Identification of Novel Parasitic Cysteine Protease Inhibitors Using Virtual Screening. 1. The ChemBridge Database

Desai, Prashant; Patny, Akshay; Sabnis, Yogesh; Tekwani, Babu L.; Gut, Jiří; Rosenthal, Philip J.; Srivastava, and Anuradha; Avery, Mitchell A.

doi:10.1021/jm0493717

Cited by 108 publications

(116 citation statements)

References 30 publications

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“…Contrary to what has been described for vinyl sulfone-based peptides (13), the inhibitors tested herein were selective for parasite over host cells and probably for parasite over host cell CPs; even at 100 M, they did not affect host cell proliferation and survival but inhibited parasite growth and reduced the infection rate of macrophages.…”

Section: Discussioncontrasting

confidence: 94%

Aziridine-2,3-Dicarboxylates, Peptidomimetic Cysteine Protease Inhibitors with Antileishmanial Activity

Ponte-Sucre

Vičík

Martina

et al. 2006

Antimicrob Agents Chemother

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Chemotherapy of leishmaniasis is mainly based on antimonials. However, they are extremely toxic and cause serious side effects, and there is a worldwide increasing frequency of chemoresistance to antimonials. These issues emphasize the urgent need for affordable alternative drugs against leishmaniasis. Leishmania cysteine proteases are essential for parasite growth, differentiation, pathogenicity, and virulence and are thus attractive targets for combating leishmaniasis. Herein we demonstrate that the cysteine protease inhibitors aziridine-2,3-dicarboxylates 13b and 13e impaired promastigote growth at mid-micromolar concentrations and decreased the infection rate of peritoneal macrophages at concentrations 8-to 13-fold lower than those needed to inhibit parasite replication. Simultaneous treatment of infected cells with compound 13b and gamma interferon resulted in an even further reduction of the concentration needed for a significant decrease in macrophage infection rate. Notably, treatment with the compounds alone modulated the cytokine secretion of infected macrophages, with increased levels of interleukin-12 and tumor necrosis factor alpha. Furthermore, the decreased infection rate in the presence of compound 13b correlated with increased nitric oxide production by macrophages. Importantly, at the concentrations used herein, compounds 13b and 13e were not toxic against fibroblasts, macrophages, or dendritic cells. Together, these results suggest that the aziridine-2,3-dicarboxylates 13b and 13e are potential antileishmanial lead compounds with low toxicity against host cells and selective antiparasitic effects.

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Section: Discussioncontrasting

confidence: 94%

Aziridine-2,3-Dicarboxylates, Peptidomimetic Cysteine Protease Inhibitors with Antileishmanial Activity

Ponte-Sucre

Vičík

Martina

et al. 2006

Antimicrob Agents Chemother

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“…Progress in proteomics and genomics will further allow rapid evolution in the field, as several new proteases are already available in gene databanks. Simultaneously, important efforts are being undertaken for the development of CP-inhibiting molecules for T. congolense, T. brucei brucei, and T. brucei rhodesiense (34,35,48,49,59,82,157).…”

Section: The Major Candidatesmentioning

confidence: 99%

Host-Parasite Interactions in Trypanosomiasis: on the Way to an Antidisease Strategy

2009

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“…20 In our drug designing strategy, we have selected few existing potential falcipain-2 inhibitors 25,26 (IC 50 value range from 1 to 10.9 µM) and composed a basic core structure by mimicking with chain length which was depicted in Figure 2. The core features of the selected structures were: a) hydrophobic moiety; commonly an aromatic residue, b) aromatic moiety (monocyclic/bicyclic), and c) linker; hydrogen bond donor and acceptor atom(s), which attached the hydrophobic moiety to the aromatic residue.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of novel 1-(4-(substituted)piperazin-1-yl)- 2-(phenylamino)ethanone derivatives as Falcipain-2 inhibitors

Mundra¹,

Mahesh²

2015

JYP

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Background: Malaria, an infectious disease transmitted by mosquitoes, has affected the world since the beginning of recorded human history and it remains an ensconced global health challenge even today. Among the various proteases, expressed in the life cycle of parasite, cysteine protease falcipain-2 plays a pivotal role in parasite food assimilation and inhibition of this protease cause deleterious effects on the growth of parasite. Methods: Employing a ligand-based approach, 1-(4-(substituted)piperazin-1-yl)-2-(phenylamino) ethanone derivatives were designed and synthesized from the starting material piperazine in a sequence of reactions. Structural assignments are based on spectral data ( 1 H NMR, mass) and elemental analyses. The purity of the final compounds was confirmed by HPLC. The compounds were tested for their in vitro falcipain-2 inhibitor activity on recombinant falcipain-2 enzyme. Furthermore, molecular docking studies were performed using Glide 5.9 software to incur a precise picture of the active ligand at the atomic level which will be helpful in the discovery of new antimalarial drugs. Results: Among the screening results of seventeen novel entities, three compounds (6h, 6n and 6o) have showed good inhibitory activity and eleven compounds were showed weak to moderate inhibitor activity. Docking studies for these active analogues revealed that the amino acids Trp 206, Ile 85, Leu 84, Val 152 most commonly involved in hydrophobic interactions and Asn 173, Cys 42, Gln 36, amino acids involved in hydrogen bonding. Conclusion: The preliminary structure-activity relationships indicated that compound 6h, is the most potent compound from this series, and it can be used as a potential lead compound in the designing of new candidates to optimize the inhibitory potencies of this class of compounds, and potentially with potent antimalarial activity.

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Identification of Novel Parasitic Cysteine Protease Inhibitors Using Virtual Screening. 1. The ChemBridge Database

Cited by 108 publications

References 30 publications

Aziridine-2,3-Dicarboxylates, Peptidomimetic Cysteine Protease Inhibitors with Antileishmanial Activity

Aziridine-2,3-Dicarboxylates, Peptidomimetic Cysteine Protease Inhibitors with Antileishmanial Activity

Host-Parasite Interactions in Trypanosomiasis: on the Way to an Antidisease Strategy

Evaluation of novel 1-(4-(substituted)piperazin-1-yl)- 2-(phenylamino)ethanone derivatives as Falcipain-2 inhibitors

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