazole to replace the pyridine ring is deleterious to the potency of the compound against the enzyme. Substitution at the 3-position of the pyridine has been investigated. The presence of the pyridine ring in the tricyclic core is preferred for antiviral activity against HIV integrase.

As part of our continuing work in the area of influenza neuraminidase inhibitors, a series of C3-aza inhibitors possessing a cyclic amine side chain was synthesized and evaluated for influenza neuraminidase inhibitory activity. Analogues possessing a six-, seven- and eight-membered ring, 4c–e, respectively, at the C3 position exhibited excellent influenza B neuraminidase inhibition.

The synthesis of (S)-9-[4-hydroxy-3-(phosphonomethoxy)butyl]guanine (3), starting from (S)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (4), is described. Alkylation of trityl derivative 7 with (diethylphosphono)methyl triflate provided phosphonate 8, which was readily converted to mesylate 12 in three steps. Nucleophilic substitution of the mesylate group of 12 by 2-amino-6-chloropurine sodium salt led to (S)-2-amino-6-chloro-9-[3-[(diethyl-phosphono)methoxy]-4-(tetrahydro- 2H-pyran-2-yloxy)butyl]purine (13). Sequential treatment of 13 with trimethylsilyl bromide and then with 2 N HCl furnished 3. Preliminary in vitro screening indicated that 3 exhibited a potent activity against human cytomegalovirus (HCMV) but was not active against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). The adenine and cytosine derivatives (14 and 15) did not exhibit activity against HSV-1 and -2 and HCMV.

A series of 9-(phosphonoalkyl)purines, which are analogues of 9-[2-(phosphonomethoxy)ethyl]purines (guanine, PMEG, 1; adenine, PMEA, 2), were synthesized. The analogues were tested for activity against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), human cytomegalovirus (HCMV), Rauscher murine leukemia virus (R-MuLV), and human immunodeficiency virus type 1 (HIV-1). With variations in the length of the alkyl chain, the optimal activity was achieved with two carbons between the purine base and the phosphonomethoxy functionality. Despite the structural similarity and the close pKa2 value of 8 to that of PMEG, no phosphorylation of 8 was observed by the bovine brain guanylate kinase. Since all isosteric analogues of PMEG (7-9) were not inhibitory against HSV-1 and HSV-2, the presence of the 3'-oxygen atom in the PME purines proved critical for anti-HSV activity. Introduction of the 1'-methyl group on the PMEG side chain significantly reduced its anti-HSV activity. Analogue 11, which is a mimic of the phosphate by incorporation of the alpha,alpha-difluoro carbon, was ineffective against HSV-1 and HSV-2. These results suggest that the structural requirements of PME purines for anti-HSV activity appear to be very strict.

Stereoselective syntheses of the 1-β-methylcarbapenem intermediates 9B (R=SPh or OCH3) have been accomplished by an aldol-type stereocontrolled reaction and stereoselective catalytic hydrogenation of an olefinic ester.