Simon Ingate

Synthesis and anti-HIV activity of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazines (TTDs): a new family of HIV-1 specific non-nucleoside reverse transcriptase inhibitors

The anti-HIV activity of a novel series of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazines (TTDs) has been described. The compounds were synthesized via Curtius rearrangement of appropriate sulfamoylcarboxy azides which, in turn, were prepared from known starting materials. Several 4-substituted-2-benzyl-derivatives were found to selectively inhibit human immunodeficiency virus type 1 [HIV-1 (IIIB)] replication in MT-4 and CEM cells. These TTDs were also effective against other strains of HIV-1 (RF, HE, MN, NDK), including those that are resistant to AZT, but not against HIV-2 (ROD) or simian immunodeficiency virus [SIV(MAC251)] at subtoxic concentrations. Some of the test compounds exhibited antiviral activity against L100I RT mutant virus, but significantly lost antiviral activity against K103N, V106A, E138K, Y181C and Y188H RT mutant viruses. Compounds 6d, 6f and 6g were inhibitory to HIV-1 RT at concentrations that rank between 16.4 and 59.8 microM (nevirapine: IC50 = 4.5 microM against HIV-1 RT). Inhibition of HIV-1 RT by compound 6g was purely non-competitive with respect to the natural substrate (dGTP), which is in agreement with the nature of inhibition shown by other NNRTIs such as nevirapine and delarvidine. A structure-activity relationship was established for the anti-HIV activity of these heterocyclic compounds. TTDs represent a new chemical class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs).

Studies into the synthesis of derivatives of 4-amino-2,3-dihydroisothiazole 1,1-dioxides and 4-amino-1,2-oxathiole 2,2-dioxides: The search for linked π-system containing analogues as potential inhibitors of HIV-1 reverse transcriptase

The synthesis, and anti HIV-1 activity, of new derivatives of 4-amino-1,2-oxathiole 2,2-dioxide (3, 5, 6 and 9) and 4-amino-2,3-dihydroisothiazole 1,l-dioxide (14). a new heterocyclic ring system, is described

From α,α-disubstituted α-aminonitriles to heterocycles: Synthesis of derivatives of 4-amino-2,3-dihydroisothiazole 1,1-dioxide, a new heterocyclic ring system

Abstract The synthesis of derivatives of 4-amino-2,3-dihydroisothiazole 1,1-dioxide (8–10, 12, 15, 16), a new heterocyclic ring system, from α,α-disubstituted α-aminonitriles, is described.

The CSIC [Carbanion mediated Sulfonate (Sulfonamido) Intramolecular Cyclization] reaction: Scope and limitations

Abstract The CSIC (Carbanion-mediated Sulfonate -Sulfonamide- Intramolecular Cyclization) reaction has been extended to new carbonyl containing substrates, showing the scope and limitations of this process. Suitable derivatives of ketones (e.g acetophenone ( 1 )), β-keto esters (e.g ethyl acetoacetate ( 4 )), γ-keto esters (e.g ethyl 2-oxocyclohexaneacetate ( 5 ) and ethyl levulinate ( 6 )) proved reluctant to undergo this protocol. Cyclopropyl methyl ketone ( 2 ) gave the heterocycle ( 3 ), only in the “sulfonamide” synthetic sequence of the CSIC reaction. Cyclic azaketones (e.g tropinone ( 7 )) failed also, but 4-piperidones ( 9, 10 ) afforded the novel 3,8-disubstituted 4-amino-8-aza-1-oxa-2-thiaspiro[4.5]dec-3-ene 2,2-dioxide ( 12, 15a-c ) and 8-substituted 4-amino-1,8-diaza-2-thiaspiro[4.5]dec-3-ene 2,2-dioxide ( 18a, 18b, 21a, 21b ) ring systems; the former compounds are the first examples of such ring systems substituted at the 3-position, whereas the latter represent the first ever representatives of spiro fused systems containing the 4-amino-2,3-dihydroisothiazole 1,1-dioxide moiety. Base promoted (NaH or DBU) cyclization of precursors 11b, 14a-c, 17b, 17c and 20 give the final adducts in good overall yield. Finally, we were unsuccessful with some conveniently functionalized anthranilonitrile derivatives ( 8a-d ), in an attempt to extend the CSIC reaction to β-aminonitriles. As a result of these studies the substrate dependent reactivity in the CSIC reaction has been analyzed in depth and some restrictions and limitations have been observed and discussed.

TSAO Derivatives: Highly Specific Inhibitors of Human Immunodeficiency Virus Type-1 (HIV-1) Replication

Abstract TSAO derivatives represent a unique class of nucleosides that are specifically targeted at HIV-1 RT. This overview is focussed on the chemical synthesis, the conformational studies, the antiviral and metabolic properties of TSAO derivatives, as well as their mechanism of antiviral action and the molecular basis of the rapid selection of resistant HIV-1 strains that emerge in cell culture in the presence of TSAO derivatives.

The CSIC Reaction on Substrates Derived From Aldehydes

Abstract The Carbanion-mediated Sulfonate (Sulfonamide) Intramolecular Cyclization reaction (CSIC reaction) on conveniently functionalized cyanoalkylsulfonates and cyanoalkylsulfonamides derived from aldehydes is possible and gives the new heterocyclic ring systems 5-alkyl-4-amino-5 H -1,2-oxathiole 2,2-dioxide and 3-alkyl-5 H -4-amino-5-cyano-5 H -2,3-dihydroisothiazole 1,1-dioxide in good yield.

New and unexpected developments of the carbanion-mediated sulfonate (sulfonamide) intramolecular cyclization reaction (CSIC reaction)

Abstract The Carbanion-mediated Sulfonate (Sulfonamide) Intramolecular Cyclization reaction (CSIC reaction) on conveniently functionalized cyanoalkylsulfonates and cyanoalkylsulfonamides derived from aldehydes is possible and gives the new heterocyclic ring systems 5-alkyl-5 H -4-amino-1,2-oxathiole-2,2-dioxide and 5-alkyl-5 H -4-amino-3-cyano-2,3-dihydroisothiazole-1,1-dioxide in good yield.

Synthesis and anti-HIV-1 Activity of [1-[2′,5′-Bis-O-(Tert-Butyldimethylsilyl)-β-L-Ribofuranosyl]Thymine]-3′-Spiro-5″-(4″-Amino-1″,2″-Oxathiole-2″,2″-Dioxide) (L-TSAO-T), the L-enantiomer of the Highly Specific HIV-1 Reverse Transcriptase Inhibitor TSAO-T

The L-isomer of the potent HIV-1-RT inhibitor TSAO-T has been stereospecifically synthesized and tested for its ‘in vitro’ antiretroviral activity against HIV-1. Unlike the D-isomer, the L-isomer did not show appreciable inhibition of HIV-1 replication. The cytotoxicity was comparable with the cytotoxicity of the D-enantiomer.

Synthesis of [1-[2′,5′-bis-O-(t-Butyldimethylsilyl)-β- L-ribofuranosyl] thymine]-3′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″,2″-dioxide) (L-TSAO-T)

Abstract Derivatives of TSAO-T based upon pentofuranose sugars with the L-configuration have been prepared and evaluated as inhibitors of HIV-1 induced cytopathicity.