title: Arylthiopyrrole (AThP) derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors: synthesis, structure-activity relationships, and docking studies (part 1).
abstract: Novel arylthio isopropyl pyridinylmethylpyrrolemethanol (AThP) derivatives 3-5, which are related to capravirine (S-1153), were synthesized and tested for their ability to block the replication cycle of HIV-1 in infected cells. The newly synthesized AThPs are active in the concentration range of 0.008-53 microM. Even if compounds 3-5 are generally less potent than S-1153, their SI values are in some cases similar to that of the reference drug. In fact, the cytotoxicities of AThPs are generally lower than that of S-1153. Compound 4e was the most active derivative of this series in cell-based assays; its potency is similar to that of S-1153 (EC(50)=8 and 3 nM, respectively), as is its selectivity index (SI=6250 and 7000, respectively). AThP derivatives were proven to target HIV-1 RT. In fact, compounds 3-5 generally inhibited the viral enzyme at concentrations similar to those observed in cell-based assays. A selected number of AThPs (4k and 5a,e) were tested against clinically relevant drug-resistant forms of recombinant reverse transcriptase (rRT) carrying the K103N and Y181I mutations. Carbamate 5e showed an approximate 240-fold decrease in activity against Y181I, but only a 10-fold loss in potency against the K103N rRT form. Docking calculations were also performed to investigate the binding mode of compounds 2, 4e, 4j, 4k and 5e into the non-nucleoside binding site of HIV-1 RT and to rationalize some structure-activity relationships and resistance data.
authors.affiliation: Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università degli Studi di Roma La Sapienza, P.le A. Moro 5, 00185 Roma, Italy. roberto.disanto@uniroma1.it
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Santo
authors.forename: Roberta
authors.initials: R
authors.lastname: Costi
authors.forename: Marino
authors.initials: M
authors.lastname: Artico
authors.forename: Gaetano
authors.initials: G
authors.lastname: Miele
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Alberto
authors.initials: A
authors.lastname: Bergamini
authors.forename: Reynel
authors.initials: R
authors.lastname: Cancio
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D006801:Humans; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011758:Pyrroles; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase