scholarly journals New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1842
Author(s):  
Francisco José Aguilar-Troyano ◽  
Archimede Torretta ◽  
Gianluca Rubbini ◽  
Alberto Fasiolo ◽  
Pilar María Luque-Navarro ◽  
...  
Keyword(s):  
Opposite Effect ◽  
Kinase Inhibitors ◽  
Antimalarial Activity ◽  
Molecular Target ◽  
Choline Kinase ◽  
Choline Uptake ◽  
Bioisosteric Replacement ◽  
Similar Good ◽  
New Compounds ◽  
New Strategies

In the fight against Malaria, new strategies need to be developed to avoid resistance of the parasite to pharmaceutics and other prevention barriers. Recently, a Host Directed Therapy approach based on the suppression of the starting materials uptake from the host by the parasite has provided excellent results. In this article, we propose the synthesis of bioisosteric compounds that are capable of inhibiting Plasmodium falciparum Choline Kinase and therefore to reduce choline uptake, which is essential for the development of the parasite. Of the 41 bioisosteric compounds reported herein, none showed any influence of the linker on the antimalarial and enzyme inhibitory activity, whereas an effect of the type of cationic heads used could be observed. SARs determined that the thienopyrimidine substituted in 4 by a pyrrolidine is the best scaffold, independently of the chosen linker. The decrease in lipophilicity seems to improve the antimalarial activity but to cause an opposite effect on the inhibition of the enzyme. While potent compounds with similar good inhibitory values have been related to the proposed mechanism of action, some of them still show discrepancies and further studies are needed to determine their specific molecular target.

scholarly journals Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1360
Author(s):  
Santiago Schiaffino-Ortega ◽  
Elena Mariotto ◽  
Pilar María Luque-Navarro ◽  
María Kimatrai-Salvador ◽  
Pablo Rios-Marco ◽  
...  
Keyword(s):  
Antiproliferative Activity ◽  
Kinase Inhibitors ◽  
Human Tumor ◽  
Structure Activity Relationship ◽  
Inhibitory Effect ◽  
Activity Relationship ◽  
Choline Kinase ◽  
Choline Uptake ◽  
Uptake Inhibition ◽  
Structure Activity

Choline kinase inhibitors are an outstanding class of cytotoxic compounds useful for the treatment of different forms of cancer since aberrant choline metabolism is a feature of neoplastic cells. Here, we present the most in-depth structure-activity relationship studies of an interesting series of non-symmetric choline kinase inhibitors previously reported by our group: 3a–h and 4a–h. They are characterized by cationic heads of 3-aminophenol bound to 4-(dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium through several linkers. These derivatives were evaluated both for their inhibitory activity on the enzyme and their antiproliferative activity in a panel of six human tumor cell lines. The compounds with the N-atom connected to the linker (4a–h) show the best inhibitory results, in the manner of results supported by docking studies. On the contrary, the best antiproliferative compounds were those with the O-atom bounded to the linker (3a–h). On the other hand, as was predictable in both families, the inhibitory effect on the enzyme is better the shorter the length of the linker. However, in tumor cells, lipophilicity and choline uptake inhibition could play a decisive role. Interestingly, compounds 3c and 4f, selected for both their ability to inhibit the enzyme and good antiproliferative activity, are endowed with low toxicity in non-tumoral cells (e.g., human peripheral lymphocytes) concerning cancer cells. These compounds were also able to induce apoptosis in Jurkat leukemic cells without causing significant variations of the cell cycle. It is worth mentioning that these derivatives, besides their inhibitory effect on choline kinase, displayed a modest ability to inhibit choline uptake thus suggesting that this mechanism may also contribute to the observed cytotoxicity.

scholarly journals Anticancer Activity and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors

2021 ◽  
Author(s):  
Santiago Schiaffino-Ortega ◽  
Elena Mariotto ◽  
Pilar María Luque-Navarro ◽  
María Kimatrai-Salvador ◽  
Ramon Hurtado-Guerrero ◽  
...  
Keyword(s):  
Antiproliferative Activity ◽  
Kinase Inhibitors ◽  
Structure Activity Relationship ◽  
Inhibitory Effect ◽  
Activity Relationship ◽  
Choline Kinase ◽  
Choline Uptake ◽  
Uptake Inhibition ◽  
Structure Activity ◽  
Relationship Of

Choline kinase inhibitors are an important class of cytotoxic compounds useful for the treatment of different forms of cancer since aberrant choline metabolism is a feature of neoplastic cells. Here we present the characterization and the structure activity relationship of a series of non-symmetrical choline kinase inhibitors characterized by a 3-aminophenol moiety, bound to 4-(dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium cationic heads through several linkers. These derivatives were evaluated both for their inhibitory activity on the enzyme and for their antiproliferative activity in a panel of six human tumor cell lines. The compounds with the best inhibitory results were those connected to the linker by the N-atom (4a-h) and these results are supported by docking studies. The compounds with the best antiproliferative results were those connected to the linker by the O-atom (3a-h). On the other hand, as was predictable in both families, the inhibitory effect on the enzyme is greater the shorter the length of the linker, while in tumor cells, lipophilicity and choline uptake inhibition could play a decisive role. Interestingly compounds 3c and 4f, selected for both their ability to inhibit the enzyme and good antiproliferative activity, are endowed with a low toxicity in non-tumoral cells (e.g human peripheral lymphocytes) respect to cancer cells. These compounds were also able to induce to induce apoptosis in Jurkat leukemic cells without causing significative variations of cell cycle. It is worth to mention that these derivatives, beside their inhibitory effect on choline kinase, displayed a modest ability to inhibit choline uptake thus suggesting that this mechanism may also contribute to the observed cytotoxicity.

scholarly journals A Systematic Review of Recently Reported Marine Derived Natural Product Kinase Inhibitors

Marine Drugs ◽  
2019 ◽  
Vol 17 (9) ◽  
pp. 493 ◽  
Author(s):  
Li ◽  
Wang ◽  
Zhang ◽  
Zhang ◽  
Sajeevan ◽  
...  
Keyword(s):  
Small Molecules ◽  
Natural Product ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Disease States ◽  
Clinical Drugs ◽  
Kinase Inhibitory Activity ◽  
New Compounds ◽  
Further Development

Protein kinases are validated drug targets for a number of therapeutic areas, as kinase deregulation is known to play an essential role in many disease states. Many investigated protein kinase inhibitors are natural product small molecules or their derivatives. Many marine-derived natural products from various marine sources, such as bacteria and cyanobacteria, fungi, animals, algae, soft corals, sponges, etc. have been found to have potent kinase inhibitory activity, or desirable pharmacophores for further development. This review covers the new compounds reported from the beginning of 2014 through the middle of 2019 as having been isolated from marine organisms and having potential therapeutic applications due to kinase inhibitory and associated bioactivities. Moreover, some existing clinical drugs based on marine-derived natural product scaffolds are also discussed.

scholarly journals Synthesis and Antimalarial Activity of 1,4-Disubstituted Piperidine Derivatives

Molecules ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 299 ◽  
Author(s):  
Rokhyatou Seck ◽  
Abdoulaye Gassama ◽  
Sandrine Cojean ◽  
Christian Cavé
Keyword(s):  
Plasmodium Falciparum ◽  
Side Effects ◽  
Antimalarial Activity ◽  
Low Cost ◽  
Compound Library ◽  
New Compounds

In order to prepare, at low cost, new compounds active against Plasmodium falciparum, and with a less side-effects, we have designed and synthesized a library of 1,4-disubstituted piperidine derivatives from 4-aminopiperidine derivatives 6. The resulting compound library has been evaluated against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. The most active molecules—compounds 12d (13.64 nM (3D7)), 13b (4.19 nM (3D7) and 13.30 nM (W2)), and 12a (11.6 nM (W2))—were comparable to chloroquine (22.38 nM (3D7) and 134.12 nM (W2)).

scholarly journals A Single-Dose Combination Study with the Experimental Antimalarials Artefenomel and DSM265 To Determine Safety and Antimalarial Activity against Blood-Stage Plasmodium falciparum in Healthy Volunteers

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
James S. McCarthy ◽  
Thomas Rückle ◽  
Suzanne L. Elliott ◽  
Emma Ballard ◽  
Katharine A. Collins ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Plasma Concentrations ◽  
Parasite Clearance ◽  
Blood Stage ◽  
Content Type ◽  
Dose Combination ◽  
Combination Study ◽  
Study Support ◽  
New Compounds

ABSTRACT Artefenomel and DSM265 are two new compounds that have been shown to be well tolerated and effective when administered as monotherapy malaria treatment. This study aimed to determine the safety, pharmacokinetics, and pharmacodynamics of artefenomel and DSM265 administered in combination to healthy subjects in a volunteer infection study using the Plasmodium falciparum-induced blood-stage malaria model. Thirteen subjects were inoculated with parasite-infected erythrocytes on day 0 and received a single oral dose of artefenomel and DSM265 on day 7. Cohort 1 (n = 8) received 200 mg artefenomel plus 100 mg DSM265, and cohort 2 (n = 5) received 200 mg artefenomel plus 50 mg DSM265. Blood samples were collected to measure parasitemia, gametocytemia, and artefenomel-DSM265 plasma concentrations. There were no treatment-related adverse events. The pharmacokinetic profiles of artefenomel and DSM265 were similar to those of the compounds when administered as monotherapy, suggesting no pharmacokinetic interactions. A reduction in parasitemia occurred in all subjects following treatment (log10 parasite reduction ratios over 48 h [PRR48] of 2.80 for cohort 1 and 2.71 for cohort 2; parasite clearance half-lives of 5.17 h for cohort 1 and 5.33 h for cohort 2). Recrudescence occurred in 5/8 subjects in cohort 1 between days 19 and 28 and in 5/5 subjects in cohort 2 between days 15 and 22. Low-level gametocytemia (1 to 330 female gametocytes/ml) was detected in all subjects from day 14. The results of this single-dosing combination study support the further clinical development of the use of artefenomel and DSM265 in combination as a treatment for falciparum malaria. (This study has been registered at ClinicalTrials.gov under identifier NCT02389348.)

scholarly journals Quantitative Structure-Activity Relationship Studies for Potential Rho-Associated Protein Kinase Inhibitors

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Giovanna Cardoso Gajo ◽  
Tamiris Maria de Assis ◽  
Letícia Cristina Assis ◽  
Teodorico Castro Ramalho ◽  
Elaine Fontes Ferreira da Cunha
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Quantitative Structure Activity Relationship ◽  
Structure Activity Relationship ◽  
Protein Kinase Inhibitors ◽  
Activity Relationship ◽  
Quantitative Structure ◽  
Qsar Analysis ◽  
Structure Activity ◽  
New Compounds

A series of pyridylthiazole derivatives developed by Lawrence et al. as Rho-associated protein kinase inhibitors were subjected to four-dimensional quantitative structure-activity relationship (4D-QSAR) analysis. The models were generated applying genetic algorithm (GA) optimization combined with partial least squares (PLS) regression. The best model presented validation values ofr2=0.773,qCV2=0.672,rpred2=0.503,Δrm2=0.197,rm test2⁡⁡=0.520,rY-rand2=0.19, andRp2=0.590. Furthermore, analyzing the descriptors it was possible to propose new compounds that predicted higher inhibitory concentration values than the most active compound of the series.

Blood schizontocidal activity of azithromycin and its combination with α/β arteether against multi-drug resistant Plasmodium yoelii nigeriensis, a novel MDR parasite model for antimalarial screening

Parasitology ◽  
2005 ◽  
Vol 131 (3) ◽  
pp. 295-301 ◽  
Author(s):  
R. TRIPATHI ◽  
S. DHAWAN ◽  
G. P. DUTTA
Keyword(s):  
Antimalarial Activity ◽  
Wide Spectrum ◽  
Oral Route ◽  
Plasmodium Yoelii ◽  
Drug Resistant ◽  
Curative Effect ◽  
Resistant Lines ◽  
High Doses ◽  
New Compounds

Many different drug-resistant lines of rodent malaria are available as screening models. It is obligatory to screen new compounds for antimalarial activity against a series of resistant lines in order to identify a compound with potential for the treatment of multi-drug resistant (MDR) malaria infections. Instead of using a battery of resistant lines, a single MDR Plasmodium yoelii nigeriensis strain that shows a wide spectrum of drug resistance to high doses of chloroquine, mepacrine, amodiaquine, mefloquine, quinine, quinidine, halofantrine as well as tetracyclines, fluoroquinolines and erythromycin, was used to assess the blood schizontocidal efficacy of a new macrolide azithromycin and other antibiotics. The present study shows that only azithromycin has the potential to control an MDR P. y. nigeriensis infection in Swiss mice, provided the treatment with a dose of 50–100 mg/kg/day by oral route is continued for a period of 7 days. Tetracycline, oxytetracycline, doxycyline, erythromycin, ciprofloxacin and norfloxacin, although active in vitro, failed to protect the mice. Tetracycline, ciprofloxacin and norfloxacin combinations with chloroquine did not control the infection. Additionally, the antimalarial efficacy of azithromycin can be potentiated with the addition of arteether, which is an ethyl ether derivative of artemisinin. A total (100%) curative effect has been obtained with a shorter regimen of 4 days only.

scholarly journals Efficient Hit-to-Lead Searching of Kinase Inhibitor Chemical Space via Computational Fragment Merging

2021 ◽  
Author(s):  
Grigorii V. Andrianov ◽  
Wern Juin Gabriel Ong ◽  
Ilya Serebriiskii ◽  
John Karanicolas
Keyword(s):  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chemical Space ◽  
Early Stage ◽  
Building Blocks ◽  
Lead Optimization ◽  
Chemical Transformations ◽  
Interaction Energies ◽  
The Individual ◽  
New Compounds

In early stage drug discovery, the stage of hit-to-lead optimization (or "hit expansion") entails starting from a newly-identified active compound, and improving its potency or other properties. Traditionally this process relies on synthesizing and evaluating a series of analogs to build up structure-activity relationships. Here, we describe a computational strategy focused on kinase inhibitors, intended to expedite the process of identifying analogs with improved potency. Our protocol begins from an inhibitor of the target kinase, and generalizes the synthetic route used to access it. By searching for commercially-available replacements for the individual building blocks used to make the parent inhibitor, we compile an enumerated library of compounds that can be accessed using the same chemical transformations; these huge libraries can exceed many millions - or billions - of compounds. Because the resulting libraries are much too large for explicit virtual screening, we instead consider alternate approaches to identify the top-scoring compounds. We find that contributions from individual substituents are well-described by a pairwise additivity approximation, provided that the corresponding fragments position their shared core in precisely the same way relative to the binding site. This key insight allows us to determine which fragments are suitable for merging into a single new compounds, and which are not. Further, the use of the pairwise approximation allows interaction energies to be assigned to each compound in the library, without the need for any further structure-based modeling: interaction energies instead can be reliably estimated from the energies of the component fragments. We demonstrate this protocol using libraries built from five representative kinase inhibitors drawn from the literature, which target four different kinases: CDK9, CHK1, CDK2, and ACK1. In each example, the enumerated library includes additional analogs reported by the original study to have activity, and these analogs are successfully prioritized within the library. We envision that the insights from this work can facilitate the rapid assembly and screening of increasingly large libraries for focused hit-to-lead optimization. To enable adoption of these methods and to encourage further analyses, we disseminate the computational tools needed to deploy this protocol.

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