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Design, Synthesis, and Biological Evaluation of Tetrahydro‐β‐carboline Derivatives as Selective Sub‐Nanomolar Gelatinase Inhibitors
Author(s) -
Mangiatordi Giuseppe Felice,
Guzzo Tatiana,
Rossano Eugenio Claudio,
Trisciuzzi Daniela,
Alberga Domenico,
Fasciglione Giovanni,
Coletta Massimiliano,
Topai Alessandra,
Nicolotti Orazio
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800237
Subject(s) - gelatinases , matrix metalloproteinase , chemistry , gelatinase , docking (animal) , gelatinase a , selectivity , pharmacokinetics , stereochemistry , combinatorial chemistry , biochemistry , pharmacology , biology , medicine , nursing , catalysis
Targeting matrix metalloproteinases (MMPs) is a pursued strategy for treating several pathological conditions, such as multiple sclerosis and cancer. Herein, a series of novel tetrahydro‐β‐carboline derivatives with outstanding inhibitory activity toward MMPs are present. In particular, compounds 9 f , 9 g , 9 h and 9 i show sub‐nanomolar IC 50 values. Interestingly, compounds 9 g and 9 i also provide remarkable selectivity toward gelatinases; IC 50 =0.15 n m for both toward MMP‐2 and IC 50 =0.63 and 0.58 n m , respectively, toward MMP‐9. Molecular docking simulations, performed by employing quantum mechanics based partial charges, shed light on the rationale behind binding involving specific interactions with key residues of S1′ and S3′ domains. Taken together, these studies indicate that tetrahydro‐β‐carboline represents a promising scaffold for the design of novel inhibitors able to target MMPs and selectively bias gelatinases, over the desirable range of the pharmacokinetics spectrum.