structure–activity relationship
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This paper is an overview of the most significant and impactful interpretation approaches of quantitative structure-activity relationship (QSAR) models, their development, and application. The evolution of the interpretation paradigm from "model → descriptors → (structure)" to "model → structure" is indicated. The latter makes all models interpretable regardless of machine learning methods or descriptors used for modeling. This opens wide prospects for application of corresponding interpretation approaches to retrieve structure-property relationships captured by any models. Issues of separate approaches are discussed as well as general issues and prospects of QSAR model interpretation.
A set of 4-benzylsulfanyl derivatives of pyridine-2-carbonitriles and pyridine-2-carbothioamides, previously tested for their antimycobacterial activity, were analysed by quantitative structure-activity relationship (QSAR) techniques, using some physicochemical and quantum-chemical parameters. The resulting QSAR revealed that the activity increases with electron withdrawing substituents in the benzyl moiety of studied compounds. HOMO orbitals can play an important role in the description of the mechanism of interactions at the molecular level. Additionally, the results of multiple linear regression indicate the differences between Mycobacterium tuberculosis and M. avium. The hydrophobicity of studied compounds is important for activity against M. avium.
In this study, we described the structure-activity relationships of substituted 3,5-dinitrophenyl tetrazoles as potent antitubercular agents. These simple and readily accessible compounds possessed high in vitro antimycobacterial activities against Mycobacterium tuberculosis, including clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with submicromolar minimum inhibitory concentrations (MICs). The most promising compounds showed low in vitro cytotoxicity and negligible antibacterial and antifungal activities, highlighting their highly selective antimycobacterial effects. 2-Substituted 5-(3,5-dinitrophenyl)-2H-tetrazole regioisomers, which are the dominant products of 5-(3,5-dinitrophenyl)-1H-tetrazole alkylation, showed better properties with respect to antimycobacterial activity and cytotoxicity than their 1-substituted counterparts. The 2-substituent of 5-(3,5-dinitrophenyl)-2H-tetrazole can be easily modified and can thus be used for the structure optimization of these promising antitubercular agents. The introduction of a tetrazole-5-thioalkyl moiety at position 2 of the tetrazole further increased the antimycobacterial activity. These compounds showed outstanding in vitro activity against M. tuberculosis (MIC values as low as 0.03 μM) and high activity against non-tuberculous mycobacterial strains.
- Klíčová slova
- Antitubercular agent, Mycobacterium tuberculosis, Regioisomers, Structure-activity relationships, Tetrazole, Tuberculosis,
- MeSH
- antituberkulotika chemie farmakologie MeSH
- druhová specificita MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- mnohočetná léková rezistence účinky léků MeSH
- molekulární struktura MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- tetrazoly chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antituberkulotika MeSH
- tetrazoly MeSH
Cyanidin and its O-glycosides have many important physiological functions in plants and beneficial effects on human health. Their biological activity is not entirely clear and depends on the structure of the molecule, in particular, on the number and type of sugar substituents. Therefore, in this study the detailed structure-activity relationship (SARs) of the anthocyanins/anthocyanidins in relation to their interactions with lipid bilayer was determined. On the basis of their antioxidant activity and the changes induced by them in size and Zeta potential of lipid vesicles, and mobility and order of lipid acyl chains, the impact of the number and type of sugar substituents on the biological activity of the compounds was evaluated. The obtained results have shown, that 3-O-glycosylation changes the interaction of cyanidin with lipid bilayer entirely. The 3-O-glycosides containing a monosaccharide induces greater changes in physical properties of the lipid membrane than those containing disaccharides. The presence of additional sugar significantly reduces glycoside interaction with model lipid membrane. Furthermore, O-glycosylation alters the ability of cyanidin to scavenge free radicals. This alteration depends on the type of free radicals and the sensitivity of the method used for their determination.
- Klíčová slova
- anthocyanin, fluorescence dyes, hydrogen peroxide, lipid peroxidation, membrane fluidity, phospholipid membrane, structure-activity relationships,
- MeSH
- anthokyaniny metabolismus MeSH
- fosfatidylcholiny metabolismus MeSH
- glykosylace MeSH
- peroxid vodíku metabolismus MeSH
- peroxidace lipidů MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 1-palmitoyl-2-oleoylphosphatidylcholine MeSH Prohlížeč
- anthokyaniny MeSH
- cyanidin MeSH Prohlížeč
- fosfatidylcholiny MeSH
- peroxid vodíku MeSH
Selective agonism of the estrogen receptor (ER) subtypes, ERα and ERβ, has historically been difficult to achieve due to the high degree of ligand-binding domain structural similarity. Multiple efforts have focused on the use of classical organic scaffolds to model 17β-estradiol geometry in the design of ERβ selective agonists, with several proceeding to various stages of clinical development. Carborane scaffolds offer many unique advantages including the potential for novel ligand/receptor interactions but remain relatively unexplored. We synthesized a series of para-carborane estrogen receptor agonists revealing an ERβ selective structure-activity relationship. We report ERβ agonists with low nanomolar potency, greater than 200-fold selectivity for ERβ over ERα, limited off-target activity against other nuclear receptors, and only sparse CYP450 inhibition at very high micromolar concentrations. The pharmacological properties of our para-carborane ERβ selective agonists measure favorably against clinically developed ERβ agonists and support further evaluation of carborane-based selective estrogen receptor modulators.
- MeSH
- beta receptor estrogenů agonisté MeSH
- estrogeny chemická syntéza chemie farmakologie MeSH
- HEK293 buňky MeSH
- lidé MeSH
- molekulární struktura MeSH
- sloučeniny boru chemická syntéza chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- beta receptor estrogenů MeSH
- estrogeny MeSH
- sloučeniny boru MeSH
Nerve agents such as sarin, VX and tabun are organophosphorus compounds able to inhibit an enzyme acetylcholinesterase (AChE). AChE reactivators and anticholinergics are generally used as antidotes in the case of intoxication with these agents. None from the known AChE reactivators is able to reactivate AChE inhibited by all kinds of nerve agents. In this work, reactivation potency of seventeen structurally different AChE reactivators was tested in vitro and subsequently, relationship between their chemical structure and biological activity was outlined. VX was chosen as appropriate member of the nerve agent family.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- krysa rodu Rattus MeSH
- molekulární struktura MeSH
- organothiofosforové sloučeniny chemická syntéza chemie farmakologie MeSH
- potkani Wistar MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
- organothiofosforové sloučeniny MeSH
- VX MeSH Prohlížeč
Structure-activity relationship analysis and profiling of a library of AB-functionalized cholestane derivatives closely related to brassinosteroids (BRs) were performed to examine their antiproliferative activities and activities on steroid hormone receptors. Some of the compounds were found to have strong cytotoxic activity in several human normal and cancer cell lines. The presence of a 3-hydroxy or 3-oxo group and 2,3-vicinal diol or 3,4-vicinal diol moiety were found to be necessary for optimum biological activity, as well as a six-membered B ring. According to the profiling of all steroid receptors in both agonist and antagonist mode, the majority of the cholestanes were weakly active or inactive compared to the natural ligands. Estrogenic activity was detected for two compounds, two compounds possessed antagonistic properties on estrogen receptors and seven compounds showed agonistic activity. Two active cholestane derivatives were shown to strongly influence cell viability, proliferation, cell cycle distribution, apoptosis and molecular pathways responsible for these processes in hormone-sensitive/insensitive (MCF7/MDA-MB-468) breast cancer cell lines.
- Klíčová slova
- Antiproliferative activity, Apoptosis, Cell cycle, Cholestane derivatives, Steroid receptor, Structure-activity relationship,
- MeSH
- apoptóza MeSH
- buněčný cyklus účinky léků MeSH
- cholestany chemie farmakologie MeSH
- inhibiční koncentrace 50 MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- protinádorové látky chemie farmakologie MeSH
- screeningové testy protinádorových léčiv MeSH
- steroidní receptory metabolismus MeSH
- viabilita buněk MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cholestany MeSH
- protinádorové látky MeSH
- steroidní receptory MeSH
Cytokinin ribosides (N(6)-substituted adenosine derivatives) have been shown to have anticancer activity both in vitro and in vivo. This study presents the first systematic analysis of the relationship between the chemical structure of cytokinins and their cytotoxic effects against a panel of human cancer cell lines with diverse histopathological origins. The results confirm the cytotoxic activity of N(6)-isopentenyladenosine, kinetin riboside, and N(6)-benzyladenosine and show that the spectrum of cell lines that are sensitive to these compounds and their tissues of origin are wider than previously reported. The first evidence that the hydroxylated aromatic cytokinins (ortho-, meta-, para-topolin riboside) and the isoprenoid cytokinin cis-zeatin riboside have cytotoxic activities is presented. Most cell lines in the panel showed greatest sensitivity to ortho-topolin riboside (IC(50)=0.5-11.6 microM). Cytokinin nucleotides, some synthesized for the first time in this study, were usually active in a similar concentration range to the corresponding ribosides. However, cytokinin free bases, 2-methylthio derivatives and both O- and N-glucosides showed little or no toxicity. Overall the study shows that structural requirements for cytotoxic activity of cytokinins against human cancer cell lines differ from the requirements for their activity in plant bioassays. The potent anticancer activity of ortho-topolin riboside (GI(50)=0.07-84.60 microM, 1st quartile=0.33 microM, median=0.65 microM, 3rd quartile=1.94 microM) was confirmed using NCI(60), a standard panel of 59 cell lines, originating from nine different tissues. Further, the activity pattern of oTR was distinctly different from those of standard anticancer drugs, suggesting that it has a unique mechanism of activity. In comparison with standard drugs, oTR showed exceptional cytotoxic activity against NCI(60) cell lines with a mutated p53 tumour suppressor gene. oTR also exhibited significant anticancer activity against several tumour models in in vivo hollow fibre assays.
- MeSH
- adenosin analogy a deriváty chemie farmakologie MeSH
- cytokininy * analýza chemie metabolismus MeSH
- geny p53 účinky léků genetika MeSH
- inhibiční koncentrace 50 MeSH
- isopentenyladenosin analogy a deriváty chemie farmakologie MeSH
- kinetin chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- National Cancer Institute (U.S.) MeSH
- protinádorové látky chemie farmakologie MeSH
- regulátory růstu rostlin farmakologie MeSH
- screeningové testy protinádorových léčiv MeSH
- stereoizomerie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Spojené státy americké MeSH
- Názvy látek
- adenosin MeSH
- cytokininy * MeSH
- isopentenyladenosin MeSH
- kinetin riboside MeSH Prohlížeč
- kinetin MeSH
- N(6)-benzyladenosine MeSH Prohlížeč
- protinádorové látky MeSH
- regulátory růstu rostlin MeSH
- zeatin riboside MeSH Prohlížeč
A series of 143 salicylanilides substituted in positions 4 and 5 and in positions 3' and 4' was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. To describe the structure-antimycobacterial activity relationships (QSARs), an approach based on the combination of the Free-Wilson and Hansch methods was employed (the substituent constants were used in the case of the substituents on the phenyl ring; indicator parameters were used for the substituents on the acyl moiety). The relationships between the antimycobacterial activity and physico-chemical parameters of all substituents were also explored. The quadratic representation of lipophilicity parameters did not lead to significant correlations.
- MeSH
- antibakteriální látky chemická syntéza chemie farmakologie MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium účinky léků MeSH
- salicylanilidy chemická syntéza chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antibakteriální látky MeSH
- salicylanilidy MeSH
A structure-activity relationship of some derivatives of 2-phenylsubstituted- 3-hydroxyquinolin-4(1H)-one-7-carboxamides was systematically studied using combinatorial solid-phase synthesis and in vitro cytotoxic activity screening on representative cancer lines. The effect of substituent type in position 2 as well as of the carboxamide group was investigated via synthesis of generic libraries constructed with respect to polarity and bulkiness of appropriate substituents. The process of development afforded a set of compounds with significant cytotoxic activity. Subsequently, corresponding 2-phenylsubstituted-3-hydroxyquinolin-4(1H)-one-6-carboxamides and 2-phenylsubstituted-3-hydroxyquinolin-4(1H)-one-8-carboxamides were prepared to evaluate the influence of the carboxamide group position on the resulting biological activity.
- MeSH
- buněčné linie MeSH
- chinoliny chemie MeSH
- lidé MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- chinoliny MeSH
