title: 1,2,5-Benzothiadiazepine and pyrrolo[2,1-d]-[1,2,5]benzothiadiazepine derivatives with specific anti-human immunodeficiency virus type 1 activity.
abstract: 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)benzene-sulphonamides by treating with triphosgene. N6-substituted pyrrolo[2,1-d][1,2,5]benzothiazepin-7(6H)-one 5,5-dioxides were active, though not 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.
authors.affiliation: Dipartimento di Studi Farmaceutici, Università di Roma La Sapienza, Roma, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Di Santo
authors.forename: R
authors.initials: R
authors.lastname: Costi
authors.forename: M
authors.initials: M
authors.lastname: Artico
authors.forename: S
authors.initials: S
authors.lastname: Massa
authors.forename: M E
authors.initials: ME
authors.lastname: Marongiu
authors.forename: A G
authors.initials: AG
authors.lastname: Loi
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 / Q000737:chemistry / Q000494:pharmacology*; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology*; D001581:Benzothiadiazines / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D015498:HIV-2 / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D001381:Azepines; D001581:Benzothiadiazines