scholarly journals Synthesis and Critical View on the Structure-Activity Relationships of N-(Substituted phenyl)-/N-Diphenylmethyl-piperazine-Based Conjugates as Antimycobacterial Agents

2021 ◽  
Vol 12 (1) ◽  
pp. 300
Author(s):  
Jana Čurillová ◽  
Mária Pecháčová ◽  
Tereza Padrtová ◽  
Daniel Pecher ◽  
Šárka Mascaretti ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
Principal Component ◽  
Biological Evaluation ◽  
Structure Activity ◽  
Physicochemical Descriptors ◽  
Hybrid Molecules ◽  
Ic50 Values ◽  
Liver Hepatocellular Carcinoma ◽  
The Impact

This research focused on a three-step synthesis, analytical, physicochemical, and biological evaluation of hybrid molecules 6a–g, containing a lipophilic 3-trifluoromethylphenyl moiety, polar carbamoyloxy bridge, 2-hydroxypropan-1,3-diyl chain and 4-(substituted phenyl)-/4-diphenylmethylpiperazin-1-ium-1-yl fragment. The estimation of analytical and physicochemical descriptors (m/zmeasured via HPLC-UV/HR-MS, log ε2 (Ch–T) from UV/Vis spectrophotometry and log kw via RP-HPLC) as well as in vitro antimycobacterial and cytotoxic screening of given compounds were carried out (i.e., determination of MIC and IC50 values). These highly lipophilic molecules (log kw = 4.1170–5.2184) were tested against Mycobacterium tuberculosis H37Ra ATCC 25177 (Mtb H37Ra), M. kansasii DSM 44162 (MK), M. smegmatis ATCC 700084 (MS), and M. marinum CAMP 5644 (MM). The impact of the 6a–g set on the viability of human liver hepatocellular carcinoma (HepG2) cells was also investigated. 1-[2-Hydroxypropyl-{(3-trifluoromethyl)- phenyl}carbamoyloxy]-4-(3,4-dichlorophenyl)piperazin-1-ium chloride (6e) and 1-[2-hydroxy- propyl-{(3-trifluoromethyl)phenyl}carbamoyloxy]-4-(4-diphenylmethyl)piperazin-1-ium chloride (6g) most effectively inhibited the growth of Mtb H37Ra (MIC < 3.80 μM). The substance 6g also showed interesting activity against MM (MIC = 8.09 μM). All obtained data served as input values for structure-activity relationship evaluations using statistical principal component analysis. In fact, the toxicity of both 6e (IC50 = 29.39 μM) and 6g (IC50 = 22.18 μM) in HepG2 cells as well as selectivity index (SI) values (SI < 10.00) prevented to consider these promising antimycobacterials safe.

Synthesis and Antitumor Activity Evaluation of New Phenanthrene-Based Tylophorine Derivatives

2019 ◽  
Vol 16 (6) ◽  
pp. 462-467
Author(s):  
Songtao Li ◽  
Hongling Zhao ◽  
Zhifeng Yin ◽  
Shuhua Deng ◽  
Yang Gao ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cell Lines ◽  
Antitumor Activities ◽  
Human Carcinoma ◽  
Carcinoma Cell Lines ◽  
Structure Activity ◽  
Human Carcinoma Cell ◽  
Ic50 Values ◽  
Relationship Of

A series of new phenanthrene-based tylophorine derivatives (PBTs) were synthesized in good yield and their structures were characterized by 1H-NMR spectroscopy and ESI MS. In vitro antitumor activity of these compounds against five human carcinoma cell lines, including HCT116 (colorectal), BGC-823 (gastric), HepG-2 (hepatic), Hela (cervical) and H460 (lung) cells, was evaluated by MTT assay. Among these PBTs, compound 6b showed the highest antitumor activities against HCT116 and HepG-2 cell lines with IC50 values of 6.1 and 6.4 μM, respectively, which were comparable to that of adriamycin hydrochloride. The structure-activity relationship of these compounds was also discussed based on the results of their antitumor activity.

Elaboration of Novel TTK1 Inhibitory Leads via QSAR-Guided Selection of Crystallographic Pharmacophores Followed By In vitro Assay

2020 ◽  
Vol 16 ◽  
Author(s):  
Mahmoud A. Al-Sha'er ◽  
Mutasem O. Taha
Keyword(s):  
Standard Error ◽  
Qsar Model ◽  
Qsar Modeling ◽  
Vitro Assay ◽  
Physicochemical Descriptors ◽  
Qsar Models ◽  
Ic50 Values ◽  
Pharmacophore Hypotheses ◽  
Selection Of

Introduction: Tyrosine threonine kinase (TTK1) is a key regulator of chromosome segregation. TTK targeting received recent concern for the enhancement of possible anticancer therapies. Objective: In this regard we employed our well-known method of QSAR-guided selection of best crystallographic pharmacophore(s) to discover considerable binding interactions that anchore inhibitors into TTK1 binding site. Method:Sixtyone TTK1 crystallographic complexes were used to extract 315 pharmacophore hypotheses. QSAR modeling was subsequently used to choose a single crystallographic pharmacophore that when combined with other physicochemical descriptors elucidates bioactivity discrepancy within a list of 55 miscellaneous inhibitors. Results: The best QSAR model was robust and predictive (r2(55) = 0.75, r2LOO = 0.72 , r2press against external testing list of 12 compounds = 0.67), Standard error of estimate (training set) (S)= 0.63 , Standard error of estimate (testing set)(Stest) = 0.62. The resulting pharmacophore and QSAR models were used to scan the National Cancer Institute (NCI) database for new TTK1 inhibitors. Conclusion: Five hits confirmed significant TTK1 inhibitory profiles with IC50 values ranging between 11.7 and 76.6 micM.

scholarly journals Impact of Biochar Application on Carbon Dynamics and Fertility of Soils Over-fertilization with Compost

2019 ◽  
Author(s):  
Chen-Chi Tsai ◽  
Yu-Fang Chang
Keyword(s):  
Swine Manure ◽  
Carbon Mineralization ◽  
Soil Nutrient ◽  
Principal Component ◽  
C Mineralization ◽  
Soil C ◽  
Fertilized Soil ◽  
Lower Fertility ◽  
The Impact

In Taiwan, farmers often apply excess compost to ensure adequate crop yield in highly frequent tillage, highly weathered, and lower fertility soils. The potential of biochar (BC) for diminishing soil C mineralization, and improving soil nutrient availability in compost over-fertilized soil is promising, but the study is still under-examined. To test the hypothesis, 434 days in vitro C mineralization kinetics of incubation experiment were conducted. Woody BC 0%, 0.5%, 1.0% and 2.0% (w/w) made of lead tree (Leucaena leucocephala (Lam.) de. Wit) were added to an Oxisols, and two Inceptisols of Taiwan. In each treatment, 5% swine manure compost (2 times recommended amount) was added and served as the over-fertilized soil. The results indicated that soil type strongly influenced the impact of BC addition on soil carbon mineralization potential. Respiration per unit of total organic carbon (total mineralization coefficient, TMC) of three studied soils significantly decreased with BC addition increased. Principal component analysis (PCA) suggested that for retaining more plant nutrients in addition to the effects of carbon sequestration, it is recommended that farmer could use locally produced biochars and composts in highly weathered and highly frequent tillage soil. Adding 0.5%-1% woody BC in soil should be reasonable and appropriate.

scholarly journals Biological Evaluation, Molecular Docking, and SAR Studies of Novel 2-(2,4-Dihydroxyphenyl)-1H- Benzimidazole Analogues

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 870
Author(s):  
Joanna Matysiak ◽  
Alicja Skrzypek ◽  
Monika Karpińska ◽  
Kamila Czarnecka ◽  
Paweł Szymański ◽  
...  
Keyword(s):  
Molecular Docking ◽  
High Selectivity ◽  
Antioxidant Properties ◽  
Binding Mode ◽  
Biological Evaluation ◽  
The Other ◽  
Docking Simulations ◽  
Sar Studies ◽  
Structure Activity

In the present study, new 4-(1H-benzimidazol-2-yl)-benzene-1,3-diols, modified in both rings, have been synthesized and their efficacies as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors have been determined. The modified Ellman’s spectrophotometric method was applied for the biological evaluation. The compounds showed strong (IC50 80–90 nM) AChE and moderate (IC50 5–0.2 µM) BuChE inhibition in vitro. Some compounds were effective toward AChE/BuChE, exhibiting high selectivity ratios versus BuChE, while the other compounds were active against both enzymes. The structure–activity relationships were discussed. The compounds inhibited also in vitro self-induced Aβ(1–42) aggregation and exhibited antioxidant properties. The docking simulations showed that the benzimidazoles under consideration interact mainly with the catalytic site of AChE and mimic the binding mode of tacrine.

scholarly journals Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 3838
Author(s):  
Thibaud Reyser ◽  
Tung H. To ◽  
Chinedu Egwu ◽  
Lucie Paloque ◽  
Michel Nguyen ◽  
...  
Keyword(s):  
Biological Evaluation ◽  
Theoretical Chemistry ◽  
Public Health Issue ◽  
Drug Resistant ◽  
Structure Activity ◽  
Ic50 Values ◽  
Bond Homolysis ◽  
Tropical Areas ◽  
Critical Public Health ◽  
Nanomolar Range

Malaria and schistosomiasis are major infectious causes of morbidity and mortality in the tropical and sub-tropical areas. Due to the widespread drug resistance of the parasites, the availability of new efficient and affordable drugs for these endemic pathologies is now a critical public health issue. In this study, we report the design, the synthesis and the preliminary biological evaluation of a series of alkoxyamine derivatives as potential drugs against Plasmodium and Schistosoma parasites. The compounds (RS/SR)-2F, (RR/SS)-2F, and 8F, having IC50 values in nanomolar range against drug-resistant P. falciparum strains, but also five other alkoxyamines, inducing the death of all adult worms of S. mansoni in only 1 h, can be considered as interesting chemical starting points of the series for improvement of the activity, and further structure activity, relationship studies. Moreover, investigation of the mode of action and the rate constants kd for C-ON bond homolysis of new alkoxyamines is reported, showing a possible alkyl radical mediated biological activity. A theoretical chemistry study allowed us to design new structures of alkoxyamines in order to improve the selectivity index of these drugs.

scholarly journals Discovery of 2-(1-(3-(4-Chloroxyphenyl)-3-oxo- propyl)pyrrolidine-3-yl)-1H-benzo[d]imidazole-4-carboxamide: A Potent Poly(ADP-ribose) Polymerase (PARP) Inhibitor for Treatment of Cancer

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 1901 ◽  
Author(s):  
Rui Min ◽  
Weibin Wu ◽  
Mingzhong Wang ◽  
Lin Tang ◽  
Dawei Chen ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Parp Inhibitor ◽  
Parp Inhibition ◽  
Anticancer Activities ◽  
Reference Drug ◽  
Structure Activity ◽  
Ic50 Values ◽  
Proliferation Assays ◽  
Parp 1

A series of benzimidazole carboxamide derivatives have been synthesized and characterized by 1H-NMR, 13C-NMR and HRMS. PARP inhibition assays and cellular proliferation assays have also been carried out. Compounds 5cj and 5cp exhibited potential anticancer activities with IC50 values of about 4 nM against both PARP-1 and PARP-2, similar to the reference drug veliparib. The two compounds also displayed slightly better in vitro cytotoxicities against MDA-MB-436 and CAPAN-1 cell lines than veliparib and olaparib, with values of 17.4 µM and 11.4 µM, 19.8 µM and 15.5 µM, respectively. The structure-activity relationship based on molecular docking was discussed as well.

scholarly journals Exploring Diverse-Ring Analogues on Combretastatin A4 (CA-4) Olefin as Microtubule-Targeting Agents

2020 ◽  
Vol 21 (5) ◽  
pp. 1817 ◽  
Author(s):  
Ming-Yu Song ◽  
Qiu-Rui He ◽  
Yi-Lin Wang ◽  
Hao-Ran Wang ◽  
Tian-Cheng Jiang ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
Annexin V ◽  
Docking Studies ◽  
Cytotoxic Agents ◽  
Tubulin Polymerization ◽  
Microtubule Network ◽  
Microtubule Targeting Agents ◽  
Ic50 Values ◽  
Tubulin Polymerization Inhibitor

Combretastatin-4 (CA-4) as a tubulin polymerization inhibitor draws extensive attentions. However, due to its weak stability of cis-olefin and poor metabolic stability, structure modifications on cis-configuration are being performed. In this work, we constructed a series of novel CA-4 analogues with linkers on olefin containing diphenylethanone, cis-locked dihydrofuran, α-substituted diphenylethanone, cyclobutane and cyclohexane on its cis-olefin. Cytotoxic activity of all analogues was measured by an SRB assay. Among them, compound 6b, a by-product in the preparation of diphenylethanone analogues, was found to be the most potent cytotoxic agents against HepG2 cells with IC50 values of less than 0.5 μM. The two isomers of 6b induced cellular apoptosis tested by Annexin V-FITC and propidium iodide (PI) double staining, arrested cells in the G2/M phase by PI staining analysis, and disrupted microtubule network by immunohistochemistry study in HepG2 cells. Moreover, 6b-(E) displayed a dose-dependent inhibition effect for tubulin assembly in in vitro tubulin polymerization assay. In addition, molecular docking studies showed that two isomers of 6b could bind efficiently at colchicine binding site of tubulin similar to CA-4.

scholarly journals Design, Synthesis, and Biological Evaluation of Pyridineamide Derivatives Containing a 1,2,3-Triazole Fragment as Type II c-Met Inhibitors

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 10 ◽  
Author(s):  
Hehua Xiong ◽  
Jianxin Cheng ◽  
Jianqing Zhang ◽  
Qian Zhang ◽  
Zhen Xiao ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cell Lines ◽  
Inhibitory Activity ◽  
Docking Simulation ◽  
Binding Mode ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Ic50 Values ◽  
Mcf 7

A series of 4-(pyridin-4-yloxy)benzamide derivatives containing a 1,2,3-triazole fragment were designed, synthesized, and their inhibitory activity against A549, HeLa, and MCF-7 cancer cell lines was evaluated. Most compounds exhibited moderate to potent antitumor activity against the three cell lines. Among them, the promising compound B26 showed stronger inhibitory activity than Golvatinib, with IC50 values of 3.22, 4.33, and 5.82 μM against A549, HeLa, and MCF-7 cell lines, respectively. The structure–activity relationships (SARs) demonstrated that the modification of the terminal benzene ring with a single electron-withdrawing substituent (fluorine atom) and the introduction of a pyridine amide chain with a strong hydrophilic group (morpholine) to the hinge region greatly improved the antitumor activity. Meanwhile, the optimal compound B26 showed potent biological activity in some pharmacological experiments in vitro, such as cell morphology study, dose-dependent test, kinase activity assay, and cell cycle experiment. Finally, the molecular docking simulation was performed to further explore the binding mode of compound B26 with c-Met.

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