A. De Montis

Synthesis and Biological Evaluation of 5H-Indolo [3,2-b][1,5]Benzothiazepine Derivatives, Designed as Conformationally Constrained Analogues of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Inhibitor L-737,126

In the presence of sodium hydride, reaction of aryldisulphides with ethyl esters of indole-2-carboxylic acids furnished ethyl 3-arylthioindole-2-carboxy-lates, which were cyclized intramolecularly to afford 5H-indolo[3,2-b][1,5]benzothiazepin-6(7H)-ones or hydrolysed in alkaline medium to give 3-arylthioindole-2-carboxylic acids. These acids, also obtained by the action of aryldisulphides on indole-2-carboxylic acids, afforded tetracyclic 5H-indolo [3,2-b][1,5]benzothiazepin-6(7H)-ones upon treatment with EDCI–DMAP. Transformation of cyclic sulphides into the required sulphones was achieved by treatment with hydrogen peroxide or with m-chloroperbenzoic acid. The title derivatives are conformationally constrained analogues of the potent human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor 3-benzene-sulphonyl-5-chloroindole-2-carboxamide (L-737, 126). Although the indolobenzothiazepine derivatives, as well as the indolyl aryl sulphones used for their synthesis, were endowed with anti-HIV-1 activities in the submicromolar and micromolar range, none of them proved more potent than L-737,126.

1,2,5-Benzothiadiazepine and Pyrrolo[2,1-d]-[1,2,5]Benzothiadiazepine Derivatives with Specific Anti-Human Immunodeficiency Virus Type 1 Activity

We synthesized and tested as novel inhibitors of human immunodeficiency virus type 1 (HIV-1) bi- and tricyclic thiadiazine ring homologues of 7-chloro-2-ethyl-2H-1,2,4-benzothiadiazin-3-(4H)-one 1,1-dioxide, which is a compound endowed with anti-HIV-1 activity at low micromolar concentrations. Benzothiadiazepine derivatives were obtained by alkylation of 8-chloro-2,3-dihydro-3-methyl-1,2,5-benzothiadiazepin-4(5H)-one 1,1-dioxide, which was obtained by intramolecular cyclization of 2-(2-amino-5-chloro-benzenesulphonamido) propanoic acid. Pyrrolobenzothiadiazepines were synthesized from N-substituted 5-chloro-2-(1H-pyrrol-1-yl)benzenesulphonamides by treating with triphosgene. N6-substituted pyrrolo[2,1-d][1,2,5]benzothiadiazepin-7(6H)-one 5,5-dioxides were active, thoughnot very potent. Both a chlorine atom and an unsaturated alkyl chain were found to be determinants of anti-HIV-1 activity. The highest potency was shown by a derivative with a TIBO-related 3,3-dimethylallyl chain. 2,3-Dihydro-1,2,5-benzothiadiazepin-4(5H)-one 1,1-dioxides were scarcely active in HIV-1-infected MT-4 cell assays; however, the introduction of the dimethylallyl chain into 7-chloro-1,2,5-benzothiadiazepine moiety led to a bicyclic derivative which was more potent and less cytotoxic than the tricyclic pyrrole-containing counterpart.

Synthesis of new 3,5-disubstituted isoxazoles with specific anti-group B rhinovirus activity in vitro

Abstract 3,5-Disubstituted isoxazoles 4a-f were synthesized as potential anti-rhinovirus agents. These compounds were prepared in good yield by treatment of the corresponding 2-(dialkylamino)chromones 3a-f with hydroxylamine. Compounds 4 were demethylated to obtain dihydroxyderivatives 5 , which were then transformed in acetyl- 6 and alkylderivatives 7 . The methylenbisderivatives 9 were obtained by reaction of bischromones 8 with hydroxylamine. Most compounds were subjected to antiviral screening. Compounds 4c, 7a, 7b and 7c were found to be specific inhibitors of group B rhinoviruses.

Acyclic Nucleotides Related to Clitocine: Synthesis and Anti-HIV Activity

Abstract The syntheses and antiviral activity of analogues of the anti-HIV agents PMEA, PMEDAP, (R)-PMPA, (R)-PMPDAP are described. In these analogues the adenine moiety is replaced by 4,6-diamino-5-nitro-pyrimidine (the aglycon of clitocine) or 2,4,6-triamino-5-nitro-pyrimidine. The synthesis of similar acyclic phosphonates related to PMEG and (R)-2′-methyl-PMEG is also reported. Some compounds proved to be active as anti-HIV agents.

8-Aza-analogues of PMEA and PMEG: Synthesis and In Vitro Anti-HIV Activity

Abstract 8-Aza-analogues of the potent antiviral nucleotide analogues 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and 9-[2-(phosphonomethoxy)-ethyl]guanine (PMEG) were prepared and evaluated for activity against human immunodeficiency viruses. When compared to the parent compounds, 8-aza-PMEA (1) and -PMEG (2) were less cytotoxic for MT-4 cells, but also less potent against HIV-1 and HIV-2. A new synthesis of PMEG starting from guanine is also reported.

Potent and Selective Inhibitors of Human Immunodeficiency Virus Protease Structurally Related to L-694,746:

A series of human immunodeficiency virus (HIV) protease inhibitors, which are analogues of N-[2(R)-hydroxy-1(S)-indanyl]-5(S)-[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-(R)-[[4-(carboxymethoxy)phenyl]methyl]hexanamide (L-694,746), a metabolite of the anti-HIV agent L-689,502, were synthesized. In these compounds, the acetic group linked to the para position of the P1′ phenyl in the reference inhibitor was replaced either by the bioisosteric phosphonomethoxy group and its diisopropyl/dibenzyl derivatives, or the 1H-tetrazol-5-yl-methoxy group and its 1-benzyl derivative. In enzyme assays, phosphonomethoxy and tetrazolmethoxy analogues proved to be potent inhibitors of the HIV-1 protease, with IC50 values as low as 0.04 nM. When tested for anti-HIV-1 activity in cell-based assays, most of the new derivatives proved active, with benzyl derivatives being more active than their highly polar, unsubstituted counterparts. The dibenzylphosphonomethoxy analogue was the most active compound, with an EC50 value of 10 nM and a selectivity index of 20 000. When compounds were examined for their capability to reduce p24 levels in both acutely and chronically infected MT-4 and H9/IIIB cells, all of them were found to be active at concentrations close to those capable of preventing HIV-1-induced cytopathic effect.

8-Aza-1-deazapurine Nucleosides as Antiviral Agents

Abstract 2′,3′-Dideoxy-8-aza-1-deazaadenosine (21) and its α-anomer (20) were synthesized via glycosylation of 7-chloro-3H-1,2,3-triazolo[4,5-b]pyridi-ne with 2,3-dideoxy-5-O-[(1, 1)-dimethylethyl)diphenylsilyl]-D-glycero-o-pen-tofuranosyl chloride. The reaction gave a mixture of α- and β-anomers of N3-, N4- and N1-glycosylated regioisorners (12–15). The α- and β-anomers of the N4-glycosylated isomer 26 and 27 were also synthesized through the glycosylation of 8-aza-1-deazaadenine with 1-acetoxy-2,3-dideoxy-5-O-f(1,1-di-methylethyl)dimethylsilyl]-D-glycero-pentouranose. These dideoxynucleo-sides and a series of previously synthesized 8-aza-1-deazapurine nucleosidcs were tested for activity against several DNA and RNA viruses, HIV-1 included. The α- and β-anomers of 7-chloro-3-(2-deoxy-D-erythro-pentofuranosyl)-3H-1,2,3-triazolo[4,5-b]pyridine (3a and 4) showed activities against Sb-1 and Coxs viruses. The α- and β-anomers of 2′,3′-dideoxy-8-aza-1-deazaadenosine (20 and 21) were found active as inhibitors ...

Arylketotetramethylene analogues of disoxaril with anti-human rhinovirus 14 activity

Arylketotetramethylene analogues of disoxaril (WIN 51711) were synthesized by reaction of 1-aryl-5-chloropentan-1-ones with 2-(4-hydroxyphenyl)-4,5-dihydro oxazoles, ethyl 4-hydroxybenzoates and 4-hydroxybenzonitrile. The new derivatives were tested for antiviral activity against various human rhinovirus (HRV) serotypes. The best activity was exhibited by the ethoxycarbonyl derivatives, whereas the oxazoline counterparts were less active and the cyano derivatives totally inactive. 5-[4-(4,5-Dihydro-2-oxazolyl)phenoxy]-1-(4-methoxyphenyl)pentan-1-one and ethyl 4-[5-(4-methylthiophenyl)-5-oxopentoxy] benzoate were more active than, and as active as, disoxaril, respectively, against HRV-14. Moreover, they were 10 times less cytotoxic.

Methyl-2-thienylketopolymethyleneoxyphenyl derivatives of alkyl-substituted 4,5-dihydro-oxazoles with anti-human picornavirus activity

The synthesis of 5-methyl-2-thienylketopolymethylene oxyphenyl 4,5-dihydro-2-(alkyl)oxazoles was accomplished by the assembly of two synthones, namely 1-(5-methyl-2-thienyl)-7-hydroxy-1-heptanone (or 1-(5-methyl-2-thienyl)-5-chloro-1-pentanone) and 4-[4,5-dihydro(alkyl)oxazol-2-yl]phenol, in the presence of diethyl azodicarboxylate(DEAD)-triphenyl phosphine (or sodium iodide and anhydrous potassium carbonate). Eighteen new disoxaril analogues were synthesized by the above procedure and tested in vitro against several rhino and enteroviruses. With a few exceptions, all test derivatives were more potent than WIN 51711 when assayed against HRV-14, and as potent as WIN 51711 against HRV-2, but none of them inhibited the other HRV serotypes. Among the various derivatives, two compounds showed the same wide spectrum activity of WIN 51711 against several rhino, and enteroviruses, but were at least 10-fold less toxic.