Synthesis and structure-activity relationships of fenbufen amide analogs

The previous discoveries of butyl fenbufen amide analogs with antitumor effects were further examined. The amide analogs with 1, 3, 4 and 8 carbons chains were prepared in 70-80% yield. Fenbufen had no cytotoxic effects at concentrations ranging from 10 to 100 μM. Methyl fenbufen amide had significant cytotoxic effects at a concentration of 100 μM. As the length of the alkyl amide side chain increased, the cytotoxic effects increased, and the octyl fenbufen amide had the greatest cytotoxic effect. After treatment with 30 μM octyl fenbufen amide, nearly seventy percent of the cells lost their viability. At the concentration of 10 μM, fenbufen amide analogs did not show cytotoxicity according to the MTT assay results. The NO scavenging activities of the fenbufen amide analogs were not significantly different from those of fenbufen.     

Synthesis and novel structure-activity relationships of potent sansalvamide A derivatives

Synthesis of twelve Sansalvamide A derivatives and their SAR against colon cancer (HT-29).     

Fuzzy structure-activity relationships

While quantitative structure-activity relationships attempt to predict the numerical value of the activities, it is found that statistically good predictors do not always do a good job of qualitatively determining the activity. This study shows how Fuzzy classifiers can be used to generate Fuzzy structure-activity relationships which can more accurately determine whether or not a compound will be highly inactive, moderately inactive or active, or highly active. Four examples of these classifiers are presented and applied to a well-studied activity dataset.     

Fuzzy structure-activity relationships

While quantitative structure-activity relationships attempt to predict the numerical value of the activities, it is found that statistically good predictors do not always do a good job of qualitatively determining the activity. This study shows how Fuzzy classifiers can be used to generate Fuzzy structure-activity relationships which can more accurately determine whether or not a compound will be highly inactive, moderately inactive or active, or highly active. Four examples of these classifiers are presented and applied to a well-studied activity dataset.     

Synthesis and structure-activity relationships of human renin inhibitors designed from angiotensinogen transition state

The synthesis and the structure-activity relationships of renin inhibitors designed from the angiotensinogen transition state are described. These inhibitors contained residues modified at P1-P1', P2, and P4-P3. Decrease in the size of side chain alkyl group in norstatine analog at P1 diminished the inhibitory activities of the compounds. Compound 5j, which contained valine residue instead of histidine residue at P2, inhibited potently cathepsin D (IC50 = 6.0 x 10(-9) M) and pepsin (IC50 = 3.5 x 10(-7) M) to the same extent as renin (IC50 = 8.5 x 10(-10) M), and thus was not specific for renin. The reduction of the beta-carbonyl group to methylene group in beta-carbonylpropionyl residue at P4-P3 decreased the potency about 2 orders against human renin (5i: IC50 = 1.1 x 10(-7) M vs. 1: IC50 = 2.4 x 10(-9) M). These results confirmed the rationality of our analysis of the interaction between an orally potent human renin inhibitor 1 and the active site of human renin using modeling techniques, showing that 1 fits the active site of renin favorably. The experimental details of the synthesis are presented.     

Synthesis of plakevulin A and structure-activity relationships of its related compounds against DNA polymerases

Synthesis of plakevulin A and structure-activity relationships of its related compounds against DNA polymerases is described. We have achieved a total synthesis and revised the structure of plakevulin A. Several analogues including untenone A, manzamenone A, and optically active plakevulin A, were prepared and tested with an enzyme inhibition assay for mammalian DNA polymerases. The effect of the methyl ester moiety, and the substituents at the 1- and 4-positions of plakevulin A on DNA polymerase activities are discussed.     

Synthesis and structure-activity relationships of o-sulfonamido-arylhydrazides as inhibitors of LL-diaminopimelate aminotransferase (LL-DAP-AT)

Recently, LL-diaminopimelate aminotransferase (LL-DAP-AT), a pyridoxal-5'-phosphate (PLP)-dependent enzyme, was reported to catalyze a key step in the biosynthesis of L-lysine in plants and Chlamydia. Previous screening of a 29,201-compound library against LL-DAP-AT identified an o-sulfonamidoarylhydrazide as a reversible inhibitor with IC(50)～ 5 μM. Structure-activity relationship (SAR) studies based on this lead compound identified key structural features essential for enzyme inhibition and led to slightly improved inhibitors. Preliminary studies on the mode of inhibition of LL-DAP-AT by this class of compounds are also reported.     

Synthesis and structure-activity relationships study of α-aminophosphonate derivatives containing a quinoline moiety

Two series of a-aminophosphonate derivatives containing a quinoline moiety have been designed and synthesized by introducing bioactive quinoline scaffold to a-aminophosphonate. The in vitro cytotoxic activities of target compounds were first investigated against two human cancer cell lines including Eca109 and Huh7 by MTT assay. Results revealed that most of target compounds exhibited moderate to high antitumor activities against the tested cancer cell lines and some demonstrated more potent inhibitory activities compared with Sunitinib. Among them, compounds 4b2 and 4b4 containing methylsubstituted aniline group were found to be more active than Sunitinib against both of two cancer cell lines, with IC50 in the range of 2.26 mmol/L–7.46 mmol/L.     

Nonlinear prediction of quantitative structure-activity relationships

Predicting the log of the partition coefficient P is a long-standing benchmark problem in Quantitative Structure-Activity Relationships (QSAR). In this paper we show that a relatively simple molecular representation (using 14 variables) can be combined with leading edge machine learning algorithms to predict logP on new compounds more accurately than existing benchmark algorithms which use complex molecular representations.     

三苯基丙烯腈衍生物的定量结构-活性关系研究

应用半经验量子化学AMl方法得到了24种三苯基丙烯腈衍生物的优势构象，利用AMl方法和分子图形学技术获得其电子结构、几何结构及拓扑结构参数，并将这些参数与三苯基丙烯腈衍生物对乳腺癌细胞(MCF-7)的生物活性相关联．结果表明，三苯基丙烯腈衍生物对MCF-7的活性与羟基指示数、分子表面积和B环上原子净电荷之和之间存在良好的多元线性相关性，成功地建立了三苯基丙烯腈衍生物的构效关系式．     

DPPH-scavenging activities and structure-activity relationships of phenolic compounds

Thirty-eight phenolic compounds (including 31 flavonoids) were examined for their DPPH radical-scavenging activities, and structure-activity relationships were evaluated. Specifically, the presence of an ortho-dihydroxyl structure in phenolics is largely responsible for their excellent anti-radical activity. 3-Hydroxyl was also essential to generate a high radical-scavenging activity. An increasing number of hydroxyls on flavones with a 3',4'-dihydroxyl basic structure, the presence of a third hydroxyl group at C-5', a phloroglucinol structure, glycosylation and methylation of the hydroxyls, and some other hydroxyls, for example 5-, and 7-hydroxyl in ring A, decreased the radical-scavenging activities of flavonoids and other phenolics.     

Oxazolidinone structure-activity relationships leading to linezolid

The development of bacterial resistance to currently available antibacterial agents is a growing global health problem. Of particular concern are infections caused by multidrug-resistant Gram-positive pathogens which are responsible for significant morbidity and mortality in both the hospital and community settings. A number of solutions to the problem of bacterial resistance are possible. The most common approach is to continue modifying existing classes of antibacterial agents to provide new analogues with improved attributes. Other successful strategies are to combine existing antibacterial agents with other drugs as well as the development of improved diagnostic procedures that may lead to rapid identification of the causative pathogen and permit the use of antibacterial agents with a narrow spectrum of activity. Finally, and most importantly, the discovery of novel classes of antibacterial agents employing new mechanisms of action has considerable promise. Such agents would exhibit a lack of cross-resistance with existing antimicrobial drugs. This review describes the work leading to the discovery of linezolid, the first clinically useful oxazolidinone antibacterial agent.     

Quantitative structure-activity relationships for calmodulin inhibitors

Using the discriminant analysis method, we completely distinguished 24 calmodulin inhibitors in three groups, as classified by Zimmer et al. The resultant discriminant functions distinguished the three groups in terms of positive potential surface area on the side chain, as well as the total and neutral surface areas on the ring in the inhibitor molecules. Group assignment of additional calmodulin inhibitors from other sources was then estimated according to the discriminant functions. The relationship between structure and inhibitory potency on calmodulin-activated phosphodiesterase for group I inhibitors, together with those estimated, was studied using the adaptive least squares method with several parameters dependent on molecular conformations. A "best conformer" was selected for each inhibitor on the basis of quantitative structure-activity relationship (QSAR). The results of QSAR analysis of group I inhibitors showed that hydrophobicity was important for the ring moiety but not for the side chain. The negative potential surface area of the side chain is necessary for activity. It is desirable for the nitrogen atom in the side chain, which is considered the center of the negative potential area, to be located far from the ring moiety. Thus, the ring moiety and side chain may possibly play different roles in interactions with the receptor system.     

Capturing structure-activity relationships from chemogenomic spaces

Modeling off-target effects is one major goal of chemical biology, particularly in its applications to drug discovery. Here, we describe a new approach that allows the extraction of structure-activity relationships from large chemogenomic spaces starting from a single chemical structure. Several public source databases, offering a vast amount of data on structure and activity for a large number of different targets, have been investigated for their usefulness in automated structure-activity relationships (SAR) extraction. SAR tables were constructed by assembling similar structures around each query structure that have an activity record for a particular target. Quantitative series enrichment analysis (QSEA) was applied to these SAR tables to identify trends and to transform these trends into topomer CoMFA models. Overall more than 1700 SAR tables with topomer CoMFA models have been obtained from the ChEMBL, PubChem, and ChemBank databases. These models were able to highlight the structural trends associated with various off-target effects of marketed drugs, including cases where other structural similarity metrics would not have detected an off-target effect. These results indicate the usefulness of the QSEA approach, particularly whenever applicable with public databases, in providing a new means, beyond a simple similarity between ligand structures, to capture SAR trends and thereby contribute to success in drug discovery.     

The nematocidal activity and the structure-activity relationships of stilbenes

The pinewood nematode, Bursaphelenchus xylophilus (Steiner et Buhrer) Nickle, is the causative agent of the pine wilt disease which has been devastating forests of Pinus densiflora Sieb.et Zucc. and P. thunbergii Parl. in Japan. To prevent the pine wilt disease, the development of nematocidal compound is required. Twenty-one synthesized stilbenes (1)-(20), (23), salicylic acid (21), and phenylsalicilate (22) were examined for their nematocidal activity against an isolate of B. xylophilus (T-4). Among the tested compounds, two fluorinated stilbenes (15) and (13), were found to be most potent compounds against T-4, demonstrating 99% and 98% lethality at 10 ppm concentration. The LD50 values of compounds 15 and 13 were 3 ppm, respectively.     

Engineered synthesis of 7-oxo- and 15-deoxy-15-oxo-amphotericins: insights into structure-activity relationships in polyene antibiotics

Site-directed mutagenesis and gene replacement were used to inactivate two ketoreductase (KR) domains within the amphotericin polyketide synthase in Streptomyces nodosus. The KR12 domain was inactivated in the DeltaamphNM strain, which produces 16-descarboxyl-16-methyl-amphotericins. The resulting mutant produced low levels of the expected 15-deoxy-15-oxo analogs that retained antifungal activity. These compounds can be useful for further chemical modification. Inactivation of the KR16 domain in the wild-type strain led to production of 7-oxo-amphotericin A and 7-oxo-amphotericin B in good yield. 7-oxo-amphotericin B was isolated, purified, and characterized as the N-acetyl methyl ester derivative. 7-oxo-amphotericin B had good antifungal activity and was less hemolytic than amphotericin B. These results indicate that modification at the C-7 position can improve the therapeutic index of amphotericin B.