Synthesis and antiviral activity of new benzothiadiazine dioxide derivatives

Abstract

A series of 2,1,3-and 1,2,4-benzothiadiazine derivatives were synthesized by alkylation via Mitsunobu reaction and evaluated for their antiviral activity against ADV, HHV-6, Cox-B5 and H-CMV. Most of them were active at micromolar level against one or more viral strains. All the molecules studied are poorly cytotoxic (maximum non toxic concentrations were >25µM), except one compound that presents a higher cytotoxicity (maximum non toxic concentration was 6 µM).

Mitsunobu and Related Reactions: Advances and Applications

“…In addition to what has been discussed in the above sections, a search through SciFinder revealed a few more cases wherein the Mitsunobu reaction has been applied. These include the preparation of (i) 2-substituted 2,3-dihydro-4-quinolones by sulfonamide activated N -alkylation, (ii) entecavir, (iii) cyclic peptolides, (iv) benzothiadiazine dioxide, (v) thymine containing pseudopeptides via N -alkylation by o -Ns activation,(vi) anhydro-nucleosides from cyclization of 6-amino-7H-purine-8(9H)-thione, (vii) 5-{4-[2-(methyl- p -substituted phenylamino)ethoxy]benzyl}thiazolidine-2,4-diones by O -alkylation (ether formation), (viii) furan containing macrolactones, (ix) C(1)−C(7) and C(17)−C(28) subunits of didemnaketal A and B, respectively, , (x) prenylflavanones, (xi) boonein from bisbenzyloxymethyl-substituted bicyclo[2.2.1]ketone, (xii) pseudo-aminosugars, (+)-valienamine and (+)-validamine, (xiii) the monomethyl ether of 1,1′-binaphthol as a precursor for poly(meth)acrylates with a pendant 1,1′-binaphthyl group, (xiv) esters of syn -diisopropyl-1-bromo-2-hydroxy-2-( p -methoxyphenyl)ethylphosphonate, (xv) racemic cyclopent-3-en-1-yl nucleoside analogues, (xvi) pregnane ketols, (xvii) aminopropyl phosphonate nucleosides with purine and pyrimidine bases, (xviii) high glass transition polyimides via etherification for NLO applications, (xix) liquid crystalline aromatic azo compounds (esterification), (xx) peptide nucleic acid monomers based on N -[2-( tert -butoxycarbonylaminomethyl)- trans -4-hydroxy]tetrahydropyrrole acetic acid Me ester, (xxi) chiral liquid crystalline polyacrylates based on l -isoleucine (esterification), (xxii) 20-hydroxyhepoxilins (inversion/rearrangement), (xxiii) α-mercaptomethyl amino acids from α-hydroxymethyl amino acids, (xxiv) β-lactamase hydrolysis resistant penicillin analogues, (xxv) (3 R )-2′3′-dihydro-β,β-caroten-3-ol, (xxvi) deuterium- and tritium-labeled multidrug resistance modulator LY 335979 (etherifcation), (xxvii) acyl glucuronides of R -(−)- and ( S )-(+)-ibuprofen, (xxviii) 2,3-dideoxy-2,3-epimino and 3,4-dideoxy-3,4-epimino derivatives of 1,6-anhydro-β- d -hexopyranoses, (xxix) azaoxamacrobicyclic ligands, (xxx) tetrahydropyrido[2,1- b ]quinazolin-11-ones, (xxxi) reversed imidazole nucleosides, protected (3- N -hydroxyamino-1-alkenyl)phosphonates via BocNHOBoc, (xxxii) poly(etherimide)s with attached NLO moieties, N -(β-phenethyl)- N -triflylvaline ( N -alkylation), and (xxxiv) (−)-cladospolide B …”

Synthesis and Evaluation of Cytotoxic Activity of New Analogues of 4‐Substituted 1,2,4‐Benzothiadiazine‐1,1‐dioxide

“…Due to numerous pharmacological uses, BTZ ring has been incorporated into numerous medicinal drugs. [10][11][12][13][14][15][16][17][18][19][20] Compound BTZ-1 to BTZ-10 have been described already previously. [21] All these compounds were further evaluated for their in vitro anti-cancer activity via one dose (10 À 5 M) against different cancer cell lines which was selected by the NCI and NCI did its own procedure for testing.…”

Oxidations of 4H‐1,2,6‐Thiadiazines

“…While 1,2,6-thiadiazine 1,1-dioxides are well known, they are mostly prepared via cyclisations of high oxidation state [S(VI)] sulfur reagents, e. g., sulfamyl chlorides, [17] sulfuryl chloride [18] and sulfamide, [19] and not from oxidations of lower oxidation state 1,2,6-thiadiazines. [1,20] Mono-S-oxides are, nevertheless, relatively rare.…”

“…To date, only a few examples of S(IV) oxidized 4H-1,2,6thiadiazines have been reported: the near infrared dye cyclopenta [1,2,6]thiadiazine 1, [7] naphtho [1,8-cd] [1,2,6]thiadiazine (2), [13] acenaphtho [5,6-cd][1,2,6]thiadiazine (3), the benzo-fused systems 4 [14] and the hetero-fused systems 5 [15,16] (Figure 2). While 1,2,6-thiadiazine 1,1-dioxides are well known, they are mostly prepared via cyclisations of high oxidation state [S(VI)] sulfur reagents, e. g., sulfamyl chlorides, [17] sulfuryl chloride [18] and sulfamide, [19] and not from oxidations of lower oxidation state 1,2,6-thiadiazines. [1,20] Mono-S-oxides are, nevertheless, relatively rare.…”