New carbohydrazide derivatives of 1H-pyrazolo[3,4-b]pyridine and trypanocidal activity

Salvador, Raquel R.S.; Bello, Murilo Lamim; Barreto, Igor Ramon Lomba; Vera, Maria A.F.; Muri, Estela M.F.; Albuquerque, Sérgio de; Dias, Luiza R.S.

doi:10.1590/0001-3765201620160087

Cited by 9 publications

(4 citation statements)

References 24 publications

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“…UBMC-6 represents another putative Tc Akt inhibitor, having an inhibitory effect on T. cruzi amastigotes and was also tested for its toxicity on human monocyte-derived macrophages 24 , 79 . According to the presented AF structure, UBMC-6 binds close to the h-motif of Tc Akt and the p-sites T290 and S450 (K128, V129, S130, L131, D132, F201, T203, K205, P431, F435, E437), an important region to regulate Akt stability 80 .…”

Section: Resultsmentioning

confidence: 99%

Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease

Stadler,

Ortiz-Joya,

Singh Sahrawat

et al. 2024

Sci Rep

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According to the World Health Organization, Chagas disease (CD) is the most prevalent poverty-promoting neglected tropical disease. Alarmingly, climate change is accelerating the geographical spreading of CD causative parasite, Trypanosoma cruzi, which additionally increases infection rates. Still, CD treatment remains challenging due to a lack of safe and efficient drugs. In this work, we analyze the viability of T. cruzi Akt-like kinase (TcAkt) as drug target against CD including primary structural and functional information about a parasitic Akt protein. Nuclear Magnetic Resonance derived information in combination with Molecular Dynamics simulations offer detailed insights into structural properties of the pleckstrin homology (PH) domain of TcAkt and its binding to phosphatidylinositol phosphate ligands (PIP). Experimental data combined with Alpha Fold proposes a model for the mechanism of action of TcAkt involving a PIP-induced disruption of the intramolecular interface between the kinase and the PH domain resulting in an open conformation enabling TcAkt kinase activity. Further docking experiments reveal that TcAkt is recognized by human inhibitors PIT-1 and capivasertib, and TcAkt inhibition by UBMC-4 and UBMC-6 is achieved via binding to TcAkt kinase domain. Our in-depth structural analysis of TcAkt reveals potential sites for drug development against CD, located at activity essential regions.

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Section: Resultsmentioning

confidence: 99%

Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease

Stadler,

Ortiz-Joya,

Singh Sahrawat

et al. 2024

Sci Rep

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“…The compound UBMC-6 has in its structure a pyrazolopyridine core that have been previously assayed against T. cruzi amastigotes, with an IC 50 of 10.47 μM [34]. In addition, its structural analogue pyrazolopyrimidine has presented promising effects against apicomplexan parasites, such as Neospora caninum and Toxoplasma gondii, acting on the protein kinase CDPK in both cases [35,36].…”

Section: Discussionmentioning

confidence: 99%

Search of Allosteric Inhibitors and Associated Proteins of an AKT-like Kinase from Trypanosoma cruzi

Ochoa

Rocha-Roa

Marín-Villa

et al. 2018

IJMS

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Proteins associated to the PI3K/AKT/mTOR signaling pathway are widely used targets for cancer treatment, and in recent years they have also been evaluated as putative targets in trypanosomatids parasites, such as Trypanosoma cruzi. Here, we performed a virtual screening approach to find candidates that can bind regions on or near the Pleckstrin homology domain of an AKT-like protein in T. cruzi. The compounds were also evaluated in vitro. The in silico and experimental results allowed us to identify a set of compounds that can potentially alter the intracellular signaling pathway through the AKT-like kinase of the parasite; among them, a derivative of the pyrazolopyridine nucleus with an IC50 of 14.25 ± 1.00 μM against amastigotes of T. cruzi. In addition, we built a protein–protein interaction network of T. cruzi to understand the role of the AKT-like protein in the parasite, and look for additional proteins that can be postulated as possible novel molecular targets for the rational design of compounds against T. cruzi.

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“…Selective activity for intracellular amastigotes was also evidenced in 3-methyl-1phenyl-1H-pyrazolo[3,4-b]pyridine-4-carbohydrazide derivatives. These analogs showed little or no activity against trypomastigotes, with the loss of trypanocidal activity attributed to the insertion of fluorine in C6, a strong electron-withdrawing group (EWG) [35]. Moreover, a similar phenomenon has been reported with posaconazole, an inhibitor of ergosterol biosynthesis, which has excellent activity against intracellular amastigotes, in the nanomolar range, but it is less effective against the non-replicative stage and low-replication cycle amastigotes (dormant amastigotes), suggesting that replication and the speed of its cycles may affect the efficacy of posaconazole [36].…”

Section: Toxicity and Trypanocidal Effect Of Pyrazole Derivativesmentioning

confidence: 99%

Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against Trypanosoma cruzi

et al. 2021

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Chagas disease, a chronic and silent disease caused by Trypanosoma cruzi, is currently a global public health problem. The treatment of this neglected disease relies on benznidazole and nifurtimox, two nitroheterocyclic drugs that show limited efficacy and severe side effects. The failure of potential drug candidates in Chagas disease clinical trials highlighted the urgent need to identify new effective chemical entities and more predictive tools to improve translational success in the drug development pipeline. In this study, we designed a small library of pyrazole derivatives (44 analogs) based on a hit compound, previously identified as a T. cruzi cysteine protease inhibitor. The in vitro phenotypic screening revealed compounds 3g, 3j, and 3m as promising candidates, with IC50 values of 6.09 ± 0.52, 2.75 ± 0.62, and 3.58 ± 0.25 µM, respectively, against intracellular amastigotes. All pyrazole derivatives have good oral bioavailability prediction. The structure–activity relationship (SAR) analysis revealed increased potency of 1-aryl-1H-pyrazole-imidazoline derivatives with the Br, Cl, and methyl substituents in the para-position. The 3m compound stands out for its trypanocidal efficacy in 3D microtissue, which mimics tissue microarchitecture and physiology, and abolishment of parasite recrudescence in vitro. Our findings encourage the progression of the promising candidate for preclinical in vivo studies.

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New carbohydrazide derivatives of 1H-pyrazolo[3,4-b]pyridine and trypanocidal activity

Cited by 9 publications

References 24 publications

Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease

Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease

Search of Allosteric Inhibitors and Associated Proteins of an AKT-like Kinase from Trypanosoma cruzi

Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against Trypanosoma cruzi

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