scholarly journals SAR:s for the Antiparasitic Plant Metabolite Pulchrol. 1. The Benzyl Alcohol Functionality

Molecules ◽  
2020 ◽  
Vol 25 (13) ◽  
pp. 3058 ◽  
Author(s):  
Paola Terrazas ◽  
Efrain Salamanca ◽  
Marcelo Dávila ◽  
Sophie Manner ◽  
Alberto Giménez ◽  
...  
Keyword(s):  
Natural Product ◽  
Qsar Model ◽  
Selectivity Index ◽  
Antiparasitic Activity ◽  
Molecular Features ◽  
Structure Activity ◽  
Plant Metabolite ◽  
Antiparasitic Agents ◽  
Positive Controls

Pulchrol (1) is a natural benzochromene isolated from the roots of Bourreria pulchra, shown to possess potent antiparasitic activity towards both Leishmania and Trypanozoma species. As it is not understood which molecular features of 1 are important for the antiparasitic activity, several analogues were synthesized and assayed. The ultimate goal is to understand the structure–activity relationships (SAR:s) and create a QSAR model that can be used for the development of clinically useful antiparasitic agents. In this study, we have synthesized 25 2-methoxy-6,6-dimethyl-6H-benzo[c]chromen analogues of 1 and its co-metabolite pulchral (5a), by semi-synthetic procedures starting from the natural product pulchrol (1) itself. All 27 compounds, including the two natural products 1 and 5a, were subsequently assayed in vitro for antiparasitic activity against Trypanozoma cruzi, Leishmania brasiliensis and Leishmania amazoniensis. In addition, the cytotoxicity in RAW cells was assayed, and a selectivity index (SI) for each compound and each parasite was calculated. Several compounds are more potent or equi-potent compared with the positive controls Benznidazole (Trypanozoma) and Miltefosine (Leishmania). The compounds with the highest potencies as well as SI-values are esters of 1 with various carboxylic acids.

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.

Antimicrobial Screening, in Silico Studies and QSAR of Chalcone-based 1,4-disubstituted 1,2,3-triazole Hybrids

Drug Research ◽  
2020 ◽  
Author(s):  
Pinki Yadav ◽  
Kashmiri Lal ◽  
Ashwani Kumar
Keyword(s):  
Topoisomerase Ii ◽  
Antimicrobial Properties ◽  
Qsar Model ◽  
Quantitative Structure Activity Relationship ◽  
Binding Modes ◽  
E Coli ◽  
Structure Activity ◽  
In Silico Studies ◽  
Microbial Strains

AbstractThe in vitro antimicrobial properties of some chalcones (1a–1c ) and chalcone tethred 1,4-disubstituted 1,2,3-triazoles (2a–2u) towards different microbial strains viz. Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Aspergillus niger and Candida albicans are reported. Compounds 2g and 2u exhibited better potency than the standard Fluconazole with MIC values of 0.0063 µmol/mL and 0.0068 µmol/mL, respectively. Furthermore, molecular docking was performed to investigate the binding modes of two potent compounds 2q and 2g with E. coli topoisomerase II DNA gyrase B and C. albicans lanosterol 14α-demethylase, respectively. Based on these results, a statistically significant quantitative structure activity relationship (QSAR) model was successfully summarized for antibacterial activity against B. subtilis.

Discovery of Potent Natural-Product-Derived SIRT2 Inhibitors Using Structure-Based Exploration of SIRT2 Pharmacophoric Space Coupled With QSAR Analyses

2021 ◽  
Vol 21 ◽  
Author(s):  
Mohammad A. Khanfar ◽  
Saja Alqtaishat
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Characteristic Curve ◽  
Pharmacophore Model ◽  
Qsar Model ◽  
Pharmacophore Modeling ◽  
Class Iii ◽  
Qsar Analysis ◽  
Starting Point

Background: SIRT2 belongs to a class III of histone deacetylase (HDAC) and has crucial roles in neurodegeneration and malignancy. Objective: Discover structurally novel natural-product-derived SIRT2 inhibitors. Methods: Structure-based pharmacophore modeling integrated with validated QSAR analysis were implemented to discover structurally novel SIRT2 inhibitors from natural products database. The targeted QSAR model combined molecular descriptors with structure-based pharmacophore capable of explaining bioactivity variation of structurally diverse SIRT2 inhibitors. Manually built pharmacophore model, validated with receiver operating characteristic curve, and selected using the statistically optimum QSAR equation, was applied as a 3D-search query to mine AnalytiCon Discovery database of natural products. Results : Experimental in vitro testing of highest-ranked hits identified asperphenamate and salvianolic acid B as active SIRT2 inhibitors with IC50 values in low micromolar range. Conclusion: New chemical scaffolds of SIRT2 inhibitors have been identified that could serve as a starting point for lead-structure optimization.

Synthesis and Modeling Study of Some Potential Pyrimidine Derivatives as HIV Inhibitors

2014 ◽  
Vol 69 (8) ◽  
pp. 913-923 ◽  
Author(s):  
Najim A. Al-Masoudi ◽  
Yossra A. Marich ◽  
Niran J. Al-Salihi ◽  
Bahjat Saeed
Keyword(s):  
Selectivity Index ◽  
Reverse Transcriptase Inhibitors ◽  
Pyrimidine Derivatives ◽  
Structure Activity ◽  
Nucleophilic Displacement ◽  
New Compounds ◽  
Pyrimidine Analogs ◽  
Anti Hiv ◽  
Hiv 1

A new series of 2-amino-6-((4-aryldiazenyl)benzyloxy)-4-chloropyrimidine derivatives 4 - 13 and 2,6-diamino-5-arylazo-4-chloro-pyrimidine analogs 15 - 20 were synthesized from the pyrimidine scaffolds 3 and 14, respectively, via diazotization with various amines. Nucleophilic displacement at the 2,4-diamino-5-arylazo-6-chloro-pyrimidine 16 by different amines afforded the 4-alkylamino analogs 21 - 27. All new compounds were evaluated for their in vitro anti-HIV activity in MT-4 cells as non-nucleoside reverse transcriptase inhibitors on the basis of our previous work. Screening results indicated that 10 and 11 were found to be the only compounds in the series inhibiting HIV-1 replication in cell cultures with EC50 of >1:23 and >2:92 μg mL-1 of a CC50 of 12.30 and 17.52 μg mL-1, resulting in a selectivity index of 10 and 6, respectively. In addition, preliminary structure-activity relationships and molecular modeling of these new analogs are detailed in this manuscript.

scholarly journals Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity

2009 ◽  
Vol 53 (7) ◽  
pp. 2824-2833 ◽  
Author(s):  
Georgina A. Holloway ◽  
William N. Charman ◽  
Alan H. Fairlamb ◽  
Reto Brun ◽  
Marcel Kaiser ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Trypanothione Reductase ◽  
Antiparasitic Activity ◽  
Class A ◽  
Structure Activity ◽  
Metabolic Properties

ABSTRACT High-throughput screening of 100,000 lead-like compounds led to the identification of nine novel chemical classes of trypanothione reductase (TR) inhibitors worthy of further investigation. Hits from five of these chemical classes have been developed further through different combinations of preliminary structure-activity relationship rate probing and assessment of antiparasitic activity, cytotoxicity, and chemical and in vitro metabolic properties. This has led to the identification of novel TR inhibitor chemotypes that are drug-like and display antiparasitic activity. For one class, a series of analogues have displayed a correlation between TR inhibition and antiparasitic activity. This paper explores the process of identifying, investigating, and evaluating a series of hits from a high-throughput screening campaign.

scholarly journals Parallel and four-step synthesis of natural-product-inspired scaffolds through modular assembly and divergent cyclization

2012 ◽  
Vol 8 ◽  
pp. 930-940 ◽  
Author(s):  
Hiroki Oguri ◽  
Haruki Mizoguchi ◽  
Hideaki Oikawa ◽  
Aki Ishiyama ◽  
Masato Iwatsuki ◽  
...  
Keyword(s):  
Natural Product ◽  
Structural Diversity ◽  
Building Blocks ◽  
Acid Group ◽  
Modular Assembly ◽  
Synthetic Process ◽  
Sar Studies ◽  
Structure Activity ◽  
Tandem Cyclization

By emulating the universal biosynthetic strategy, which employs modular assembly and divergent cyclizations, we have developed a four-step synthetic process to yield a collection of natural-product-inspired scaffolds. Modular assembly of building blocks onto a piperidine-based manifold6, having a carboxylic acid group, was achieved through Ugi condensation,N-acetoacetylation and diazotransfer, leading to cyclization precursors. The rhodium-catalyzed tandem cyclization and divergent cycloaddition gave rise to tetracyclic and hexacyclic scaffolds by the appropriate choice of dipolarophiles installed at modules 3 and 4. A different piperidine-based manifold15bearing an amino group was successfully applied to demonstrate the flexibility and scope of the unified four-step process for the generation of structural diversity in the fused scaffolds. Evaluation of in vitro antitrypanosomal activities of the collections and preliminary structure–activity relationship (SAR) studies were also undertaken.

scholarly journals Concise Chemoenzymatic Total Synthesis and Identification of Cellular Targets of Cepafungin I

2020 ◽  
Author(s):  
Alexander Amatuni ◽  
Anton Shuster ◽  
Alexander Adibekian ◽  
Hans Renata
Keyword(s):  
Total Synthesis ◽  
Natural Product ◽  
Product Family ◽  
Enzymatic Oxidation ◽  
Hydroxyl Group ◽  
Cellular Targets ◽  
Structure Activity ◽  
Covalent Inhibitors

The natural product cepafungin I was recently reported to be one of the most potent covalent inhibitors of the 20S proteasome core particle through a series of in vitro activity assays. Here, we report a short chemoenzymatic total synthesis of cepafungin I featuring the use of a regioselective enzymatic oxidation to prepare a key hydroxylated amino acid building block in a scalable fashion. The strategy developed herein enabled access to a chemoproteomic probe, which in turn revealed the exceptional selectivity and potency of cepafungin I towards the b2 and b5 subunits of the proteasome. Further structure-activity relationship studies suggest the key role of the hydroxyl group in the macrocycle and the identity of the lipid tail in modulating the potency of this natural product family. This study lays the groundwork for further medicinal chemistry exploration to fully realize the anticancer potential of cepafungin I. <br>

scholarly journals SARs for the Antiparasitic Plant Metabolite Pulchrol. Part 2: B- and C-Ring Substituents

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4510
Author(s):  
Paola Terrazas ◽  
Sophie Manner ◽  
Olov Sterner ◽  
Marcelo Dávila ◽  
Alberto Giménez ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Neglected Tropical Diseases ◽  
Leishmania Species ◽  
Positive Control ◽  
Leishmania Braziliensis ◽  
General Tendency ◽  
Antiparasitic Activity ◽  
Plant Metabolite ◽  
Derivatives Of

Neglected tropical diseases affect most of the underprivileged populations in tropical countries. Among these are chagas and leishmaniasis, present mainly in South and Central America, Africa and East Asia. Current treatments are long and have severe adverse effects, therefore there is a strong need to develop alternatives. In this study, we base our research on the plant metabolite pulchrol, a natural benzochromene which has been shown to possess antiparasitic activity against Trypanosoma and Leishmania species. In a recent study, we investigated how changes in the benzyl alcohol functionality affected the antiparasitic activity, but the importance of B- and C-ring substituents is not understood. Fifteen derivatives of pulchrol with different substituents in positions 1, 2, 3, and 6 while leaving the A-ring intact, were therefore prepared by total synthesis, assayed, and compared with pulchrol and positive controls. The generated series and parental molecule were tested in vitro for antiparasitic activity against Trypanosoma cruzi, Leishmania braziliensis, and L. amazonensis, and cytotoxicity using RAW cells. Substantial differences in the activity of the compounds synthesized were observed, of which some were more potent towards Trypanosoma cruzi than the positive control benznidazole. A general tendency is that alkyl substituents improve the potency, especially when positioned on C-2.

scholarly journals Quantitative structure-activity relationships to predict antibacterial effect of some benzimidazole derivatives

2008 ◽  
pp. 181-191 ◽  
Author(s):  
Sanja Podunavac-Kuzmanovic ◽  
Dijana Barna ◽  
Dragoljub Cvetkovic
Keyword(s):  
Antibacterial Activity ◽  
Qsar Model ◽  
Quantitative Structure Activity Relationship ◽  
Biologically Active ◽  
Benzimidazole Derivatives ◽  
Quantitative Structure ◽  
Structure Activity ◽  
Lipophilicity Parameter ◽  
Office Software

The antibacterial activity of some substituted benzimidazole derivatives against Gram negative bacteria Escherichia coli was investigated. The tested compounds displayed in vitro inhibitory activity and their minimum inhibitory concentrations were determined. Quantitative structure-activity relationship has been used to study the relationships between the antibacterial activity and lipophilicity parameter, logP. Lipophilicity parameters were calculated for each molecule by using CS Chem-Office Software version 7.0. Multiple linear regression was used to correlate the logP values and antibacterial activity of benzimidazole derivatives. The results are discussed on the basis of statistical data. The most acceptable QSAR model for prediction of antibacterial activity of the investigated series of benzimidazoles was developed. High agreement between experimental and predicted inhibitory values was obtained. The results of this study indicate that the lipophilicity parameter has a significant effect on antibacterial activity of this class of compounds, thus simplifying design of new biologically active molecules.

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