Epibatidine isomers and analogues: structure-activity relationships

Binding affinities for a range of epibatidine isomers and analogues at the alpha4beta2 and alpha3beta4 nAChR subtypes are reported; compounds having similar N-N distances to epibatidine show similar, high potencies.     

8-Aminocyclazocine analogues: synthesis and structure-activity relationships

Opioid binding affinities were assessed for a series of cyclazocine analogues where the prototypic 8-OH substituent of cyclazocine was replaced by amino and substituted-amino groups. For mu and kappa opioid receptors, secondary amine derivatives having the (2R,6R,11R)-configuration had the highest affinity. Most targets were efficiently synthesized from the triflate of cyclazocine or its enantiomers using Pd-catalyzed amination procedures.     

Combined tachykinin receptor antagonist: synthesis and stereochemical structure-activity relationships of novel morpholine analogues

We report herein the synthesis and stereochemical structure-activity relationships of novel morpholine analogues 12 and 13 with regards to NK1, NK2 and NK3 tachykinin receptor binding affinity. An essential requirement for more potent binding affinities was controlled by absolute configuration. (S,R)-12 and (S,R)-13 exhibited high binding affinities for NK1, NK2 and NK3 receptors.     

Quantitative structure-activity relationships of nicotine analogues as neuronal nicotinic acetylcholine receptor ligands

Quantitative structure-activity relationships of 34 pyrrolidine-modified nicotine agonists are investigated for their binding affinity toward neuronal nicotinic acetylcholine receptor. The results indicate that a large substituent at the R₁, R₂, and R₃ position is detrimental to the binding affinity. Likewise, a large substituent at the R₂ or R₃ position as well as a hydrogen bond accepting substituent at the R_2β position are not beneficial to the binding.     

Antimicrobial effects of flavone analogues and their structure-activity relationships

It has been well known that the use of Saccharomyces cerevisiae can cause fungemia in critically ill patients and flavone shows an antimicrobial effect on S. cerevisiae. Therefore, we have investigated the activities of thirteen flavone analogues on S. cerevisiae in our studies. Because flavonoids including flavones have antioxidative effects, we try to carry out the activity studies of flavone analogues in vitro and in vivo. In addition, the relationships between the structures of flavone analogues and their biological activities, such as antimicrobial and antioxidative effects, were elucidated using Comparative Molecular Field Analysis calculations. Of the flavone analogues tested here, 3,2'-dihydroxyflavone showed both good antimicrobial and antioxidative activities.     

Synthesis and structure-activity relationships of open D-Ring galanthamine analogues

Open D-ring galanthamine analogues were prepared using ring-opening reactions of the quaternarized urethane or oxazolidine functions and were evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition potency.     

Selective manipulation of predators using pheromones: responses to frontalin and ipsdienol pheromone components of bark beetles in the Great Lakes region

Abstract 1 One proposed approach to improving biological control of bark beetles (Coleoptera: Scolytidae; alt. Curculionidae: Scolytinae) is to manipulate predator movement using semiochemicals. However, selective manipulation is impeded by attraction of both predators and pests to bark beetle pheromones. 2 The primary bark beetle affecting pine plantations in Wisconsin, U.S.A., is the pine engraver, Ips pini (Say). Other herbivores include Ips grandicollis (Eichhoff) and Dryophthorus americanus Bedel (Curculionidae). The predominant predators are the beetles Thanasimus dubius (Cleridae) and Platysoma cylindrica (Histeridae). 3 We conducted field assays using two enantiomeric ratios of ipsdienol, and frontalin plus α‐pinene. Ipsdienol is the principal pheromone component of I. pini, and frontalin is produced by a number of Dendroctonus species. α‐Pinene is a host monoterpene commonly incorporated into commercial frontalin lures. 4 Thanasimus dubius was attracted to frontalin plus α‐pinene, and also to racemic ipsdienol. By contrast, I. pini was attracted to racemic ipsdienol, but showed no attraction to frontalin plus α‐pinene. Platysoma cylindrica was attracted to 97%‐(–)‐ipsdienol and, to a lesser extent, racemic ipsdienol, but not to frontalin plus α‐pinene. Ips grandicollis was attracted to frontalin plus α‐pinene but not to ipsdienol. Dryophthorus americanus was attracted to both ipsdienol and frontalin plus α‐pinene. 5 This ability to selectively attract the predator T. dubius without attracting the principal bark beetle in the system, I. pini, provides new opportunities for research into augmentative biological control and basic population dynamics. Moreover, the attraction of T. dubius, but not P. cylindrica, to frontalin plus α‐pinene creates opportunities for selective manipulation of just one predator. 6 Patterns of attraction by predators and bark beetles to these compounds appear to reflect various degrees of geographical and host tree overlap with several pheromone‐producing species.     

Synthesis and structure-activity relationships of berberine analogues as a novel class of low-density-lipoprotein receptor up-regulators

Berberine (BBR, 1) is a novel cholesterol-lowering agent that up-regulates low-density-lipoprotein receptor (LDLR) expression through a mechanism different from that of statins. Because of the unique mode of action and good safety record, BBR provoked our interest to do structure modification at different domains for its cholesterol-lowering activity. Nineteen BBR analogues with substituents on the benzene ring D were synthesized in the present study. The analysis of structure-activity relationship (SAR) indicated that the two methoxyl groups in an ortho-distribution on this benzene ring afforded a good activity. Among the 19 analogues, compound 8j bearing a methoxyl at both 10- and 11-position showed an increased LDLR up-regulatory activity in respect to BBR, and therefore has been selected as a promising cholesterol-lowering drug candidate for further evaluation.     

Synthetic ceramide analogues as skin permeation enhancers: structure-activity relationships

The study presents new information about the structure–activity relationships of the skin permeation enhancers. A series of ceramide analogues including eight different polar head groups and six different chain lengths was synthesised. The compounds were evaluated as permeation enhancers in vitro using porcine skin. The physico-chemical parameters of the tested compounds obtained by computer modelling were used to evaluate, by multiple linear regression, the enhancement ratios (ERs) of the compounds. The regression analysis suggests that the hydrogen bonding ability of the compounds is inversely related to the ER values and that the molecular size and lipophilicity must be well balanced. In the studied enhancers having the same chain length, the enhancement activity is dependent only on their permeability coefficients. This finding confirms the Warner's hypothesis that the polar head of an enhancer is responsible for the permeation and anchoring of the molecule into the stratum corneum lipids and that it does not influence the mechanism of action. For the specific action of enhancers, that is disordering of the intercellular lipid packing, the length of the hydrophobic chain(s) and not the lipophilicity is important. Furthermore, the examination of the FTIR spectra indicated that the most active substances possess the most ordered chains. The described relationships could bring more rational approaches in designing new potent enhancers for transdermal formulations.     

Combined NK1 and NK2 tachykinin receptor antagonists: synthesis and structure-activity relationships of novel oxazolidine analogues

We report herein the synthesis and structure-activity relationships of a series of novel oxazolidine analogues with regards to NK1 and NK2 tachykinin receptor binding affinity. Among this series of oxazolidine analogues, some compounds exhibited excellent high binding affinities for both NK1 and NK2 receptors. In addition, we describe the inhibitory effect in vivo on SP-induced airway vascular hyperpermeability and NKA-induced bronchoconstriction in guinea pigs.     

Synthesis and structure-activity relationships of thiotetronic acid analogues of thiolactomycin

3-Acetyl analogues of thiolactomycin, a thiotetronic acid natural product, were synthesized and profiled against livestock pathogens. Some analogues showed improved activity over thiolactomycin against Staphylococcus aureus and comparable activity against Pasteurella multocida. Several semisynthetically modified analogues of thiolactomycin showed no improvement in activity over thiolactomycin.     

Attraction of southern pine engravers and associated bark beetles (Coleoptera: Scolytidae) to ipsenol, ipsdienol, and lanierone in southeastern United States

We determined the response of the small southern pine engraver, Ips avulsus (Eichhoff); eastern fivespined ips, Ips grandicollis (Eichhoff); sixspined ips, Ips calligraphus (Germar); and pine engraver, Ips pini (Say) to the pheromones (+/-)-ipsenol, (+/-)-ipsdienol, and lanierone in the southeastern United States. Catches of I. avulsus and I. grandicollis to baited multiple-funnel traps were increased by (+/-)-ipsenol and (+/-)-ipsdienol in Florida, Georgia, Louisiana, and North Carolina. In all four localities, the highest numbers of I. avulsus were caught in traps baited with the combination of (+/-)-ipsenol, (+/-)-ipsdienol, and lanierone. In Florida, the highest numbers of I. grandicollis were captured in traps baited with the combination of (+/-)-ipsenol and (+/-)-ipsdienol (with or without lanierone). In the remaining three localities, the largest catches of I. grandicollis occurred in traps baited with (+/-)-ipsenol alone or the combination of (+/-)-ipsenol and (+/-)-ipsdienol (with or without lanierone). (+/-)-Ipsdienol was the only consistent attractant for I. calligraphus and I. pini. Attraction of I. pini in North Carolina to (+/-)-ipsdienol-baited traps was synergized by lanierone but interrupted with (+/-)-ipsenol. The interruptive effect of (+/-)-ipsenol on attraction of I. pini to (+/-)-ipsdienol was negated by lanierone. (+/-)-Ipsdienol was attractive to black turpentine beetle, Dendroctonus terebrans (Olivier), in Florida but not North Carolina, whereas (+/-)-ipsdienol was attractive to I. calligraphus in Louisiana, Georgia, and Florida. Both (+/-)-ipsenol and (+/-)-ipsdienol affected catches of Gnathotrichus materiarus (Fitch) in North Carolina. Trap catches of Hylurgops rugipennis pinifex (Fitch), Hylastes salebrosus Eichhoff, and Hylastes tenuis Eichhoff were unaffected by the pheromone treatments. The combination of (+/-)-ipsenol, (+/-)-ipsdienol, and lanierone may be a cost-effective general lure for I. avulsus, I. grandicollis, and I. pini.     

Synthesis and structure-activity relationships of 5-substituted pyridine analogues of 3

In an effort to probe the steric influence of C5 substitution of the pyridine ring on CNS binding affinity, analogues of 1 substituted with a bulky moiety--such as phenyl, substituted phenyl, or heteroaryl-were synthesized and tested in vitro for neuronal nicotinic acetylcholine receptor binding affinity. The substituted analogues exhibited Ki values ranging from 0.055 to 0.69 nM compared to a Ki value of 0.15 nM for compound 1. Assessment of functional activity at subtypes of neuronal nicotinic acetylcholine receptors led to identify several agonists and antagonists.     

Alpha-helical small molecular size analogues of neuropeptide Y: structure-activity relationships.

C-terminal analogues of neuropeptide Y (NPY) of small molecular size have been synthesized. The influence of chain length, single or multiple amino acid substitution, and segment substitutions on receptor binding, pre- and postsynaptic biological activity, and conformational properties have been investigated. Receptor binding and in vivo assays revealed biological activity for NPY Ac-25-36 that increased with increasing alpha-helicity. In attempts to stabilize the alpha-helical content, three independent types of modified NPY Ac-25-36 analogues were synthesized. Strong agonistic activities could be detected in a series of discontinuous analogues, which are constructs of N-terminal parts linked via different spacer molecules to C-terminal segments. One of the most active molecules was NPY 1-4-Aca-25-36 (Aca, epsilon-aminocaproic acid). For the first time conformational properties of a series of small NPY analogues have been investigated by CD, and correlated with biological activity and receptor binding. A C-terminal dodecapeptide segment of NPY with an amount of 50% substitution to the native C-terminal sequence of NPY was found to exhibit significant receptor binding.     

Synthesis and structure-activity relationships study of novel anti-tumor carbamate anhydrovinblastine analogues

A series of 3-demethoxycarbonyl-3-carbamate methyl anhydrovinblastine derivatives (compounds 8b-32b) were designed, synthesized, and evaluated for their inhibition activities against human non-small cell lung cancer cell line (A549) and a human cervix epithelial adenocarcinoma cell line (HeLa). The structure-activity relationships of this new series are described in this paper. Cytotoxicity data revealed that the size of substituents and substitution position had important influence on cytotoxic activity. On two cell lines, compounds (8b and 30b) had more potent cytotoxic activity than the lead compound (1e, AVLB). The preliminary antitumor studies of 8b in vivo showed that it might be promising for the development of new antitumor agents.     

Synthesis and structure-activity relationships of novel camphecene analogues as anti-influenza agents

A chemical library was constructed based on the scaffold of camphecene (2-(E)-((1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene-aminoethanol). The modifications included introduction of mono-and bicyclic heterocyclic moieties in place of the terminal hydroxyl group of camphecene. All compounds were tested for cytotoxicity and anti-viral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells. Among 15 tested compounds 11 demonstrated a selectivity index (SI) higher than 10 and IC₅₀ values in the micromolar range. The antiviral activity and toxicity were shown to strongly depend on the nature of the heterocyclic substituent. Compounds 2 and 14 demonstrated the highest virus-inhibiting activity with SIs of 106 and 183, and bearing pyrrolidine and piperidine moieties, correspondingly. Compound 14 was shown to interfere with viral reproduction at early stages of the viral life cycle (0–2 h post-infection). Taken together, our data suggest potential of camphecene derivatives in particular and camphor-based imine derivatives in general as effective anti-influenza compounds.     

Synthesis and structure-activity relationships of andrographolide analogues as novel cytotoxic agents

Andrographolide 1, the cytotoxic agent of the plant Andrographis paniculata was subjected to semi-synthetic studies leading to the preparation of a number of potent and novel analogues. Of the analogues synthesized, while 8,17-epoxy andrographolide 6 retained the cytotoxic activity of 1, ester derivatives of 6 exhibited considerable improvement in activity. Lower activity was observed when the epoxy moiety in the triacetate 9, derived from 6 was modified. Synthesis and structure-activity relationships are discussed.     

Inhibitors of adenosine deaminase: continued studies of structure-activity relationships in analogues of coformycin

Synthesis and adenosine deaminase (ADA) inhibitory activity of two analogues of coformycin, containing the imidazo[4,5-e][1,2,4]triazepine ring system, have been reported as part of the structure-activity relationship (SAR) studies to explore the factors responsible for the extremely tight-binding characteristics of coformycins to ADA.     

Ophiostomatoid fungi isolated from Japanese red pine and their relationships with bark beetles

We isolated ophiostomatoid fungi from bark beetles infesting Pinus densiflora and their galleries at 24 sites in Japan. Twenty-one ophiostomatoid fungi, including species of Ophiostoma, Grosmannia, Ceratocystiopsis, Leptographium, and Pesotum, were identified. Among these, 11 species were either newly recorded in Japan or were previously undescribed species. Some of these fungal species were isolated from several bark beetles, but other species were isolated from only a particular beetle species. Thus, it is suggested that some ophiostomatoid fungi have specific relationships with particular beetle species. In addition, fungus-beetle biplots from redundancy analysis (RDA) summarizing the effects of beetle ecological characteristics suggested that the association patterns between bark beetles and the associated fungi seemed to be related to the niches occupied by the beetles.     

Nonpeptide Urotensin-II receptor agonists and antagonists: review and structure-activity relationships

Human Urotensin-II (hU-II) is a cyclic 11-amino acid peptide that plays a role in cardiovascular homeostasis. Its receptor is a member of the class A of G-protein-coupled receptors, called GPR14. In recent years, several nonpeptide ligands have been reported in the literature. Most were identified by high-throughput screening and optimized by medicinal chemistry methods. Other nonpeptide ligands were discovered starting from the 3D structure of hU-II or other ligands. They were identified by a virtual screening approach based on a 3D pharmacophore or by structural similarity with others cyclic peptides. In this review, nonpeptide agonists and antagonists are presented in relation to structure-activity relationships.