Synthesis, design, and optimization of a potent and selective series of pyridylpiperazines as promising antimalarial agents.

An optimization of the pyridylpiperazine series against Plasmodium falciparum has been performed, exploring a structure-activity relationship carried out on the toluyl fragment of hit 1, a compound with low micromolar activity against Plasmodium falciparum discovered by high-throughput screening. After confirming the crucial role played by this aryl fragment in the antiplasmodial activity, the replacement of the ortho-methyl substituent of 1 by halogenated ones led to an improvement for four analogs, either in terms of potency, expected pharmacokinetics profile, or both. Further introduction of endocyclic nitrogens in this fragment identified two more optimized compounds, 20 and 23, which are expected to be much more metabolically stable than 1. Additional assessment of the cytotoxicity, Ligand Lipophilic Efficiency, potency against the chloroquine-resistant Dd2 strain and in silico ADMET predictions revealed a satisfactory profile for most compounds, ultimately identifying the four optimized compounds 7, 9, 20 and 23 as promising compounds for further lead optimization of this series against Plasmodium falciparum.

New Palladium(II) Complexes Containing Methyl Gallate and Octyl Gallate: Effect against Mycobacterium tuberculosis and Campylobacter jejuni.

This work describes the preparation, characterization and antimicrobial activity of four palladium(II) complexes, namely, [Pd(meg)(1,10-phen)] 1, [Pd(meg)(PPh3)2] 2, [Pd(og)(1,10-phen)] 3 and [Pd(og)(PPh3)2] 4, where meg = methyl gallate, og = octyl gallate, 1,10-phen = 1,10-phenanthroline and PPh3 = triphenylphosphine. As to the chemical structures, spectral and physicochemical studies of 1-4 indicated that methyl or octyl gallate coordinates a palladium(II) ion through two oxygen atoms upon deprotonation. A chelating bidentate phenanthroline or two triphenylphosphine molecules complete the coordination sphere of palladium(II) ion, depending on the complex. The metal complexes were tested against the Mycobacterium tuberculosis H37Rv strain and 2 exhibited high activity (MIC = 3.28 µg/mL). As to the tests with Campylobacter jejuni, complex 1 showed a significant effect in reducing bacterial population (greater than 7 log CFU) in planktonic forms, as well as in the biomass intensity (IBF: 0.87) when compared to peracetic acid (IBF: 1.11) at a concentration of 400 µg/mL. The effect provided by these complexes has specificity according to the target microorganism and represent a promising alternative for the control of microorganisms of public health importance.

Hit-to-lead optimization of a pyrazinylpiperazine series against Leishmania infantum and Leishmania braziliensis.

An early hit-to-lead optimization of a novel pyrazinylpiperazine series against L. infantum and L. braziliensis has been performed after an extensive SAR focusing on the benzoyl fragment of hit (4). Deletion of the meta-Cl of (4) led to the obtention of the para-hydroxyl derivative (12), on which the design of most monosubstituted derivatives of the SAR was based. Further optimization of the series, involving disubstituted benzoyl fragments and the hydroxyl substituent of (12), allowed the obtention of a total of 15 compounds with increased antileishmanial potency (IC50 < 10 µM), nine of which displayed activity in the low micromolar range (IC50 < 5 µM). This optimization ultimately identified the ortho, meta-dihydroxyl derivative (46) as an early lead for this series (IC50 (L. infantum) = 2.8 µM, IC50 (L. braziliensis) = 0.2 µM). Additional assessment of some selected compounds against other trypanosomatid parasites revealed that this series is selective towards Leishmania parasites, and in silico ADMET predictions revealed satisfactory profiles for these compounds, allowing further lead optimization of the pyrazinylpiperazine class against Leishmania.

Quinic acid derivatives inhibit dengue virus replication in vitro.

BACKGROUND: Dengue is the most prevalent arboviral disease in tropical and sub-tropical areas of the world. The incidence of infection is estimated to be 390 million cases and 25,000 deaths per year. Despite these numbers, neither a specific treatment nor a preventive vaccine is available to protect people living in areas of high risk. RESULTS: With the aim of seeking a treatment that can mitigate dengue infection, we demonstrated that the quinic acid derivatives known as compound 2 and compound 10 were effective against all four dengue virus serotypes and safe for use in a human hepatoma cell line (Huh7.5). Both compounds were non-virucidal to dengue virus particles and did not interfere with early steps of the dengue virus life cycle, including binding and internalization. Experiments using a replicon system demonstrated that compounds 2 and 10 impaired dengue virus replication in Huh7.5 cells. Additionally, the anti-dengue virus effects of the quinic acid derivatives were preserved in human peripheral blood mononuclear cells. CONCLUSIONS: Taken together, these data suggest that quinic acid derivatives represent a novel chemical class of active compounds that could be used to combat dengue virus infection.