Novel Indolyl Aryl Sulfones Active against HIV-1 Carrying NNRTI Resistance Mutations:  Synthesis and SAR Studies

Abstract

The potent anti-HIV-1 activities of L-737,126 (2) and PAS sulfones prompted us to design and test against HIV-1 in acutely infected MT-4 cells a number of novel 1- and 3-benzenesulfonylindoles. Indoles belonging to the 1-benzenesulfonyl series were found poorly or totally inactive. On the contrary, some of the 3-benzenesulfonyl derivatives turned out to be as potent as 2, being endowed with potencies in the low nanomolar concentration range. In particular, (2-methylphenyl)sulfonyl (72) and (3-methylphenyl)sulfonyl (73) derivatives showed EC(50) values of 1 nM. Introduction of two methyl groups at positions 3 and 5 of the phenyl ring of 2 furnished derivatives (80 and 83) which showed very potent and selective anti-HIV-1 activity not only against the wt strain, but also against mutants carrying NNRTI-resistant mutations at positions 103 and 181 of the reverse transcriptase gene.

A Practical Regioselective Synthesis of Alkylthio- or Arylthioindoles without the Use of Smelly Compounds Such as Thiols

“…Many 3-alkylthio-and 3-arylthioindole derivatives are important biologically active substances (e.g., cyclooxygenase-2 (COX-2) inhibitors, 8) 5-lipoxygenase inhibitors, 9) anti-human immunodeficiency virus (HIV) compounds, 10) anti-nociceptive compounds, 11) anti-allergy drugs, 12) anti-obesity compounds, 13) and endothelin antagonists. 14) Many methods have been reported [15][16][17][18][19][20][21] for the synthesis of 3-alkyl-(or aryl-) thioindole derivatives, and some studies have utilized alkylsulfenyl chloride [15][16][17] alkyldisulfide, 18) or N-alkylthiophthalimide 20,21) as umpolung sulfonium cations.…”

Identification of a Novel Scaffold for Allosteric Inhibition of Wild Type and Drug Resistant HIV-1 Reverse Transcriptase by Fragment Library Screening

“…Examples of nonbinding fragments(21)(22)(23)(24)(25) representing substructures of published NNRTIs(3,(18)(19)(20) [22][23][24]. Compound 3 is delavirdine, one of the reference compounds used.…”

SN H reactions of 3-fluoronitroarenes with chloromethyl sulfone as the method for the construction of 6-fluoro-3-sulfonylindoles

“…Sulfonyl derivatives of indole also have various pharmacological properties. Suffice it to mention that suc cinate of [3 (2 dimethylamino)ethyl 1H indol 5 yl] N methylmethanesulfonamide ("Sumatripan") is used for the migraine treatment, 5 N arylsulfonylindolecarboxamides are effective toward the HIV 1 infection, 8 whereas N aryl and N alkylindolyl sulfones have anti tumor ac tivity and are the modulators of 5HT 6 receptors for the treatment of central nervous system diseases. 9-11 Among the fluoro substituted N sulfonylindoles, compounds having anti asthmatic and anti allergic properties are found.…”

“…5 3 Sulfonyl 1H indole 2 carboxami des were synthesized by the oxidation of 3 arylthio 1H indole 2 carboxamides with 3 chloroperbenzoic acid. 8 The synthesis of 3 sulfonyl substituted indoles by the cyclization of o substituted arylsulfonylmethylnitro benzenes, obtained by the substitution of hydrogen in nitro derivatives of arenes upon treatment with vicarious nucleophiles, viz., aryl chloromethyl sulfones, 13,14 is the most promising method. In the literature, there is no data on methods for the synthesis of fluoro containing 3 sul fonylindoles.…”