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The remarkably potent and specific activity against varicella-zoster virus (VZV) shown by 2‘-deoxynucleosides of furo[2,3-d]pyrimidin-2(3H)-one and related ring systems is dependent on key structural features including the length and nature of the side-chain at C6 and the structure and stereochemistry of the sugar moiety at N3. Removal of the 3‘-hydroxyl group from potent anti-VZV 2‘-deoxynucleosides results in loss of the VZV activity, but such 2‘,3‘-dideoxynucleoside analogues have shown anti-HCMV activity. We now report acyclic analogues with comparable side-chains at C6, but with the sugar moiety at N3 replaced with the (2-hydroxyethoxy)methyl group (present in the antiherpes drug acyclovir). Examples of both furo[2,3-d]- and pyrrolo[2,3-d]pyrimidin-2(3H)-one acyclic analogues were prepared and evaluated in a number of virus-infected cells and in tumor cell cultures. Certain of the long-chain analogues showed activity against VZV and HCMV. No significant activity against other DNA and RNA virus replication or against tumor cell proliferation was observed.

Starting from the structure of known β-lactam covalent human cytomegalovirus (HCMV) protease inhibitors and from the knowledge of the residues implicated in the active site of this enzyme, we designed a series of phenylalanine-derived 2-azetidinones bearing a 4-carboxylate moiety that could be apt for additional interactions with the guanidine group of the Arg165/Arg166 residues of the viral protease. Some compounds within this series showed anti-HCMV activity at 10−50 μM, but rather high toxicity. The presence of aromatic 1-acyl groups and a certain hydrophobic character in the region of the 4-carboxylate were stringent requirements for anti-HCMV activity. To go a step ahead into the search for effective HCMV medicines, we then envisaged a series of noncovalent inhibitors by simple deletion of the carbonyl group in the β-lactam derivatives to provide the corresponding azetidines. This led to low micromolar inhibitors of HCMV replication, with 17 and 27 being particularly promising lead compounds for further investigation, although their toxicity still needs to be lowered.

New [2‘,5‘-bis-O-(tert-butyldimethylsilyl)-β-d-ribofuranosyl]-3‘-spiro-5‘ ‘-(4‘ ‘-amino-1‘ ‘,2‘ ‘-oxathiole-2‘ ‘,2‘ ‘-dioxide) (TSAO) derivatives substituted at the 4‘ ‘-amino group of the spiro moiety with different carbonyl functionalities have been designed and synthesized. Various synthetic procedures, on the scarcely studied reactivity of the 3‘-spiroaminooxathioledioxide moiety, have been explored. The compounds were evaluated for their inhibitory effect on both wild-type and TSAO-resistant HIV-1 strains, in cell culture. The presence of a methyl ester (10) or amide groups (12) at the 4‘ ‘-position conferred the highest anti-HIV-1 activity, while the free oxalyl acid derivative (11) was 10- to 20-fold less active against the virus. In contrast, the presence at this position of (un)substituted ureido or acyl groups markedly diminished or annihilated the anti-HIV-1 activity. Surprisingly, some of the target compounds also showed inhibition of human cytomegalovirus (HCMV) replication at subtoxic concentrations. This has never been observed previously for TSAO derivatives. In particular, compound 26 represents the first TSAO derivative with dual anti-HIV-1 and -HCMV activity.

In vitro evaluation of the novel cycloalkyl-N-(4-chlorophenyl)-hydroxamic acids (2a−g) demonstrated that 2b,d,e exhibited rather marked inhibitory activity (IC50 = 7−10 μM) against pancreatic carcinoma, 2b−d against colon carcinoma, 2d against laryngeal carcinoma, and 2b,d against breast carcinoma. 2e showed the most pronounced anti-cytomegalovirus activity (EC50 = 1.5 and 0.8 μg mL^-1) only at ≥5-fold lower than the cytotoxic concentration. 2d and 2f showed modest, albeit selective, activity against cytomegalovirus (2d, EC50 = 7.3−8.9 μg mL^-1, selectivity index 7−10; 2f, EC50 = 7−13 μg mL^-1, selectivity index 10).

The novel l- and d-amino acid derivatives of hydroxyurea 5a−o were prepared by aminolysis of N-(1-benzotriazolecarbonyl)amino acid amides 4a−o with hydroxylamine. The hydantoin derivatives 6a−e,m,p were synthesized by base-catalyzed cyclization of amides 4, common precursors for 5 and 6. X-ray crystal structure analysis shows that the C5 atom in 6e possesses the S configuration, which is consistent with the configuration of the starting reagent, l-leucine. Among l-amino acid derivatives of hydroxyurea, 5h and 5i inhibited specifically murine leukemia and human T-lymphocytes (IC50 = 10−19 μM) and showed selectivity with respect to normal human fibroblasts (WI 38). d-Amino acid derivatives of hydroxyurea 5m and 5o inhibited the growth of all tumor cell lines (IC50 = 4.8−83.9 μM), but not the growth of normal fibroblasts (WI 38; IC50 > 100 μM). Results on antiviral evaluations showed that N-(1-benzotriazolecarbonyl)amino acid amide 4m and hydantoin 6m had marked activity against the Davis strain of CMV (4m, EC50 = 3.2 μg/mL; 6m, EC50 = 4.0 μg/mL). However, these compounds showed also rather expressed cytotoxicity (4m, CC50 = 43.4 μg/mL; 6m, CC50 = 12.5 μg/mL^-1).

Following our discovery of the potent anti-varicella zoster virus action of lipophilic alkyl furano pyrimidine 2‘-deoxynucleosides, we now report that 2‘,3‘-dideoxy sugar analogues are devoid of anti-VZV activity but are potent and selective inhibitors of human cytomegalovirus (HCMV). The present compounds are active in vitro at ca. 1 μM with cytotoxicity only above 200 μM. Importantly, we have discovered that the new agents do not act as nucleoside analogues, despite their nucleosidic structure, and time of addition studies revealed that the compounds may inhibit HCMV at an event in the replication cycle of the virus that precedes DNA synthesis. They represent new leads in the discovery of improved therapies for HCMV, particularly in view of their novel mechanism of action.

2,4-Diamino-6-hydroxypyrimidines substituted in position 5 by an allyl, benzyl, cyanomethyl, ethoxycarbonylmethyl, phenyl, cyclopropyl, or methyl group were prepared either by C5-alkylation or by formation of the pyrimidine ring by cyclization. Their alkylation with 2-[(diisopropoxyphosphoryl)methoxy]ethyl tosylate afforded N1- and O6-regioisomers that were separated and converted to the free phosphonic acids by treatment with bromotrimethylsilane followed by hydrolysis. Reaction of 2,4-diamino-6-{[(diisopropoxyphosphoryl)methoxy]ethoxy}pyrimidine with elemental bromine, N-chloro-, or N-iodosuccinimide gave the corresponding phosphorus-protected 5-bromo-, 5-chloro-, and 5-iodo derivatives, respectively. Their deprotection afforded 2,4-diamino-5-bromo- and -5-chloro-6-[2-(phosphonomethoxy)ethoxy]pyrimidines. 2,4-Diamino-5-methyl-6-[2-(phosphonomethoxy)ethoxy]pyrimidine was synthesized also by cross-coupling of the 5-bromo compound with AlMe3, followed by deprotection. The compounds showed poor, if any, inhibitory activity against DNA viruses such as herpes simplex virus type 1 and type 2, cytomegalovirus, varicella-zoster virus, and vaccinia virus. In contrast, several 5-substituted 2,4-diaminopyrimidine derivatives markedly inhibited retrovirus replication in cell culture. The 5-methyl derivative was exquisitely inhibitory to human immunodeficiency virus and Moloney murine sarcoma virus-induced cytopathicity in cell culture (EC50 ~ 0.00018 μmol/mL) but also cytostatic to CEM cell cultures. In contrast, the 5-halogen-substituted derivatives showed pronounced antiretroviral activity (EC50 = 0.0023−0.0110 μmol/mL), comparable to that of the reference drugs adefovir and tenofovir, but were devoid of measurable toxicity at 0.3 μmol/mL.

6-Hydroxypyrimidines substituted at positions 2 and 4 by hydrogen, methyl, amino, cyclopropylamino, dimethylamino, methylsulfanyl, or hydroxyl group afford by the reaction with diisopropyl 2-(chloroethoxy)methylphosphonate in the presence of NaH, Cs2CO3, or DBU a mixture of N¹- and O⁶-[2-(diisopropylphosphorylmethoxy)ethyl] isomers which were converted to the free phosphonic acids by treatment with bromotrimethylsilane followed by hydrolysis. Analogously, 2,4-diamino-6-hydroxypyrimidine gave on reaction with [(R)- and (S)-2-(diisopropylphosphorylmethoxy)propyl] tosylate, followed by deprotection, the enantiomeric 6-[2-(phosphonomethoxy)propoxy]pyrimidines. 2,4-Diamino-6-sulfanylpyrimidine gave, on treatment with diisopropyl 2-(chloroethoxy)methylphosphonate in the presence of NaH and subsequent deprotection, 2,4-diamino-6-{[2-(phosphonomethoxy)ethyl]sulfanyl}pyrimidine. 2-Amino-4-hydroxy-6-[2-(phosphonomethoxy)ethyl]pyrimidine was obtained from the appropriate 2-amino-4-chloropyrimidine derivative by alkaline hydrolysis and ester cleavage. Direct alkylation of 2-amino-4,6-dihydroxypyrimidine afforded a mixture of 2-amino-4,6-bis[2-(phosphonomethoxy)ethyl]- and 2-amino-1,4-bis[2-(phosphonomethoxy)ethyl]pyrimidine. None of the N¹-[2-(phosphonomethoxy)ethyl] isomers exhibited any antiviral activity against DNA viruses or RNA viruses tested in vitro. On the contrary, the O⁶-isomers, namely the compounds derived from 2,4-diamino-, 2-amino-4-hydroxy-, or 2-amino-4-[2-(phosphonomethoxy)ethoxy]-6-hydroxypyrimidine, inhibited the replication of herpes viruses [herpes simplex type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster virus (VZV), and cytomegalovirus (CMV)] and retroviruses [Moloney sarcoma virus (MSV) and human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2)], their activity being most pronounced against the latter. The antiviral activity was lower if the oxygen at the position 6 was replaced by a sulfur atom, as in 2,4-diamino-6-[2-(phosphonomethoxy)ethylsulfanyl]pyrimidine. In analogy to N⁹-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine (PMPDAP), solely the (R)-2,4-diamino-6-[2-(phosphonomethoxy)propoxy]pyrimidine exerted antiviral activity, whereas its (S)-enantiomer was essentially inactive.

In addition to our recent report on the potent anti-varicella-zoster virus (VZV) activity of some unusual bicyclic furopyrimidine nucleosides bearing long alkyl side chains, we herein report the further significant enhancement of the antiviral potency by inclusion of a phenyl group in the side chain of these compounds. The target structures were prepared by the Pd-catalyzed coupling of a series of para-substituted arylacetylenes with 5-iodo-2‘-deoxyuridine, to give intermediate 5-alkynyl nucleosides which were cyclized in the presence of Cu to give the desired bicyclic systems. The compounds display extraordinary potency and selectivity for VZV; the most active are ca. 10 000 times more potent than the reference compound acyclovir and ca. 100 times more potent than the alkyl analogues earlier reported by us. The current compounds show little cytotoxicity, leading to selectivity index values  1 000 000. From a range of DNA and RNA viruses tested, only VZV was inhibited by these compounds indicating their extreme selectivity for this target virus. The novelty of the molecules, coupled with their extreme potency and selectivity, their desirable physicochemical properties, and their relative ease of synthesis, makes them of considerable interest for potential drug development for VZV infections.

A second generation of benzothiadiazine dioxide (BTD) derivatives was synthesized employing benzylation reactions mainly. The chlorophenylmethyl BTD derivatives showed activity against human cytomegalovirus (HCMV) with IC50 values ranging from 3 to 10 μM. Their 50% cytotoxic concentrations were often >200 μM to lung fibroblast HEL cell proliferation and between 20 and 35 μM for lymphocyte CME cell growth. When cytotoxicity for cell morphology was considered, the minimum cytotoxic concentration for the different BTD derivatives varied between 5 and 200 μM. Some of the anti-HCMV compounds also showed activity against HIV-1 and HIV-2. The chlorophenylmethyl derivative 21 was active against a variety of HCMV clinical isolates from patients with different clinical manifestations and fully maintained its activity against a ganciclovir-resistant HCMV strain. The dibenzyl BTD derivatives did not inhibit HCMV protease, and preliminary pharmacological experiments revealed that their anti-HCMV action stems from interference with an early stage of the viral replicative cycle.

Both enantiomers of cyclohexenylguanine were synthesized in a stereospecific way starting from the same starting material:  R-(−)-carvone. Both compounds showed potent and selective anti-herpesvirus activity (HSV-1, HSV-2, VZV, CMV). The binding of both cyclohexene nucleosides in the active site of HSV-1 thymidine kinase was investigated, and a model for the binding of both enantiomers is proposed. The amino acids involved in binding of the optical antipodes are the same, but the interaction energy of both enantiomers is slightly different. This may be attributed to the interaction of the secondary hydroxyl function of the nucleoside analogues with Glu-225. Structural analysis has demonstrated the flexibility of the cyclohexenyl system, and this may be considered as an important conformational characteristic explaining the potent antiviral activity.

We herein report the discovery of an entirely new category of potent antiviral agents based on novel deoxynucleoside analogues with unusual bicyclic base moieties. Target structures, previously known as byproducts in Pd-catalyzed coupling of terminal alkynes with 5-iodo-nucleosides, are recognized herein for the first time to be potent and selective inhibitors of varicella-zoster virus (VZV) in vitro. As an unusual structure−activity relationship we noted the absolute requirement of a long alkyl side chain, with an optimum length of C8−C10, for antiviral activity. We thus report the synthesis and characterization of a series of chain-modified analogues and their extensive in vitro evaluation. The lead compounds have a ca. 300-fold enhancement in anti-VZV activity over the reference compound acyclovir, with no detectable in vitro cytotoxicity. The novel structure of these compounds, coupled with their ease of synthesis, excellent antiviral profile, and promising physical properties, makes them of great interest for possible antiviral drug development.

A series of dialkyl esters of purine and pyrimidine N-[2-(phosphonomethoxy)ethyl] derivatives substituted at position 2, 6, or 8 of the purine base or position 2, 4, or 5 of the pyrimidine base were prepared by alkylation of the appropriate heterocyclic base with 2-chloroethoxymethylphosphonate diester in the presence of sodium hydride, cesium carbonate, or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) in dimethylformamide. Additional derivatives were obtained by the transformations of the bases in the suitably modified intermediates bearing reactive functions at the base moiety. The diesters were converted to the corresponding monoesters by sodium azide treatment, while the free acids were obtained from the diester by successive treatment with bromotrimethylsilane and hydrolysis. None of the PME derivatives in the pyrimidine series, their 6-aza or 3-deaza analogues, exhibited any activity against DNA viruses or retroviruses tested, except for the 5-bromocytosine derivative. Substitution of the adenine ring in PMEA at position 2 by Cl, F, or OH group decreased the activity against all DNA viruses tested. PMEDAP was highly active against HSV-1, HSV-2, and VZV in the concentration range (EC50) of 0.07−2 μg/mL. Also the 2-amino-6-chloropurine derivative was strongly active (EC50 = 0.1−0.4 μg/mL) against herpes simplex viruses and (EC50 = 0.006−0.3 μg/mL) against CMV and VZV. PMEG was the most active compound of the whole series against DNA viruses (EC50 ~ 0.01−0.02 μg/mL), though it exhibited significant toxicity against the host cells. The base-modified compounds did not show any appreciable activity against DNA viruses except for 7-deazaPMEA (IC50 ~ 7.5 μg/mL) against HIV-1 and MSV. The neutral (diisopropyl, diisooctyl) diesters of PMEA were active against CMV and VZV, while the corresponding monoesters were inactive. The diisopropyl ester of the 2-chloroadenine analogue of PMEA showed substantially (10−100×) higher activity against CMV and VZV than the parent phosphonate. Also, the diisopropyl and diisooctyl ester of PMEDAP inhibited CMV and VZV, but esterification of the phosphonate residue did not improve the activity against either MSV or HIV.

The first acyclonucleosides based on the benzothiadiazine dioxide system were synthesized following the silylation procedure. Several acyclic moieties, including acetoxyethoxymethyl, benzyloxymethyl, and propargyloxymethyl groups, were introduced. Two synthetic strategies were designed to selectively obtain the N-1 or N-3 derivatives. Lipase-mediated deacylation was used for the deprotection of the acyclonucleosides. Some of the benzothiadiazine dioxide acyclonucleosides, in particular 16, proved active against human cytomegalovirus (CMV) at concentrations slightly higher than that found for ganciclovir [50% inhibitory concentration (IC50) = 3.5−3.7 μg/mL, cytotoxicity (CC50) ≥ 40 μg/mL, MCC = 20 μg/mL]. Additionally, compound 16 inhibited the replication of human immunodeficiency virus type 1 (HIV-1) and HIV-2 in CEM cells at concentrations that were 5-fold lower than its cytotoxic concentration.

The syntheses and the antiviral activities of 2-halo derivatives of neplanocin A (1b,c), (6‘R)-6‘-C-methylneplanocin A (2b), and dehydroxymethylneplanocin A (3b,c) are described. SN2 reaction of the known cyclopentenyl units 12 and 13 with 2-haloadenines under basic conditions gave the protected carbocyclic nucleosides 14b,c and 15b,c, respectively. Starting from the cyclopentenone derivative 5, the optically active tosyloxycyclopentene derivative 11 was prepared, which was similarly condensed with 2-fluoroadenine to give the protected (6‘R)-6‘-C-methyl derivative 16b. Deprotection of these compounds afforded the target 2-halo derivatives of neplanocin A. Of these new compounds, 2-fluoroneplanocin A (1b) showed an antiviral potency and a spectrum that was comparable to that of neplanocin A (1a). It was particularly active against vaccinia virus, vesicular stomatitis virus, parainfluenza virus, reovirus, arenaviruses (Junin, Tacaribe), and human cytomegalovirus, i.e., those viruses that fall within the purview of the S-adenosyl-l-homocysteine hydrolase inhibitors.

The synthesis of some new aminoadamantane derivatives is described. The new compounds were evaluated against a wide range of viruses [influenza A H1N1, influenza A H2N2, influenza A H3N2, influenza B, parainfluenza 3, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), thymidine kinase-deficient (TK^-) HSV-1, vaccinia, vesicular stomatitis, polio 1, Coxsackie B4, Sindbis, Semliki forest, Reo 1, varicella-zoster virus (VZV), TK^- VZV, human cytomegalovirus (HCMV), and human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2)]. Some of them proved markedly active against the influenza A H2N2 (compounds 4a,b, 5a, 6a, and 7a), H3N2 (compounds 5a, 6a, and 7a), and H1N1 (compounds 4b,c and 6d). Since compounds 5a, 6a, and 7a, amantadine, and rimantadine showed the same comparative pattern of potency against influenza strains H2N2, H3N2, and B, it may postulated that they act according to a similar mechanism, with regard to their “amine” effect, on the M2 ion channel of influenza A (H1N1, H2N2, or H3N2). In general, no significant activity was noted with any of the new compounds against any of the other viruses tested, making their activity against influenza virus more specific and striking. Borderline activity was noted with some of the compounds (4b,c, 5a−c, and 8a) against HIV-1.

A series of purine and pyrimidine N-(2-(phosphonomethoxy)ethyl) derivatives bearing aminomethyl, (dimethylamino)methyl, morpholinomethyl, and (trimethylammonio)methyl groups at the 2‘-position were synthesized. The compounds were prepared by alkylation of the heterocyclic bases with appropriately substituted (aminoalkyl)oxiranes followed by condensation of the resulting intermediates with dialkyl ((p-tolylsulfonyl)oxy)methanephosphonate and subsequent treatment of the obtained diester with bromotrimethylsilane. 9-(3-Amino-2-(phosphonomethoxy)propyl)adenine (2a) proved active against varicella zoster virus (VZV), cytomegalovirus (CMV), and Moloney murine sarcoma virus (MSV) in the concentration range of 7−35 μg/mL. None of the other aminoalkyl derivatives demonstrated significant antiviral activity against herpes simplex virus type 1 and 2 (HSV-1 and HSV-2), VZV, (CMV), vaccinia virus (VV), MSV, and human immunodeficiency virus type 1 and 2 (HIV-1 and HIV-2).

The synthesis and the antiviral activities of C-3 acyclic nucleoside analogues of imidazo[1,2-a]pyridine and pyrimidine are reported. From these compounds, 20, 21, 22, 23, 28, and 34 showed a specific activity against cytomegalovirus and/or varicella-zoster virus.

The design, synthesis, and antiviral activities of 6‘-homoneplanocin A (HNPA, 3) and its congeners having nucleobases other than adenine, such as 3-deazaadenine (4), guanine (5), thymine (6), and cytosine (7), were described. Starting from the known cyclopentenone derivative 8, the optically active (mesyloxy)cyclopentene derivative 15 was prepared, which was condensed with nucleobases then deprotected to give target compounds 3−7. Of these compounds, HNPA showed an antiviral activity spectrum that was comparable to, and an antiviral specificity that was higher than, that of neplanocin A. HNPA proved particularly active against human cytomegalovirus, vaccinia virus, parainfluenza virus, vesicular stomatitis virus, and arenaviruses, which is compatible with an antiviral action targeted at S-adenosylhomocysteine hydrolase. HNPA appears to be a promising candidate drug for the treatment of these viruses.

New polyanionic compounds were obtained from radical addition of thiomalic acid and mercaptopropionic acid onto perallylated cyclodextrins (CDs) under UV irradiation with a catalytic amount of α,α‘-azobis(isobutyronitrile). All these polyanions, bearing 18−48 carboxylate groups, inhibited human immunodeficiency virus type 1 (HIV-1) strain IIIB replication in MT-4 cells at a 50% inhibitory concentration (IC50) of 0.1−2.9 μM, while not being toxic to the host cells at concentrations up to 62 μM. These compounds were also active against a clinical HIV-1 isolate (HE) at ≥4-fold higher concentrations. Only some compounds showed activity against the two HIV-2 strains (ROD and EHO) but at higher concentrations than those required to inhibit HIV-1 (IIIB and HE) replication. In addition, these compounds were not active against the M-tropic HIV-1 strain BaL but were active against simian immunodeficiency virus [SIV (MAC251)]. These compounds were also inhibitory to the replication of human cytomegalovirus at an IC50 of 1−10 μM, but not herpes simplex virus (type 1 and type 2) or other (picorna-, toga-, reo-, orthomyxo-, paramyxo-, bunya-, rhabdo-, and poxvirus) viruses. Radical addition on perallylated CDs of a protected cysteine gave polyzwitterionic compounds. None of these last compounds proved inhibitory to the replication of HIV-1, HIV-2, or any of the other viruses tested.

The synthesis of original imidazo[1,2-a]pyridines bearing a thioether side chain at the 3 position and their antiviral activity are reported. From the synthesized compounds, 4, 15, and 21 were highly active against human cytomegalovirus with a therapeutic index superior to 150. These compounds also showed pronounced activity against varicella-zoster virus. Their structure−activity relationship is discussed.

Using the observation that the side effects of aristeromycin (carbocyclic adenosine) were reduced by removing the methylene at the center in aristeromycin where phosphorylation occurs, derivatives of carbocyclic oxetanocin A (4a), oxetanocin G (4b), and 2-aminooxetanocin A (16) lacking the 3‘-methylene have been prepared in racemic form. The only viruses for which an appreciable inhibitory effect of the compounds (minimum inhibitory concentration ranging from 1 to 40 μg/mL) was noted were herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV). However, when directly compared for their antiviral potency against HSV-1 with their parents oxetanocin A and oxetanocin G, compounds 4a and 4b proved clearly less active.

ω-Acryloyl anionic surfactants, whose polar heads are derived from amino acids, have been telomerized to prepare polyanions of a predetermined molecular weight. The main goal of this study was to verify whether the antiviral activity is influenced by the degree of polymerization of the polyanions. The oligomeric polyanions were evaluated for their activity against human immunodeficiency virus (HIV-1 or HIV-2) and various other RNA and DNA viruses. With regard to their anti-HIV activity, a minimum number of anionic groups was necessary to achieve an inhibitory effect. Moreover, to be active the overall conformation of the polyanion must be such that the anionic groups are located on the external site of the molecule. With some of the polyanions, a 50% inhibition concentration (IC50) as low as 1 μg/mL, or even 0.1 μg/mL, was noted against HIV-1 in CEM-4 and MT-4 cells, respectively. The most potent polyanions also proved active against human cytomegalovirus and herpex simplex virus at concentrations of 5−10 and 20−40 μg/mL, respectively. No activity was observed against any of the other viruses tested (i.e., vesicular stomatitis, Sindbis, Semliki forest, parainfluenza, Junin, Tacaribe, Coxsackie, polio, reo, and vaccinia). No toxicity for the host cells was observed at concentrations up to 200 μg/mL.

A new class of polyanionic compounds, inhibitors of human immunodeficiency virus, was obtained from radical addition of mercapto acid or mercapto ester on a perallylated carbohydrate under UV irradiation with a catalytic amount of AIBN. Unlike the polyanions that we have previously prepared by polymerization reactions, the compounds are structurally well defined. Polyanions bearing 16 carboxylate groups showed a 50% inhibitory concentration (IC50) of 0.1−4.1 μg/mL against HIV-1 in MT-4 cells while not being toxic to the host cells at concentrations up to 125 μg/mL. The most potent polyanions also proved active against human cytomegalovirus at concentrations of 1−14 μg/mL. No activity was observed against any of the other viruses tested (i.e., herpes simplex virus, vesicular stomatitis virus, Sindbis, Semliki forest, parainfluenza-3, Junin, Tacaribe, Coxsackie B4, polio-1, reo-1, or vaccinia virus).