Caffeic acid derivatives as growth inhibitors of Setaria viridis: Structure-activity relationships and mechanisms

Weeds bring severe threats to agricultural production and most traditional herbicides cause serious pollution to the environment. Caffeic acid is a potential allelochemical of many crops. To develop novel herbicides, a series of trans-caffeic acid analogues were prepared to evaluate their growth inhibition on S. viridis and investigate structure-activity relationships. Presence of hydroxyl groups on the benzene ring greatly reduced the phytotoxicity of analogues and the double bond seemed not to be necessary. Moreover, it was found that halogenated cinnamic acid analogues showed potent inhibitory activity. 4-Fluorocinnamic acid (4-FCA) displayed the strongest growth inhibition in a concentration-dependent manner, whereas it induced significantly weaker inhibition on wheat. This selectivity could help us to develop a novel herbicide. Exposure of S. viridis to 4-FCA increased levels of H₂O₂ and catalase (CAT) in roots, suggesting that the inhibitory effect of 4-FCA might be related to oxidative stress. Thus, we have found an active lead compound for a novel herbicide derived from crop allelochemicals, which may help in the development of new environmentally safe herbicides.     

Benzoic acid and pyridine derivatives as inhibitors of Trypanosoma cruzi trans-sialidase

Benzoic acid and pyridine derivatives inhibit recombinant trans-sialidase from Trypanosoma cruzi with I50 values between 0.4 and 1mM. The best compounds, 4-acetylamino-3-hydroxymethylbenzoic acid and 5-acetylamino-6-aminopyridine-2-carboxylic acid, provide new leads to inhibitors not containing the synthetically complex sialic acid structure. The weak inhibition by such compounds contrasts with their much stronger inhibition of neuraminidase from Influenza virus.     

Structure-activity relationship of 4-azaindole-2-piperidine derivatives as agents against Trypanosoma cruzi

The structure-activity relationship of a 4-Azaindole-2-piperidine compound selected from GlaxoSmithKline’s recently disclosed open-resource “Chagas box” and possessing moderate activity against Trypanosoma cruzi, the parasite responsible for Chagas disease, is presented. Despite considerable medicinal chemistry efforts, a suitably potent and metabolically stable compound could not be identified to advance the series into in vivo studies. This research should be of interest to those in the area of neglected diseases and in particular anti-kinetoplastid drug discovery.     

Structure-activity relationships for a class of selective inhibitors of the major cysteine protease from Trypanosoma cruzi

Chagas' disease is a parasitic infection widely distributed throughout Latin America, with devastating consequences in terms of human morbidity and mortality. Cruzain, the major cysteine protease from Trypanosoma cruzi, is an attractive target for antitrypanosomal chemotherapy. In the present work, classical two-dimensional quantitative structure-activity relationships (2D QSAR) and hologram QSAR (HQSAR) studies were performed on a training set of 45 thiosemicarbazone and semicarbazone derivatives as inhibitors of T. cruzi cruzain. Significant statistical models (HQSAR, q² = 0.75 and r² = 0.96; classical QSAR, q² = 0.72 and r² = 0.83) were obtained, indicating their consistency for untested compounds. The models were then used to evaluate an external test set containing 10 compounds which were not included in the training set, and the predicted values were in good agreement with the experimental results (HQSAR, = 0.95; classical QSAR, = 0.91), indicating the existence of complementary between the two ligand-based drug design techniques.     

Structure-activity relationships of biphenyl tetrazoles as metallo-beta-lactamase inhibitors.

Resistance to carbapenem antibiotics in gram-negative bacteria is due, in part, to expression of a wide spectrum metallo-beta-lactamase, which renders the drug inactive. Biphenyl tetrazoles containing 3-n-butyl-1-phenylpyrazole-5-carboxylates or the corresponding 5-ethyl esters were found to inhibit metallo-beta-lactamases as well as renal dehydropeptidase I to a lesser extent.     

Anacardic acid derivatives as inhibitors of glyceraldehyde-3-phosphate dehydrogenase from Trypanosoma cruzi

Chagas' disease, a parasitic infection caused by the flagellate protozoan Trypanosoma cruzi, is a major public health problem affecting millions of individuals in Latin America. On the basis of the essential role in the life cycle of T. cruzi, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been considered an attractive target for the development of novel antitrypanosomatid agents. In the present work, we describe the inhibitory effects of a small library of natural and synthetic anacardic acid derivatives against the target enzyme. The most potent inhibitors, 6-n-pentadecyl- and 6-n-dodecylsalicilic acids, have IC(50) values of 28 and 55 microM, respectively. The inhibition was not reversed or prevented by the addition of Triton X-100, indicating that aggregate-based inhibition did not occur. In addition, detailed mechanistic characterization of the effects of these compounds on the T. cruzi GAPDH-catalyzed reaction showed clear noncompetitive inhibition with respect to both substrate and cofactor.     

New potent 5-nitroindazole derivatives as inhibitors of Trypanosoma cruzi growth: Synthesis,biological evaluation,and mechanism of action studies

New 5-nitroindazole derivatives were developed and their antichagasic properties studied. Eight compounds (14–18, 20, 26 and 28) displayed remarkable in vitro activities against Trypanosoma cruzi (T. cruzi). Its unspecific cytotoxicity against macrophages was evaluated being not toxic at a concentration at least twice that of T. cruzi IC₅₀, for some derivatives. The electrochemical studies, parasite respiration studies and ESR experiment showed that 5-nitroindazole derivatives not be able to yield a redox cycling with molecular oxygen such as occurs with nifurtimox (Nfx). The study on the mechanism of action proves to be related to the production of reduced species of the nitro moiety similar to that observed with benznidazole.     

Structure-activity relationships of neuropeptide FF and related peptidic and non-peptidic derivatives

Neuropeptide FF, a member of the RFamide family of peptides, has demonstrated an interesting array of pharmacological effects. To date however, little information has been obtained as to the exact pharmacological roles of the individual NPFF1 and NPFF2 receptors. Through peptide analogs of NPFF and related peptides, the essential pharmacophore has emerged somewhat. Yet, the field is lacking small molecule ligands selective for each receptor. This review of the structure-activity relationships of the reported NPFF peptide analogs and some non-selective small molecule ligands highlights the current understanding of the pharmacophoric elements required for affinity and activity at the NPFF receptors. The lack of mutagenesis data on the receptor as well as a crystal structure has also hindered the understanding of ligand recognition at the receptor level. If the targets can be further investigated as to their requirements for ligand recognition, the successful development of highly selective ligands should follow.     

Structure-activity relationships of 3,4-dihydro-1H-quinazolin-2-one derivatives as potential CDK5 inhibitors

Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that plays a critical role in the early development of the nervous system. Deregulation of CDK5 is believed to contribute to the abnormal phosphorylation of various cellular substrates associated with neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and ischemic stroke. Acyclic urea 3 was identified as a potent CDK5 inhibitor and co-crystallographic data of urea 3/CDK2 enzyme were used to design a novel series of 3,4-dihydroquinazolin-2(1H)-ones as CDK5 inhibitors. In this investigation we present our synthetic studies toward this series of compounds and discuss their biological relevance as CDK5 inhibitors.     

Structure-activity relationships of epolactaene analogs as DNA polymerases inhibitors

Epolactaene, a neuritogenic compound in human neuroblastoma cells, showed inhibitory activities against DNA polymerases alpha and beta. The synthesis and inhibitory activities of epolactaene analogs are described. The alpha,beta-epoxy-gamma-lactam moiety in the core and the length of the side chain greatly influenced the activities. Compound 5 was the strongest inhibitor of DNA polymerase alpha and beta of all synthesized compounds with IC(50) values of 13 and 78 microM, respectively. N- and O-alkyl derivatives that had modified core moieties showed moderate inhibition.     

Effects of proteinase inhibitors on the growth and differentiation of Trypanosoma cruzi

Abstract Three proteinase inhibitors, one peptidyl acyloxymethyl ketone (AMK), Z-Phe-Lys-CH₂-OCO-(2,4,6-Me₃)Ph.HCl, and two diazomethyl ketones (DMKs), Z-Phe-Phe-DMK and Z-Phe-Ala-DMK, have been studied for their effects in vitro on the four developmental stages of Trypanosoma cruzi . The three inhibitors penetrated living parasites and inhibited the major cysteine proteinase, cruzipain. The AMK was the most potent inhibitor of cruzipain itself and at 20 μM caused lysis of epimastigotes and trypomastigotes. When at lower concentrations, however, it had little effect on epimastigote growth but reduced metacyclogenesis. The DMKs had no effect against epimastigotes but inhibited differentiation to metacyclics. All three inhibitors markedly reduced infection of Vero cells by the parasite and the multiplication of the intracellular amastigotes, whereas release of trypomastigotes was almost entirely prevented. The results confirm the importance of cysteine proteinases in the life cycle of T. cruzi , and suggest that the differentiation steps are the most susceptible to cysteine proteinase inhibitors.     

Structure-activity relationship of N-methyl-bisindolylmaleimide derivatives as cell death inhibitors

A series of N-methyl-bisindolylmaleimide derivatives was synthesized and evaluated as cell death inhibitors. N-Methyl-2-[1-(3-aminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)maleimide (21) was the most potent inhibitor of H2O2-induced necrotic death of human leukemia HL60 cells among them.     

Structure-activity relationships between cryptopleurine and related compounds acting on yeast cell-free systems

The inhibitory effects on poly(U)-directed polyphenylalanine synthesis of cryptopleurine and a number of structurally related analogs have been compared in a yeast cell-free system. Results suggest that the quinolidine structure by itself does not promote biological activity, and for an inhibitory effect it must be condensed with a phenanthrene or another related compound such as naphthalene. The results are presented and possible relationships between structure and activity for the compounds emetine, tubolosine, tylophora alkaloids, and various cryptopleurine analogs are considered.     

Structure-activity relationships of novel N-acyloxy-1,4-dihydropyridines as P-glycoprotein inhibitors

Series of novel N-acyloxy-1,4-dihydropyridines have been synthesized and evaluated as P-glycoprotein inhibitors in an in vitro assay to estimate their potential to act as multidrug resistance modulators in cancer cells. Structure-activity relationships are discussed and prove a significant and regiospecific influence of certain functional groups.     

Fluorine-containing aryloxyethyl thiocyanate derivatives are potent inhibitors of Trypanosoma cruzi and Toxoplasma gondii proliferation

As a part of our project aimed at developing new safe chemotherapeutic and chemoprophylactic agents against tropical diseases, fluorine-containing drugs structurally related to 4-phenoxyphenoxyethyl thiocyanate (1) were designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible of American trypanosomiasis (Chagas' disease), and Toxoplasma gondii, the etiological agent of toxoplasmosis. This thiocyanate derivative had previously proven to be an effective agent against T. cruzi proliferation. Fluorine-containing thiocyanate derivatives 2 and 3 were threefold more potent than our lead drug 1 against intracellular T. cruzi. The biological evaluation against T. gondii was also very promising. The IC(50) values corresponding to 2 and 3 were at the very low micromolar level against tachyzoites of T. gondii. Both of these drugs are interesting examples of effective antiparasitic agents that have outstanding potential not only as lead drugs but also to be used for further in vivo studies.     

New potent 5-substituted benzofuroxans as inhibitors of Trypanosoma cruzi growth: quantitative structure-activity relationship studies

Benzofuroxan derivatives have been shown to inhibit the growth of Trypanosoma cruzi, the etiological agent of Chagas' disease. Therefore, 2D- and 3D-QSAR models of their in vitro antichagasic activity were developed. Six new derivatives were synthesized to complete a final set of 26 structurally diverse benzofuroxans. The 2D-QSAR model (r = 0.939, r(adj)(2) = 0.849) was generated using multiple regression analysis of tabulated substituents' physicochemical properties and indicator variables. In addition, a 3D-QSAR model (r(2) = 0.997, q(2) = 0.802) was obtained using a comparative molecular field analysis (CoMFA). Due to the well-known benzofuroxan tautomerism, in both approaches (2D- and 3D-QSAR) it was necessary to include an indicator variable to consider the N-oxide position (I(6)). This parameter was established using low-temperature NMR experiments. Both QSAR models identified the electrophilic character of the substituent alpha-atom as a requirement for activity. Further support was found using a density functional theory (DFT) approach.     

Bisphosphonates as inhibitors of Trypanosoma cruzi hexokinase: kinetic and metabolic studies

Trypanosoma cruzi, the etiologic agent of Chagas disease, has an unusual ATP-dependent hexokinase (TcHK) that is not affected by D-glucose 6-phosphate, but is non-competitively inhibited by inorganic pyrophosphate (PP(i)), suggesting a heterotropic modulator effect. In a previous study we identified a novel family of bisphosphonates, metabolically stable analogs of PP(i), which are potent and selective inhibitors of TcHK as well as the proliferation of the clinically relevant intracellular amastigote form of the parasite in vitro (Hudock, M. P., Sanz-Rodriguez, C. E., Song, Y., Chan, J. M., Zhang, Y., Odeh, S., Kosztowski, T., Leon-Rossell, A., Concepcion, J. L., Yardley, V., Croft, S. L., Urbina, J. A., and Oldfield, E. (2006) J. Med. Chem. 49, 215-223). In this work, we report a detailed kinetic analysis of the effects of three of these bisphosphonates on homogeneous TcHK, as well as on the enzyme in purified intact glycosomes, peroxisome-like organelles that contain most of the glycolytic pathway enzymes in this organism. We also investigated the effects of the same compounds on glucose consumption by intact and digitonin-permeabilized T. cruzi epimastigotes, and on the growth of such cells in liver-infusion tryptose medium. The bisphosphonates investigated were several orders of magnitude more active than PP(i) as non-competitive or mixed inhibitors of TcHK and blocked the use of glucose by the epimastigotes, inducing a metabolic shift toward the use of amino acids as carbon and energy sources. Furthermore, there was a significant correlation between the IC(50) values for TcHK inhibition and those for epimastigote growth inhibition for the 12 most potent compounds of this series. Finally, these bisphosphonates did not affect the sterol composition of the treated cells, indicating that they do not act as inhibitors of farnesyl diphosphate synthase. Taken together, our results suggest that these novel bisphosphonates act primarily as specific inhibitors of TcHK and may represent a novel class of selective anti-T. cruzi agents.     

Bisphosphonates derived from fatty acids are potent growth inhibitors of Trypanosoma cruzi

We have investigated the effect of a series of bisphosphonates derived from fatty acids against Trypanosoma cruzi proliferation in in vitro assays. Some of these drugs proved to be potent inhibitors against the intracellular form of the parasite exhibiting IC50 values at the low micromolar level. As bisphosphonates are FDA clinically approved for treatment of bone resorption, their potential innocuousness makes them good candidates to control tropical diseases.