title: 2H-Pyrrolo[3,4-b] [1,5]benzothiazepine derivatives as potential inhibitors of HIV-1 reverse transcriptase.
abstract: A number of 2H-pyrrolo[3,4-b] [1,5]benzothiazepine derivatives (PBTAs) 7-25 and the related synthetic intermediates 3-pyrrolyl aryl sulfones (PASs) 26-32 were designed, synthesized and tested as potential anti-HIV-1 agents targeted at the reverse transcriptase (RT). The PBTAs were conceived as tricyclic analogs of nevirapine, pyrrolo[1,2-b] [1,2,5]benzothiadiazepine 5 (PBTD) and pyrrolo[2,1-d] [1,2,5]benzothiadiazepine 6, NNRTIs endowed with potent anti-HIV-1 activities. The majority of tested PBTAs were active against HIV-1-induced cytopathicity in MT-4 cells at concentrations ranging from 0.3 to 40 microM. In particular, compound 10 was the most potent derivative with EC50 = 0.3 microM, comparable to that of nevirapine used as reference drug. In the 3-pyrrolyl aryl sulfones (26-32) series only three sulfones were found active against HIV-1 replication cycle. The following preliminary SAR could be depicted for the title derivatives: i) the conformationally restrained PBTAs are more potent than the corresponding open counterparts (PASs); ii) the DMA group give the highest anti-HIV-1 potency in the PBTAs series; iii) PBTAs and the corresponding thiones are equipotent; iv) an unsubstituted amino group, as part of p-chloroanilino moiety, is a strong determinant for the antiviral activity in the PASs series. The most potent derivatives in cell-based assays were proven to target the RT in enzyme assays. Unfortunately, none of the test compounds inhibited the multiplication of clinically relevant drug-resistant viruses (mutants of HIV-1 carrying K103N and Y181C mutations) at concentrations lower than 30 microM. However, the good results obtained against replication of wt HIV-1, lead us to consider compound 10 as a lead compound for further investigation in this field. In particular, our efforts will be directed to modifications of 10 devoted to obtain new derivatives active against HIV-1 mutant strains.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università di Roma La Sapienza, p.le Aldo Moro 5, I-00185 Rome, Italy. roberto.disanto@uniroma1.it
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Santo
authors.forename: Roberta
authors.initials: R
authors.lastname: Costi
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D013841:Thiazepines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D011758:Pyrroles; D013450:Sulfones; D013841:Thiazepines; D054303:HIV Reverse Transcriptase