title: 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.
abstract: In the presence of sodium hydride, reaction of aryl-disulphides with ethyl esters of indole-2-carboxylic acids furnished ethyl 3-arylthioindole-2-carboxylates, 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.
authors.affiliation: Dipartimento di Studi Farmaceutici, Università di Roma La Sapienza, Roma, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Silvestri
authors.forename: M
authors.initials: M
authors.lastname: Artico
authors.forename: B
authors.initials: B
authors.lastname: Bruno
authors.forename: S
authors.initials: S
authors.lastname: Massa
authors.forename: E
authors.initials: E
authors.lastname: Novellino
authors.forename: G
authors.initials: G
authors.lastname: Greco
authors.forename: M E
authors.initials: ME
authors.lastname: Marongiu
authors.forename: A
authors.initials: A
authors.lastname: Pani
authors.forename: A
authors.initials: A
authors.lastname: De Montis
authors.forename: P
authors.initials: P
authors.lastname: La Colla
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D054303:HIV Reverse Transcriptase / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C116809:3-benzenesulfonyl-5-chloroindole-2-carboxamide; D019380:Anti-HIV Agents; D007211:Indoles; D018894:Reverse Transcriptase Inhibitors; D013450:Sulfones; D054303:HIV Reverse Transcriptase