Correction to: The structure–activity relationship review of the main bioactive constituents of Morus genus plants

The article The structure–activity relationship review of the main bioactive constituents of Morus genus plants, written by Jiejing Yan, Jingya Ruan, Peijian Huang, Fan Sun, Dandan Zheng, Yi Zhang and Tao Wang was originally published Online First without Open Access.     

3D-QSAR study of pyrrolidine derivatives as matrix metalloproteinase-2 inhibitors

In order to develop potent inhibitors of matrix metalloproteinase-2(MMP-2) as anticancer agents, a three-dimensional quantitative structure–activity relationship (3D-QSAR) model was established by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. This study correlates the MMP-2 inhibitory activities of 67 pyrrolidine derivatives to steric, electrostatic, hydrophobic, and hydrogen-bond donor and acceptor fields. After using two different molecular alignments, both CoMFA and CoMSIA models resulted in good statistical predictions, a case in point being their high q ² values of between 0.757 and 0.843. The CoMFA and CoMSIA models established herein will be helpful in understanding the structure–activity relationship of pyrrolidine derivatives as well as in the design of novel derivatives with enhanced MMP-2 inhibitory activity.     

Mitragyna speciosa, a psychoactive tree from Southeast Asia with opioid activity

Mitragyna speciosa Korth. (Rubiaceae) is a tree that is commonly found in Southeast Asia. Leaves from this tree have been traditionally been used for both their stimulant properties as well as an opium substitute. The tree/leaves are currently illegal in four countries, but is currently legal and widely available in the United States. To date over 40 compounds have been isolated from the leaves. The major alkaloid found within the crude extract, mitragynine, has been the subject of many pharmacological studies. In addition to the pharmacological studies, two total syntheses of mitragynine have been published as well as general structure-activity relationships (SARs) with respect to opioid activity.     

Antitrypanosomal activities of acetylated bruceines A and C; a structure–activity relationship study

The crude extract of Brucea javanica showed strong in vitro inhibitory activity against Trypanosoma evansi. Among the isolated quassinoids, bruceines A, C, and bruceantinol were found to be the most potent compounds against T. evansi. To gain a deeper understanding of the relationship between the free hydroxyl groups and the activity, several O-acetylated derivatives of bruceines A and C were synthesized and their in vitro antitrypanosomal activities against trypomastigotes of T. evansi were examined and compared with those of the original compounds. The following structure–activity relationships were observed: (1) the free hydroxyl groups at positions C-3, C-11, and C-12 are essential for antitrypanosomal activity; (2) the C-11 and C-12 hydroxyl groups are more important for the activity than the enolic hydroxyl group at C-3, and; (3) the free hydroxyl group at C-4′ of bruceine C does not have any significant effect on the activity.     

Synthesis and antibacterial,antifungal activities of some 2<Emphasis Type="Italic">r</Emphasis>,4<Emphasis Type="Italic">c</Emphasis>-diaryl-3-azabicyclo[3.3.1]nonan-9-one-4-aminobenzoyl hydrazones

A series of biologically active seven 2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-one-4-aminobenzoyl hydrazone derivatives have been synthesized in good yield. The structures of compounds have been established on the basis of IR, ¹H, ¹³C NMR, and elemental analysis. The structure–activity relationships (SAR) have been studied by screening of antimicrobial activity over a representative panel of bacterial and fungal strains using two-fold serial dilution method. All these synthesized compounds exhibited significant activities against all bacterial and fungal strains.     

The hydrophobic fragmental constant approach forcalculating log P in octanol/water and aliphatic hydrocarbon/water systems

We have investigated the relationship between drug retention in immobilized liposome partitioning chromatography and liposome partitioning and found a strong linear correlation. Separate linear relationships were found depending on the charge of the compound when liposome chromatographic measurements were related to the octanol/water partition coefficients. We have also investigated the importance of the water/octanol partition coefficient in quantitative structure–property relationships related to drug transport properties. The studies show that the inclusion of a parameter related to lipophilicity causes only, at best, a marginal increase in internal predictivity and, at worst, a decrease in external predictivity. The studies also show that parameters related to hydrogen bonding, polarizability and size are important properties that need to be included in quantitative models for drug transport processes. We believe that the use of multivariate characterizations of compounds based on non-composite parameters may result in better and more predictive models compared with models based on parameters of a more composite nature when investigating the possibilities to establish quantitative structure–property relationships. This revised version was published online in August 2006 with corrections to the Cover Date.     

Linckosides M–Q: neuritogenic steroid glycosides from the Okinawan starfish <Emphasis Type="Italic">Linckia laevigata</Emphasis>

Five new steroid glycosides, linckosides M–Q (1–5), and two known related metabolites, mimics and/or enhancers of the neuritogenic activity of nerve growth factor (NGF), have been isolated from the Okinawan blue starfish Linckia laevigata. Their structures, including stereochemistry, were elucidated by spectroscopic methods and chemical derivatization. The most active metabolite linckoside P (4) induced neurite outgrowth in 55% of PC12 cells 6 days after treatment. Linckosides M–O (1–3) were less active, in the range 21 to 32%. The monoglycosides, linckoside Q (5) and the two known metabolites, 6 and 7, were much less active than the bisglycosides. All the metabolites enhanced the neuritogenic activity of a trace amount of NGF, from 11% to 60–99% three days after treatment. These structure–activity relationships suggest the importance of xylose on a side chain, especially at the C-24 carbon branch rather than at the terminal C-26, for NGF-mimic activity.     

The latest review on the polyphenols and their bioactivities of Chinese Morus plants

The mulberry tree (Morus alba) plays a key role in agriculture, and its different parts have been used as popular Traditional Chinese Medicines for thousands of years. There are 16 species belonging to the Morus genus. Among them, 11 species distribute in China, most of which have been used as the substitutes of M. alba in local provinces. This review summarizes the structural characters of polyphenols, the main components in Morus, including Diels–Alder-type adducts, flavonoids, 2-arylbenzofurans, and stilbenes, and also their related bioactivities in the last 10 years.     

熊果酸衍生物构效关系研究进展

综述了近年来对熊果酸的结构修饰及其衍生物构效关系的研究进展。熊果酸是一种广泛存在于天然植物中的五环三萜类化合物,具有抗肿瘤、降血糖、抗炎、抗HIV等药理活性,故而受到研究人员的广泛关注。对熊果酸进行结构修饰及构效关系探索,以获得高效低毒的候选化合物,已成为该化合物的研究热点之一。     

Design, synthesis, and biological evaluation of novel pyridine acid esters of podophyllotoxin and esters of 4′-demethylepipodophyllotoxin

Podophyllotoxin and related analogs present numerous challenges associated with optimal antitumor activity and severe unpredictable toxicity. In the course of our ongoing investigation of quantitative structure–activity relationships to find biorational antitumor drugs, two series of pyridine acid ester derivatives of podophyllotoxin and 4′-demethylepipodophyllotoxin have been prepared by reacting the corresponding pyridine acids with the hydroxyl group of podophyllotoxin and 4′-demethyl epipodophyllotoxin in the presence of dimethylaminopyridine (DMAP) and N,N-dicyclohexylcarbodiimde (DCC). The structures of the compounds were extensively characterized by using ¹H-nuclear magnetic resonance, mass spectroscopy, infrared, and elemental analysis and evaluated for their in vitro cytotoxicity on two neoplastic cell lines (P-388 murine leukemia, A-549 human lung carcinoma) using a MTT-based assay, the results indicated significantly higher efficacy of these compounds in comparison with the prototypical inhibitor etoposide. On the basis of the preliminary biological testing results, it suggested that the cytotoxic activity of OCH₃ at C-4′ is more potent than that of its demethylated analogs and the podophyllotoxin substitution at C-4 may be optimal for synthesizing more potent cytotoxic compounds.     

Synthesis and in vitro microbial activities of amides of pyridoquinolone

In this study, we report the antimicrobial evaluation of newly synthesized amides of pyridoquinolones from substituted aniline, substituted phenyl thioureas and 4-amino-N-(substitutedphenyl)benzenesulfonamide. Structures of selected compounds have been established by IR and ¹H NMR spectra and elemental analysis. The structure–activity releationships have been studied by screening of antimicrobial activity over S. aureus, B. subtilis, E. coli, P. aeruginosa, and C. albicans using cup–plate method.     

Adenine: an important drug scaffold for the design of antiviral agents

Adenine derivatives, in particular the scaffold bearing the acyclic nucleoside phosphonates (ANPS), possess significant antiviral and cytostatic activity. Till now, several effective adenine derivatives have been marketed for the treatment of HIV, HBV, CMV and other virus-infected diseases. These compounds are represented by tenofovir (PMPA), a medicine for both HIV and HBV, and adefovir as an anti-HBV agent. More than this, other analogs, such as GS9148, GS9131, and GS7340, are also well-known anti-viral agents that have been progressed to the clinical studies for their excellent activity. In general, the structures of these compounds include an adenine nucleobase linked to a phosphonate side chain. Considerable structural modifications on the scaffold itself and the peripheral sections were made. The structure-activity relationships (SARs) of this skeleton will provide valuable clues to identify more effective adenine derivatives as antiviral drugs. Here, we systematically summarized the SARs of the adenine derivatives, and gave important information for further optimizing this template.KEY WORDS: Antiviral, Structure–activity relationship, Adenine, Acyclic nucleoside phosphonates, Scaffold     

cAMP-dependent phosphodiesterase inhibition and SAR studies on novel 6,8-disubstituted 2-phenyl-3-(substituted benzothiazole-2-yl)-4[3H]-quinazolinone

Two series of 6,8-disubstituted-2-phenyl-3-(substituted benzothiazole-2-yl)-4[3H]-quinazolinone (1–13 and 14–26) were synthesized by reported method and evaluated for their phosphodiesterase inhibitory activity. All test compounds exhibited good activity. The structure–activity relationships based on the results obtained for these series were also studied. In both series, electron-withdrawing substitutions showed more activity. Among the tested compounds 6,8-dibromo-2-phenyl-3-(5-chloro benzothiazole-2-yl)-4[3H]-quinazolinone (20) and 6,8-dibromo-2-phenyl-3-(6-nitro benzothiazole-2-yl)-4[3H]-quinazolinone (24) were found to be even more potent than theophylline (IC₅₀ of 1438 ± 85 μM for 20 and 1520 ± 48 μM for 24). Presented at National Symposium on Challenges in Drug Discovery Research: Networking opportunities between Academia & Industries April 7th–8th, 2006 at Birla Institute of Technology & Science, Pilani and submitted to Nagpur University as an M-pharm thesis.     

Chalcones as promising pesticidal agents against diamondback moth (Plutella xylostella): microwave-assisted synthesis and structure–activity relationship

A series of chalcones (A–CH=CH–CO–B) were synthesized under microwave irradiation, and for the first time their pesticidal activity against diamondback moth (Plutella xylostella) was evaluated to identify the promising lead structures. The structure–activity relationship (SAR) analysis revealed that electron-withdrawing substituents on ring A of chalcone provided good pesticidal agents, whereas, ring B can bear either electron-withdrawing or electron-releasing substituents. Moreover, compound 22 having para-Cl substitution on ring A as well on ring B showed maximum activity with LC₅₀ value of 170.24 μg mL⁻¹.     

Modification of N 1-(2,6-dimethylphenyl)-N 2,N 2-diethylglycinamide and 4-amino-N[2-(diethylamino)ethyl]benzamide in order to increase their antiarrhythmic effect

A structure–antiarrhythmic activity relationship has been investigated using a chloroform model of arrhythmia in rats. A mathematical model capable of predicting and recognizing antiarrhythmic activity with 84% reliability is formulated. Optimization of the molecular design of lidocaine and procainamide, which have weak antiarrhythmic activity, has resulted in modeling and predicting 51 much more effective antiarrhythmic compounds that can be synthesized for further testing.     

Synthesis, antioxidant evaluation, and quantitative structure�Cactivity relationship studies of chalcones

Synthesis, antioxidant activity, and quantitative structure–activity relationship (QSAR) of 25 of chalcone derivatives is reported here. They were synthesized by Claisen–Schmidt reaction and were characterized by FTIR, NMR, and mass spectroscopy. Antioxidant activity is evaluated through four different methods namely, superoxide radical-scavenging, hydrogen peroxide scavenging, reducing power, and DPPH radical-scavenging assays. Generally, compounds with –SCH₃ and –OCH₃ in the para position of the A-ring and –OH in the B-ring were more active than others. In few cases some of the compounds were more active than ascorbic acid or butylated hydroxytoluene. QSAR was developed correlating the antioxidant activity with the structural features of the compounds and the predictive capability of the models was estimated using internal and external validation methods. All the predictions were within the 99% confidence level. Spatial, structural, and lipophilic properties of the compounds determine their antioxidant properties.     

Synthesis and biological activities of Schiff bases of gabapentin with different aldehydes and ketones: a structure–activity relationship study

A series of novel gabapentin derivatives 6a–k and 7a–f were synthesized, and their biological activities were determined. The chemical structures were confirmed by elemental analyses, UV–visible, FT-IR, and ¹H NMR spectral studies. The structure–activity relationships (SAR) for anticonvulsant and antioxidant activities were discussed. Compounds 7a–f were evaluated for their possible anticonvulsant activity by Maximal Electroshock Seizure (MES) test, and their neurotoxic effects were determined by rotorod test. Majority of the compounds were active in MES tests. Compounds 7b and 7e showed good protective effect from seizure when compared to standard drug, phenytoin (100 mg/kg). The same compounds showed no neurotoxicity at the maximum dose administered (100 mg/kg). Most of the novel compounds showed DPPH radical scavenging activity, where compounds 6f, 6j, and 7a were the best radical scavengers (IC₅₀ was about 60 μg/ml).