title: Design, synthesis and QSAR studies on N-aryl heteroarylisopropanolamines, a new class of non-peptidic HIV-1 protease inhibitors.
abstract: A series of N-aryl heteroarylisopropanolamines in which an indole or a 3-arylpyrrole moiety was linked to an aryl group through an isopropanolamine linker, were designed and synthesized as potential anti-HIV-1-PR agents. Series was tested for their ability in blocking PR activity. As a rule, indole derivatives of class 1 exhibited more potency than pyrrole analogues of class 2 while tert-butylamide substituents increased anti-PR potency. In fact, bis tert-butylamide 1e showed the highest activity with IC(50)=25 microM. Even if not very potent, a simple class of anti-PR agents, with a facile synthetic pathway was discovered. QSAR studies on isopropanolamines 1 and 2 were performed in comparison with diarylbutanols, a new class of non peptidic anti-PR agents, recently discovered by Agouron Pharmaceuticals. QSAR and CoMFA models based on 30 diarylbutanols used as a training set were developed. The obtained models were used to investigate the binding mode of the newly synthesized derivatives 1 and 2. The results of this study suggest that N-aryl heteroarylisopropanolamines bind to the PR active site similarly to the diarylbutanols of Agouron.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università degli Studi di Roma La Sapienza, P.le A. Moro 5, I-00185 Rome, Italy.
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: Silvio
authors.initials: S
authors.lastname: Massa
authors.forename: Rino
authors.initials: R
authors.lastname: Ragno
authors.forename: Garland R
authors.initials: GR
authors.lastname: Marshall
authors.forename: Paolo
authors.initials: P
authors.lastname: La Colla
mesh_terms: D002082:Butylamines / Q000494:pharmacology; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D011412:Propanolamines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011758:Pyrroles / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D002082:Butylamines; D017320:HIV Protease Inhibitors; D007211:Indoles; D011412:Propanolamines; D011758:Pyrroles; D016333:HIV Protease; C008544:monoisopropanolamine