Tackling antimicrobial resistance (AMR) represents a social responsibility aimed at renewing the antimicrobial armamentarium and identifying novel therapeutical approaches. Among the possible strategies, efflux pumps inhibition offers the advantage to contrast the resistance against all drugs which can be extruded. Efflux pump inhibitors (EPIs) are molecules devoid of any antimicrobial activity, but synergizing with pumps-substrate antibiotics. Herein, we performed an in silico scaffold hopping approach starting from quinolin-4-yloxy-based Staphylococcus aureus NorA EPIs by using previously built pharmacophore models for NorA inhibition activity. Four scaffolds were identified, synthesized, and modified with appropriate substituents to obtain new compounds, that were evaluated for their ability to inhibit NorA and synergize with the fluoroquinolone ciprofloxacin against resistant S. aureus strains. The two quinoline-4-carboxamide derivatives 3a and 3b showed the best results being synergic (4-fold MIC reduction) with ciprofloxacin at concentrations as low as 3.13 and 1.56 µg/mL, respectively, which were nontoxic for human THP-1 and A549 cells. The NorA inhibition was confirmed by SA-1199B ethidium bromide efflux and checkerboard assays against the isogenic pair SA-K2378 (norA++)/SA-K1902 (norA-). These in vitro results indicate the two compounds as valuable structures for designing novel S. aureus NorA inhibitors to be used in association with fluoroquinolones.
Abstract The activity of the cyclin‐dependent kinase 9 (CDK9) is critical for HIV‐1 Tat‐mediated transcription and represents a promising target for antiviral therapy. Here we present computational studies that, along with preliminary synthetic efforts, allowed us to identify and characterize a new class of nontoxic anti‐CDK9 chemotypes based on the 2‐phenylquinazolinone scaffold. Inhibition of CDK9 translated into the ability to interfere selectively with Tat‐mediated transactivation of the viral promoter and in the inhibition of HIV‐1 reactivation from latently infected cells, with the most potent derivative 37 (2‐(4‐aminophenyl)‐7‐chloroquinazolin‐4(3 H )‐one) showing an IC 50 value of 4.0 μ M . Because the herein reported 2‐phenylquinazolinones are merely fragments, they are largely optimizable, paving the way to derivatives with improved potency.
Facile procedures exploiting three-component reactions were developed to regioselectively obtain 2-amino-7-methyl-5-phenyl- and 2-amino-5-methyl-7-phenyl-[1,2,4]triazolo[1,5- a ]pyrimidine analogues bearing a C-6 electron withdrawing group.
Ring opening of 2,2-dimethylthiirane by deactivated aromatic amines to afford 2-(arylamino)ethanethiols as 6-substituted 1,4-benzothiazine precursors, was investigated. The reaction takes place under mild conditions using copper(II) triflate or indium(III) triflate as catalysts. The regioselectivity of the addition depends on the catalysts and the substituents of the arylamines.
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Nontuberculous mycobacteria (NTM) are ubiquitous microbes belonging to the Mycobacterium genus. Among all NTM pathogens, M. avium is one of the most frequent agents causing pulmonary disease, especially in immunocompromised individuals and cystic fibrosis patients. Recently, we reported the first ad hoc designed M. avium efflux pump inhibitor (EPI; 1b) able to strongly boost clarithromycin (CLA) MIC against different M. avium strains. Since the 3-phenylquinolone derivative 1b suffered from toxicity issues toward human macrophages, herein we report a two-pronged medicinal chemistry workflow for identifying new potent and safe NTM EPIs. Initially, we followed a computational approach exploiting our pharmacophore models to screen FDA approved drugs and in-house compounds to identify "ready-to-use" NTM EPIs and/or new scaffolds to be optimized in terms of EPI activity. Although nicardipine 2 was identified as a new NTM EPI, all identified molecules still suffered from toxicity issues. Therefore, based on the promising NTM EPI activity of 1b, we undertook the design, synthesis, and biological evaluation of new 3-phenylquinolones differently functionalized at the C6/C7 as well as N1 positions. Among the 27 synthesized 3-phenylquinolone analogues, compounds 11b, 12b, and 16a exerted excellent NTM EPI activity at concentrations below their CC50 on human cells, with derivative 16a being the most promising compound. Interestingly, 16a also showed good activity in M. avium-infected macrophages both alone as well as in combination with CLA. The antimycobacterial activity observed for 16a only when tested in the ex vivo model suggests a high therapeutic potential of EPIs against M. avium, which seems to need functional efflux pumps to establish intracellular infections.
The current anti-HIV combination therapy does not eradicate the virus that persists mainly in quiescent infected CD4(+) T cells as a latent integrated provirus that resumes after therapy interruption. The Tat-mediated transactivation (TMT) is a critical step in the HIV replication cycle that could give the opportunity to reduce the size of latent reservoirs. More than two decades of research led to the identification of various TMT inhibitors. While none of them met the criteria to reach the market, the search for a suitable TMT inhibitor is still actively pursued. Really promising compounds, including one in a Phase III clinical trial, have been recently identified, thus warranting an update.
ATP-Sensitive potassium channel openers (KATPCOs) are a group of compounds with a broad spectrum of potential therapeutic applications, as they constitute efficient tools for dampening cell excitability. Interest in the KATPCOs was triggered in the early 1980s by the discovery of the benzopyran-based structure cromakalim (CRK), which is a powerful smooth muscle relaxant. CRK can be considered the archetype of KATPCOs and is by far the most mimicked structure. In many structure-activity studies various substitutions have been made at the different positions of the benzopyran ring permitting the optimal activity to be correlated with a specific set of structural characteristics and stereochemical features of the molecule. Thus, many potent benzopyran derivatives have been identified. The benzopyran nucleus itself has also been modified in both the aromatic ring and in the pyran moiety. The intention of this review is to bring together all the different structural classes of KATPCOs arising from the replacement of CRK benzopyran-based structure with various ring systems; design, structure-activity relationship, and synthesis will be given. Keywords: KATP channels, cromakalim analogues, thienopyrans, pyranopyridines, benzoxepines, indanes, benzothiopyrans, quinolines, naphthalenes, benzoxazines
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