Novel 2,6-diketopiperazine-derived Acetohydroxamic Acids as Promising Anti-
            <i>Trypanosoma Brucei</i>
            Agents

Fytas, George; Zoidis, Grigoris; Taylor, Martin C.; Kelly, John M.; Tsatsaroni, Alexandra; Tsotinis, Andrew

doi:10.4155/fmc-2018-0599

Cited by 5 publications

(5 citation statements)

References 14 publications

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“…More recent studies are focusing on the original hypothesis based on the barbituric analogue 18 . Modifying the basic structure of these molecules resulted in spiro 2,6-diketopiperazine (2,6-DKP) derivatives combined with acetohydroxamic moieties in the imidic nitrogen [ 101 ]. This class of compounds proved to be a valuable scaffold as a lead, and the hydroxamic unit seems indispensable due to its potency.…”

Section: Trypanosoma Brucei 6-oxopurine Phosphoribosyltransf...mentioning

confidence: 99%

“…To identify the exact parameters necessary for inhibiting the growth of T. brucei parasites, nonconstrained 3-alkyl-3-aryl-2,6-DKP molecules were designed and synthesized. The most active compound of this class was N -4-methyl derivative 11 ( Figure 8 ) with a submicromolar IC 50 (0.55 μΜ) followed by compounds 16 and 17 ( Figure 8 ), which were remarkably selective against T. brucei parasites [ 101 ]. Following these findings, another active analogue, namely, (S)-chiral 1f ( Figure 9 ), bearing a benzyl substitution exhibited an IC 50 value of 6.8 nM against T. brucei .…”

Section: Trypanosoma Brucei 6-oxopurine Phosphoribosyltransf...mentioning

confidence: 99%

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Targeting Metalloenzymes: The “Achilles’ Heel” of Viruses and Parasites

Moianos,

Prifti,

Makri

et al. 2023

Pharmaceuticals

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Metalloenzymes are central to the regulation of a wide range of essential viral and parasitic functions, including protein degradation, nucleic acid modification, and many others. Given the impact of infectious diseases on human health, inhibiting metalloenzymes offers an attractive approach to disease therapy. Metal-chelating agents have been expansively studied as antivirals and antiparasitics, resulting in important classes of metal-dependent enzyme inhibitors. This review provides the recent advances in targeting the metalloenzymes of viruses and parasites that impose a significant burden on global public health, including influenza A and B, hepatitis B and C, and human immunodeficiency viruses as well as Trypanosoma brucei and Trypanosoma cruzi.

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Section: Trypanosoma Brucei 6-oxopurine Phosphoribosyltransf...mentioning

confidence: 99%

Section: Trypanosoma Brucei 6-oxopurine Phosphoribosyltransf...mentioning

confidence: 99%

Targeting Metalloenzymes: The “Achilles’ Heel” of Viruses and Parasites

Moianos,

Prifti,

Makri

et al. 2023

Pharmaceuticals

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“…Over the years, we have synthesized a variety of structurally diverse adamantane derivatives that target influenza A virus, T. brucei and T. cruzi [96][97][98][99][100][101][102][103]. In continuation of our studies, we were interested in developing further active adamantane-based compounds that could inhibit the proliferation of the above-mentioned trypanosomatids.…”

Section: Adamantane-based Guanylhydrazone Analoguesmentioning

confidence: 99%

Lipophilic Guanylhydrazone Analogues as Promising Trypanocidal Agents: An Extended SAR Study

Pardali

Giannakopoulou

Balourdas

et al. 2020

CPD

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In this report, we extend the SAR analysis of a number of lipophilic guanylhydrazone analogues with respect to in vitro growth inhibition of Trypanosoma brucei and Trypanosoma cruzi. Sleeping sickness and Chagas disease, caused by the tropical parasites T. brucei and T. cruzi, constitute a significant socioeconomic burden in low-income countries of sub-Saharan Africa and Latin America, respectively. Drug development is underfunded. Moreover, current treatments are outdated and difficult to administer, while drug resistance is an emerging concern. The synthesis of adamantane-based compounds that have potential as antitrypanosomal agents is extensively reviewed. The critical role of the adamantane ring was further investigated by synthesizing and testing a number of novel lipophilic guanylhydrazones. The introduction of hydrophobic bulky substituents onto the adamantane ring generated the most active analogues, illustrating the synergistic effect of the lipophilic character of the C1 side chain and guanylhydrazone moiety on trypanocidal activity. The n-decyl C1-substituted compound G8 proved to be the most potent adamantane derivative against T. brucei with activity in the nanomolar range (EC50=90 nM). Molecular simulations were also performed to better understand the structure-activity relationships between the studied guanylhydrazone analogues and their potential enzyme target.

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“…Structures of spiro carbocyclic 2,6-diketopiperazine-1-acetohydroxamic acid derivatives 1 – 5 , and 3-alkyl-3-aryl 2,6-diketopiperazine-1-acetohydroxamic acids 6 – 17 reported previously, along with structures of the new hydroxamic acid derivatives 18 – 28 based on spiro carbocyclic 2,6-diketopiperazine scaffolds.…”

mentioning

confidence: 96%

“…This modification led to a novel series of acetohydroxamic acid derivatives (Figure 1, Additionally, the most active of these compounds had promising selectivity over the parasite with respect to mammalian cells. 14 SAR studies demonstrated that compounds bearing a methyl, n-propyl or nbutyl substituent at the N(4)-position of the 2,6-DKP ring portion exhibited the highest activity against bloodstream form T. brucei.…”

mentioning

confidence: 99%

New Lipophilic Hydroxamates as Promising Trypanocidal Agents: Design, Synthesis, SAR, and Conformational Behavior Studies

Fytas,

Zoidis,

Drakopoulos

et al. 2024

ACS Med. Chem. Lett.

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A series of novel hydroxamic acid derivatives was designed and synthesized, and their growth inhibitory activity against bloodstream form Trypanosoma brucei was evaluated. These compounds are based on conformationally constrained, lipophilic, spiro carbocyclic 2,6-diketopiperazine (2,6-DKP) scaffolds and bear a side pharmacophoric functionality that contains an acetohydroxamic acid moiety (CH 2 CONHOH) linked with the imidic nitrogen atom of the 2,6-DKP ring via an acetamido portion [CH 2 CON(R), R = H, CH 3 ]. Most of these analogues were active in the midnanomolar to low micromolar range against T. brucei. (S)-Isobutyl-or (S)-benzyl-substitution on the methylene carbon located between the amine nitrogen atom and carbonyl of the 2,6-DKP ring was studied. The effect of the methyl-substitution on the nitrogen atom of the acetamido portion in the side pharmacophoric functionality was also examined. Compounds 22 and 23, bearing an isobutyl-or benzyl-substituent, respectively, and concurrently a methyl-substituent, were found to be the most potent hydroxamates of this series (IC 50 = 34 and 53 nM, respectively). Both had promising selectivity over the parasite compared to mammalian cells (SI = 940 and 470, respectively). Moreover, an E/Z conformational behavior study on hydroxamic acid 18 and its methyl-substituted counterpart 21 was undertaken using NMR spectroscopy and theoretical calculations.

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Novel 2,6-diketopiperazine-derived Acetohydroxamic Acids as Promising Anti- Trypanosoma Brucei Agents

Cited by 5 publications

References 14 publications

Targeting Metalloenzymes: The “Achilles’ Heel” of Viruses and Parasites

Targeting Metalloenzymes: The “Achilles’ Heel” of Viruses and Parasites

Lipophilic Guanylhydrazone Analogues as Promising Trypanocidal Agents: An Extended SAR Study

New Lipophilic Hydroxamates as Promising Trypanocidal Agents: Design, Synthesis, SAR, and Conformational Behavior Studies

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