scholarly journals Pyrazoline derivatives as promising novel antischistosomal agents

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Cristiane S. Morais ◽  
Ana C. Mengarda ◽  
Fábio B. Miguel ◽  
Karine B. Enes ◽  
Vinícius C. Rodrigues ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Effective Concentration ◽  
Selectivity Index ◽  
Pharmaceutical Companies ◽  
Parasitic Disease ◽  
Relationship Analysis ◽  
Structure Activity ◽  
Negative Effect ◽  
Low Cytotoxicity ◽  
Predicted Values

AbstractPraziquantel is the only available drug to treat schistosomiasis, a parasitic disease that currently infects more than 240 million people globally. Due to increasing concerns about resistance and inadequate efficacy there is a need for new therapeutics. In this study, a series of 17 pyrazolines (15–31) and three pyrazoles (32–34) were synthesized and evaluated for their antiparasitic properties against ex vivo adult Schistosoma mansoni worms. Of the 20 compounds tested, six had a 50% effective concentration (EC50) below 30 μM. Our best hit, pyrazoline 22, showed promising activity against adult schistosomes, with an EC50 < 10 µM. Additionally, compound 22 had low cytotoxicity, with selectivity index of 21.6 and 32.2 for monkey and human cell lines, respectively. All active pyrazolines demonstrated a negative effect on schistosome fecundity, with a marked reduction in the number of eggs. Structure–activity relationship analysis showed that the presence of the non-aromatic heterocycle and N-substitution are fundamental to the antischistosomal properties. Pharmacokinetics, drug-likeness and medicinal chemistry friendliness studies were performed, and predicted values demonstrated an excellent drug-likeness profile for pyrazolines as well as an adherence to major pharmaceutical companies’ filters. Collectively, this study demonstrates that pyrazoline derivatives are promising scaffolds in the discovery of novel antischistosomal agents.

scholarly journals Resveratrol Inhibits HCoV-229E and SARS-CoV-2 Coronavirus Replication In Vitro

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 354
Author(s):  
Sébastien Pasquereau ◽  
Zeina Nehme ◽  
Sandy Haidar Ahmad ◽  
Fadoua Daouad ◽  
Jeanne Van Assche ◽  
...  
Keyword(s):  
Drug Repurposing ◽  
Effective Concentration ◽  
Selectivity Index ◽  
Viral Titer ◽  
Human Coronavirus ◽  
Candidate Drug ◽  
Drug Compounds ◽  
Low Cytotoxicity ◽  
Novel Coronavirus

A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China at the end of 2019 causing a large global outbreak. As treatments are of the utmost importance, drug repurposing embodies a rich and rapid drug discovery landscape, where candidate drug compounds could be identified and optimized. To this end, we tested seven compounds for their ability to reduce replication of human coronavirus (HCoV)-229E, another member of the coronavirus family. Among these seven drugs tested, four of them, namely rapamycin, disulfiram, loperamide and valproic acid, were highly cytotoxic and did not warrant further testing. In contrast, we observed a reduction of the viral titer by 80% with resveratrol (50% effective concentration (EC50) = 4.6 µM) and lopinavir/ritonavir (EC50 = 8.8 µM) and by 60% with chloroquine (EC50 = 5 µM) with very limited cytotoxicity. Among these three drugs, resveratrol was less cytotoxic (cytotoxic concentration 50 (CC50) = 210 µM) than lopinavir/ritonavir (CC50 = 102 µM) and chloroquine (CC50 = 67 µM). Thus, among the seven drugs tested against HCoV-229E, resveratrol demonstrated the optimal antiviral response with low cytotoxicity with a selectivity index (SI) of 45.65. Similarly, among the three drugs with an anti-HCoV-229E activity, namely lopinavir/ritonavir, chloroquine and resveratrol, only the latter showed a reduction of the viral titer on SARS-CoV-2 with reduced cytotoxicity. This opens the door to further evaluation to fight Covid-19.

scholarly journals TRYPANOCIDAL, ANTI-LEISHMANIAL, AND CYTOTOXIC ACTIVITY OF MUEHLENBECKIA TAMNIFOLIA (KUNTH) MEINS (POLYGONACEAE)

2019 ◽  
pp. 208-211
Author(s):  
RODRÍGUEZ A OSCAR E ◽  
TORRENEGRA G RUBÉN D ◽  
POMBO O LUIS M
Keyword(s):  
Inhibitory Concentration ◽  
Effective Concentration ◽  
Light Petroleum ◽  
Selectivity Index ◽  
Intracellular Amastigotes ◽  
Leishmania Panamensis ◽  
Low Cytotoxicity ◽  
High Cytotoxicity ◽  
The Town ◽  
Enzymatic Micromethod

Objective: The objective of this study was to evaluate the activity against amastigotes of Leishmania panamensis and epimastigotes of Trypanosoma cruzi (Chagas), extracts and fractions obtained from leaves and stems of Muehlenbeckia tamnifolia. Methods: Plant material was collected during the flowering, in the town of La Calera (Cundinamarca), at a height of 2746 m above sea level, 4°43’11”N, 3°58’12”W. Leaves and stems were extracted with light petroleum and then with ethanol. The extracts were fractionated by column chromatography on silica gel with petrol; CH2Cl2, AcOEt, and MeOH. The activity against epimastigotes and cytotoxicity was evaluated by the enzymatic micromethod with MTT. The active extracts against epimastigotes and with low cytotoxicity were also evaluated in trypomastigotes and intracellular amastigotes. Results: The dichloromethane fraction from leaves and stems of M. tamnifolia showed the highest activity against Leishmania panamensis with an 50% of the effective concentration of 0.006 (μg/ml) and a selectivity index of 4.16. In U937 cells, six of the extracts and fractions tested showed high cytotoxicity, 50 inhibitory concentration <50 μg/ml. Conclusions: The extracts obtained from leaves and stems of different polarities of M. tamnifolia (Kunth) Meins, revealed a moderate effect against amastigotes of L. panamensis (Leishmaniosis) (low polarity fractions) and a low effect against epimastigotes of T. cruzi (Chagas).

An Update on JAK Inhibitors

2019 ◽  
Vol 26 (10) ◽  
pp. 1806-1832 ◽  
Author(s):  
Francesca Musumeci ◽  
Chiara Greco ◽  
Ilaria Giacchello ◽  
Anna Lucia Fallacara ◽  
Munjed M. Ibrahim ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinases ◽  
Chemical Structure ◽  
Receptor Tyrosine Kinases ◽  
Myeloproliferative Neoplasms ◽  
Pharmaceutical Companies ◽  
Jak Inhibitors ◽  
Pyrimidine Derivatives ◽  
Janus Kinases ◽  
Structure Activity

Janus kinases (JAKs) are a family of non-receptor tyrosine kinases, composed by four members, JAK1, JAK2, JAK3 and TYK2. JAKs are involved in different inflammatory and autoimmune diseases, as well as in malignancies, through the activation of the JAK/STAT signalling pathway. Furthermore, the V617F mutation in JAK2 was identified in patients affected by myeloproliferative neoplasms. This knowledge prompted researchers from academia and pharmaceutical companies to investigate this field in order to discover small molecule JAK inhibitors. These efforts recently afforded to the market approval of four JAK inhibitors. Despite the fact that all these drugs are pyrrolo[2,3-d]pyrimidine derivatives, many compounds endowed with different heterocyclic scaffolds have been reported in the literature as selective or multi-JAK inhibitors, and a number of them is currently being evaluated in clinical trials. In this review we will report many representative compounds that have been published in articles or patents in the last five years (period 2013-2017). The inhibitors will be classified on the basis of their chemical structure, focusing, when possible, on their structure activity relationships, selectivity and biological activity. For every class of derivatives, compounds disclosed before 2013 that have entered clinical trials will also be briefly reported, to underline the importance of a particular chemical scaffold in the search for new inhibitors.

Isolation of Natural Compounds from Syzygium densiflorum Fruits and Exploring its Chemical Property, Therapeutic Role in Diabetic Management

2020 ◽  
Vol 10 (2) ◽  
pp. 168-176
Author(s):  
Krishnasamy Gopinath ◽  
Nagarajan Subbiah ◽  
Muthusamy Karthikeyan
Keyword(s):  
Density Functional ◽  
Chemical Reactivity ◽  
Natural Compounds ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Computational Studies ◽  
Therapeutic Role ◽  
Relationship Analysis ◽  
Structure Activity

Background: Syzygium densiflorum Wall. ex Wight & Arn (Myrtaceae) has been traditionally used by the local tribes of the Nilgiris, Tamil Nadu, India, for the treatment of diabetes. Objective: This study aimed to isolate the major phytoconstituents from the S. densiflorum fruits and to perform computational studies for chemical reactivity and biological activity of the isolated compound. Materials and Methods: Two different compounds were isolated from ethanolic extract of S. densiflorum fruits and purified using HPLC. The structures of the compounds were elucidated on the basis of their 1H NMR, 13C NMR, 1H-1H COSY, HMBC, HRESIMS, and FT-IR data. Further, the chemical reactivity of the compounds was analyzed by density functional theory calculations and its therapeutic role in diabetic management was examined by comparing the structure of isolated compounds with previously reported bioactive compounds. Results: Of the two compounds ((6,6 & 1-kestopentaose (1) and 6-(hydroxymethyl)-3-[3,4,5- trihydroxy- 6-[(3,4,5-trihydroxyoxan-2-yl)oxymethyl]oxan-2-yl]oxyoxane-2,4,5-triol)(2)). β-glucosidase, β-galactosidase, α-glucosidase and β-amylase inhibition activity of the compounds were predicted by structure activity relationship. Conclusion: Structure-activity relationship analysis was performed to predict the therapeutic role of isolated compounds. These computational studies may be performed to minimize the efforts to determine the therapeutic role of natural compounds.

scholarly journals Semi-Synthesis of Harringtonolide Derivatives and Their Antiproliferative Activity

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1380
Author(s):  
Xiutao Wu ◽  
Lijie Gong ◽  
Chen Chen ◽  
Ye Tao ◽  
Wuxi Zhou ◽  
...  
Keyword(s):  
Antiproliferative Activity ◽  
Normal Cell ◽  
Selectivity Index ◽  
Cytotoxic Activities ◽  
Structure Activity ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Hct 116 ◽  
Systematic Structure

Harringtonolide (HO), a natural product isolated from Cephalotaxus harringtonia, exhibits potent antiproliferative activity. However, little information has been reported on the systematic structure−activity relationship (SAR) of HO derivatives. Modifications on tropone, lactone, and allyl positions of HO (1) were carried out to provide 17 derivatives (2–13, 11a–11f). The in vitro antiproliferative activity against four cancer cell lines (HCT-116, A375, A549, and Huh-7) and one normal cell line (L-02) was tested. Amongst these novel derivatives, compound 6 exhibited comparable cell growth inhibitory activity to HO and displayed better selectivity index (SI = 56.5) between Huh-7 and L-02 cells. The SAR results revealed that the tropone and lactone moieties are essential for the cytotoxic activities, which provided useful suggestions for further structural optimization of HO.

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