作者: Lin, Zhihong ; Li, Junan ; Moitra, Samrat ; Basu, Somrita ; Qin, Lingli ; Werbovetz, Karl A. ; Jin, Yiru ; Junaid Dar, M ; La Rosa, Chris ; Wu, Meng ; Junaid Dar, M. ; Uchenik, Dmitriy ; Roy, Anuradha ; Werbovetz, Karl A ; Kendall, Allie ; Zhang, Kai ; Sharma, Pankaj ; Zhuo Wang, Michael

CYP5122A1, an enzyme involved in sterol biosynthesis in Leishmania, was recently characterized as a sterol C4-methyl oxidase. Screening of a library of compounds against CYP5122A1 and CYP51 from Leishmania resulted in the identification of two structurally related classes of inhibitors of these enzymes. Analogs of screening hit N-(3,5-dimethylphenyl)-4-(pyridin-4-ylmethyl)piperazine-1-carboxamide (4a) were generally strong inhibitors of CYP51 but were less potent against CYP5122A1 and typically displayed weak inhibition of L. donovani promastigote growth. Analogs of screening hit N-(4-(benzyloxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18a) were stronger inhibitors of both CYP5122A1 and L. donovani promastigote proliferation but also remained selective for inhibition of CYP51. Two compounds in this series, N-(4-((3,5-bis(trifluoromethyl)benzyl)oxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18e) and N-(4-((3,5-di-tert-butylbenzyl)oxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18i) showed modest selectivity for inhibiting L. donovani promastigote proliferation compared to J774 macrophages and were effective against intracellular L. donovani with EC₅₀ values in the low micromolar range. Replacement of the 4-pyridyl ring present in 18e with imidazole resulted in a compound (4-(2-(1H-imidazol-1-yl)ethyl)-N-(4-((3,5-bis(trifluoromethyl)benzyl)oxy)phenyl)piperazine-1-carboxamide, 18p) with approximately fourfold selectivity for CYP5122A1 over CYP51 that inhibited both enzymes with IC₅₀ values ≤ 1 µM, although selective potency against L. donovani promastigotes was lost. Compound 18p also inhibited the proliferation of L. major promastigotes and caused the accumulation of 4-methylated sterols in L. major membranes, indicating that this compound blocks sterol demethylation at the 4-position in Leishmania parasites. The molecules described here may therefore be useful for the future identification of dual inhibitors of CYP51 and CYP5122A1 as potential antileishmanial drug candidates and as probes to shed further light on sterol biosynthesis in Leishmania and related parasites.

2024-09-13·ACS Infectious Diseases

4-(3-Phenylsulfonylindol-2-yl)-1-(pyridin-2-yl)piperazinyl-methanones as Potent Inhibitors of both SARS-CoV-2 and HCoV-OC43 Viruses

Article

作者: Arduino, Irene ; Tramontano, Enzo ; Antonelli, Guido ; Ortore, Maria Grazia ; Donalisio, Manuela ; Esposito, Francesca ; La Regina, Giuseppe ; Cocomazzi, Paolo ; Manetto, Simone ; Nalli, Marianna ; Hucke, Friederike ; Fracella, Matteo ; Corona, Angela ; Bugert, Joachim Jakob ; Coluccia, Antonio ; Dondio, Giulio ; Lembo, David ; Milani, Mario ; Mastrangelo, Eloise ; Puxeddu, Michela ; Sciò, Pietro ; Mazzoccanti, Giulia ; Bigogno, Chiara ; Silvestri, Romano ; Moretti, Paolo

SARS-CoV-2 and HCoV-OC43 belong to the same β genus of the Coronaviridae family. SARS-CoV-2 was responsible for the recent COVID-19 pandemic, and HCoV-OC43 is the etiological agent of mild upper respiratory tract infections. SARS-COV-2 and HCoV-OC43 co-infections were found in children with respiratory symptoms during the COVID-19 pandemic. The two β-coronaviruses share a high degree of homology between the 3CLpro active sites, so much so that the safer HCoV-OC43 has been suggested as a tool for the identification of new anti-SARS-COV-2 agents. Compounds 5 and 24 inhibited effectively both Wuhan and British SARS-CoV-2 patient isolates in Vero E6 cells and the HCoV-OC43 in MRC-5 cells at low micromolar concentrations. The inhibition was apparently exerted via targeting the 3CLpro active sites of both viruses. Compounds 5 and 24 at 100 μM inhibited the SARS-CoV-2 3CLpro activity of 61.78 and 67.30%, respectively. These findings highlight 5 and 24 as lead compounds of a novel class of antiviral agents with the potential to treat SARS-COV-2 and HCoV-OC43 infections.

2023-05-01·Acta crystallographica. Section E, Crystallographic communications

Synthesis and crystal structure of a new copper(II) complex based on 5-ethyl-3-(pyridin-2-yl)-1,2,4-triazole

Article

作者: Raspertova, Ilona V ; Doroshchuk, Roman O ; Petrenko, Yuliia P ; Khomenko, Dmytro M ; Lampeka, Rostyslav D ; Shova, Sergiu

The title compound, bis[μ-3-ethyl-5-(pyridin-2-yl)-1H-1,2,4-triazol-1-ido]bis[acetato(dimethylformamide)copper(II)], [Cu2(C9H9N4)2(C2H3O2)2(C3H7NO)2] or [Cu2(LEt)2(OAc)2(dmf)2], is a triazolate complex, which contains two 3-(2-pyridyl)-5-ethyl-triazolates (LEt)− in bidentate-bridged coordination modes. Both copper atoms are involved in the formation of a planar six-membered metallocycle Cu–[N—N]2–Cu. The inversion center of the complex is located at the mid-point of the Cu...Cu vector. Each CuII atom has a distorted trigonal–bipyramidal environment formed by the three nitrogen atoms of the deprotonated bridging 3-(2-pyridyl)-5-ethyl-triazolate unit, oxygen atoms of the OAc− group and dmf molecule. In the crystal, C—H...O hydrogen bonds link the molecules into chains running along the c-axis direction.

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