Synthesis and Anti- Activity of 3-Cyanopyridine Derivatives.

Chagas disease (CD) is a parasitic neglected tropical disease (NTD) caused by the protozoan that affects 6 million people worldwide, often resulting in financial burden, morbidity, and mortality in endemic regions. Given a lack of highly efficient and safe treatments, new, affordable, and fit-for-purpose drugs for CD are urgently needed. In this work, we present a hit-to-lead campaign for novel cyanopyridine analogues as antichagasic agents.

Multiparameter Optimization of Trypanocidal Cruzain Inhibitors With Activity and Favorable Pharmacokinetics.

Cruzain, the main cysteine protease of , plays key roles in all stages of the parasite's life cycle, including nutrition acquisition, differentiation, evasion of the host immune system, and invasion of host cells. Thus, inhibition of this validated target may lead to the development of novel drugs for the treatment of Chagas disease. In this study, a multiparameter optimization (MPO) approach, molecular modeling, and structure-activity relationships (SARs) were employed for the identification of new benzimidazole derivatives as potent competitive inhibitors of cruzain with trypanocidal activity and suitable pharmacokinetics.

Hit-to-lead optimization of a benzene sulfonamide series for potential antileishmanial agents.

A series of benzene sulphonamides with good potency and selectivity against spp. intracellular amastigotes was identified by high-throughput screening. Approximately 200 compounds were synthesized as part of a hit-to-lead optimization program.

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.

Benzimidazole inhibitors of the major cysteine protease of .

Limitations in available therapies for trypanosomiases indicate the need for improved medicines. Cysteine proteases cruzain and rhodesain are validated targets for treatment of Chagas disease and human African trypanosomiasis. Previous studies reported a benzimidazole series as potent cruzain inhibitors.

Molecular modeling and structure-activity relationships for a series of benzimidazole derivatives as cruzain inhibitors.

Aim: Chagas disease is endemic in Latin America and no effective treatment is available. Efforts in drug research have focused on several enzymes from Trypanosoma cruzi, among which cruzain is a validated pharmacological target.

Methodology: Chemometric analyses were performed on the data set using the hologram quantitative structure-activity relationship, comparative molecular field analysis and comparative molecular similarity index analysis methods.

Synthesis, biological evaluation, and structure-activity relationships of potent noncovalent and nonpeptidic cruzain inhibitors as anti-Trypanosoma cruzi agents.

The development of cruzain inhibitors has been driven by the urgent need to develop novel and more effective drugs for the treatment of Chagas' disease. Herein, we report the lead optimization of a class of noncovalent cruzain inhibitors, starting from an inhibitor previously cocrystallized with the enzyme (K(i) = 0.8 μM).

Analysis of cytokinin nucleotides by capillary zone electrophoresis with diode array and mass spectrometric detection in a recombinant enzyme in vitro reaction.

A capillary zone electrophoresis (CZE) method for separation of adenosine and N(6)-isopentenyladenosine (cytokinin) nucleotides was developed, optimized and validated. Aqueous solutions of several amino acids were evaluated as the background electrolyte constituents. Separation of six nucleotides in less than 20 min with high theoretical plate number (up to 400000 for isopentenyladenosine triphosphate) was achieved using a 100 mM sarcosine/ammonia buffer at pH 10.

Identification of enterodiol as a masker for caffeine bitterness by using a pharmacophore model based on structural analogues of homoeriodictyol.

Starting from previous structure-activity relationship studies of taste modifiers based on homoeriodictyol, dihydrochalcones, deoxybenzoins, and trans-3-hydroxyflavones as obvious analogues were investigated for their masking effect against caffeine. The most active compounds of the newly investigated taste modifiers were phloretin, the related dihydrochalcones 3-methoxy-2',4,4'-trihydroxydihydrochalcone and 2',4-dihydroxy-3-methoxydihydrochalcone, and the deoxybenzoin 2-(4-hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)ethanone. Starting with the whole set of compounds showing activity >22%, a (Q)SAR pharmacophore model for maskers of caffeine bitterness was calculated to explain the structural requirements.

In vitro and in vivo production of new aminocoumarins by a combined biochemical, genetic, and synthetic approach.

The aminocoumarin antibiotics clorobiocin, novobiocin, and coumermycin A(1) are inhibitors of bacterial gyrase. Their chemical structures contain amide bonds, formed between an aminocoumarin ring and an aromatic acyl component, which is 3-dimethylallyl-4-hydroxybenzoate in the case of novobiocin and clorobiocin. These amide bonds are formed under catalysis of the gene products of cloL, novL, and couL, respectively.

A proposed mechanism for the reductive ring opening of the cyclodiphosphate MEcPP, a crucial transformation in the new DXP/MEP pathway to isoprenoids based on modeling studies and feeding experiments.

Experimental and theoretical investigations concerning the second-to-last step of the DXP/MEP pathway in isoprenoid biosynthesis in plants are reported. The proposed intrinsic or late intermediates 4-oxo-DMAPP (12) and 4-hydroxy-DMAPP (11) were synthesized in deuterium- or tritium-labeled form according to new protocols especially adapted to work without protection of the diphosphate moiety. When the labeled compounds MEcPP (7), 11, and 12 were applied to chromoplast cultures, aldehyde 12 was not incorporated.