1,4-Naphthoquinone Cations as Antiplasmodial Agents: Hydroxy-, Acyloxy-, and Alkoxy-Substituted Analogues

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Synthesis and in Vitro and in Vivo Pharmacological Evaluation of New 4-Aminoquinoline-Based Compounds

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Synthesis and Antiplasmodial and Antimycobacterial Evaluation of New Nitroimidazole and Nitroimidazooxazine Derivatives

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The Bicyclic Form of galacto-Noeurostegine Is a Potent Inhibitor of β-Galactocerebrosidase

Competitive inhibitors of galactocerebrosidase (GALC) could be candidates for pharmacological chaperone therapy of patients with Krabbe disease. The known and selective nortropane-type iminosugar galacto-noeurostegine has been found to competitively inhibit GALC with K_i = 7 μM at pH 4.6, which is 330-fold more potent than the analogous deoxynoeurostegine. It was shown through X-ray protein crystallography that galacto-noeurostegine binds to the active site of GALC in its bicyclic form.     

Inhibition of Plasmodium falciparum pH regulation by small molecule indole derivatives results in rapid parasite death

The V-type H⁺-ATPase is critical during the intraerythrocytic stage of the human malaria parasite Plasmodium falciparum. It is responsible for maintaining a near-neutral cytosolic pH (pH 7.3), an acidic digestive vacuole (pH 4.5-5.5) and the generation of an inside-negative plasma membrane potential (∼−95 mV). Inhibition of this pump is therefore likely to result in profound physiological disturbances within the parasite and parasite death, as illustrated previously by the antiplasmodial activity of the potent and specific inhibitors of the V-type H⁺-ATPase, bafilomycin A₁ and concanamycin A. In this study we examined the antiplasmodial activity of a series of compounds previously designed, on the basis of the active structural constituents of bafilomycin A₁, to inhibit the osteoclast V-type H⁺-ATPase. The compounds were tested against up to 4 strains of P. falciparum with varying chloroquine sensitivities. Of the 30 novel compounds tested, 9 had sub-micromolar antiplasmodial IC₅₀ values, with the most active compound having an IC₅₀ of 160 ± 20 nM. The activity of a number of these compounds was investigated in more detail. We show that these inhibitors acidify the parasite cytosol within seconds and that some inhibitors irreversibly kill the parasite within 0.5-4 h. The antiplasmodial activity of the V-type H⁺-ATPase inhibitors was strongly correlated with their ability to acidify the parasite cytosol (correlation coefficient 0.98). In combination studies, we show that the inhibitors act indifferently when combined with current antimalarials. Our data support the disruption of parasite pH regulation through inhibition of its V-type H⁺-ATPase as an antimalarial approach.     

Influence of 4′-Substitution on the Activity of Gemcitabine and Its ProTide Against VZV and SARS-CoV-2

In addition to its therapeutic value as a chemotherapy drug, gemcitabine is of ongoing interest to the scientific community for its broad-spectrum antiviral activity. Herein the synthesis of 4′-methoxy- and 4′-fluoro-substituted gemcitabine analogues along with their phosphoramidate prodrugs is described. Among these derivatives, 4′-fluorogemcitabine proved to be active against varicella zoster virus (VZV, TK+ strain) with an EC₅₀ of 0.042 μM and produced significant cytotoxicity (CC₅₀ = 0.11 μM). Upon derivatization of this trifluoro nucleoside as its prodrug, decreased anti-VZV activity was observed, but with a concomitantly improved selectivity index (SI = 36). When this prodrug was tested against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), its antiviral activity (EC₅₀ = 0.73 μM) was comparable to or slightly lower than its cytotoxic concentration in measurements of cell growth and cell morphology, respectively.     

Design and Catalyzed Activation of Mycophenolic Acid Prodrugs

Mycophenolic acid (MPA) and its morpholino ester prodrug mycophenolate mofetil (MMF) are widely used in solid organ transplantation. These drugs prevent rejection due to their potent inhibition of inosine-5′-monophosphate dehydrogenase (IMPDH), an enzyme vital for lymphocyte proliferation. As a strategy to provide localized immunosuppression in cell transplantation, four mycophenolic acid prodrugs designed to release MPA by two distinct mechanisms were synthesized and characterized. A nitrobenzyl ether prodrug was effectively converted to MPA upon exposure to bacterial nitroreductase, while a propargyl ether was converted to the active drug by immobilized Pd⁰ nanoparticles. In vitro, both prodrugs were inactive against IMPDH and exhibited reduced toxicity relative to the active drug, suggesting their potential for providing localized immunosuppression.     

Synthesis,Antiplasmodial Activity,and β-Hematin Inhibition of Hydroxypyridone–Chloroquine Hybrids

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Amide–Amine Replacement in Indole-2-carboxamides Yields Potent Mycobactericidal Agents with Improved Water Solubility

Indolecarboxamides are potent but poorly soluble mycobactericidal agents. Here we found that modifying the incipient scaffold by amide–amine substitution and replacing the indole ring with benzothiophene or benzoselenophene led to striking (10–20-fold) improvements in solubility. Potent activity could be achieved without the carboxamide linker but not in the absence of the indole ring. The indolylmethylamine, N-cyclooctyl-6-trifluoromethylindol-2-ylmethylamine (33, MIC_90Mtb 0.13 μM, MBC_99.9Mtb 0.63 μM), exemplifies a promising member that is more soluble and equipotent to its carboxamide equivalent. It is also an inhibitor of the mycolate transporter MmpL3, a property shared by the methylamines of benzothiophene and benzoselenophene.     

Positional Isomers of Biphenyl Antimicrobial Peptidomimetic Amphiphiles

Small-molecule antimicrobial peptidomimetic amphiphiles represent a promising class of novel antimicrobials with the potential for widespread therapeutic application. To investigate the role of spatial positioning for key hydrophobic and hydrophilic groups on the antimicrobial efficacy and selectivity, positional isomers of the lead biphenyl antimicrobial peptidomimetic compound 1 were synthesized and subjected to microbial growth inhibition and mammalian toxicity assays. Positional isomer 4 exhibited 4–8× increased efficacy against the pathogenic Gram-negative bacteria Pseudomonas aeruginosa and Escherichia coli (MIC = 2 μg/mL), while isomers 2, 3, and 7 exhibited a 4× increase in activity against Acinetobacter baumannii (MIC = 4 μg/mL). Changes in molecular shape had a significant impact on Gram-negative antibacterial efficacy and the resultant spectrum of activity, whereas all structural isomers exhibited significant efficacy (MIC = 0.25–8 μg/mL) against Gram-positive bacterial pathogens (e.g., methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecalis).     

Novel 2-Aryloxazoline Compounds Exhibit an Inhibitory Effect on Candida spp., Including Antifungal-Resistant Isolates

Because of the increased resistance to currently available antifungals, fungal infections represent a significant challenge to human health. Herein, we report the synthesis of 2-aryloxazoline derivatives from the reaction between l-threonine and derivatives of salicylic or naphthoic acid. In total, 26 compounds were obtained and tested against species of Candida, Cryptococcus, and Aspergillus. We found that all of the compounds inhibited the growth of Candida species at low concentrations (<0.25 μg/mL) and exhibited reduced hemolytic and cytotoxic activities. Additionally, compounds 4i and 9i were especially effective against antifungal-resistant isolates and the emerging fungus Candida auris. However, the compounds were less active on Cryptococcus and Aspergillus. Because of the improved in vitro antifungal efficacy and attenuated cytotoxicity, these two 2-aryloxazolines obtained from salicylic and naphthoic acid derivatives, respectively, may be considered lead molecules for the development of novel antifungal drugs.     

Dual-Stage Picolinic Acid-Derived Inhibitors of Toxoplasma gondii

Toxoplasma gondii causes a prevalent human infection for which only the acute stage has an FDA-approved therapy. To find inhibitors of both the acute stage parasites and the persistent cyst stage that causes a chronic infection, we repurposed a compound library containing known inhibitors of parasitic hexokinase, the first step in the glycolysis pathway, along with a larger collection of new structural derivatives. The focused screen of 22 compounds showed a 77% hit rate (>50% multistage inhibition) and revealed a series of aminobenzamide-linked picolinic acids with submicromolar potency against both T. gondii parasite forms. Picolinic acid 23, designed from an antiparasitic benzamidobenzoic acid class with challenging ADME properties, showed 60-fold-enhanced solubility, a moderate LogD_7.4, and a 30% improvement in microsomal stability. Furthermore, isotopically labeled glucose tracing revealed that picolinic acid 23 does not function by hexokinase inhibition. Thus, we report a new probe scaffold to interrogate dual-stage inhibition of T. gondii.     

HPLC methods for choloroquine determination in biological samples and pharmaceutical products

ObjectiveReview and assess pharmaceutical and clinical characteristics of chloroquine including high-performance liquid chromatography (HPLC)-based methods used to quantify the drug in pharmaceutical products and biological samples.Evidence acquisitionA literature review was undertaken on the PubMed, Science Direct, and Scielo databases using the following keywords related to the investigated subject: ‘chloroquine’, ‘analytical methods’, and ‘HPLC’.ResultsFor more than seven decades, chloroquine has been used to treat malaria and some autoimmune diseases, such as lupus erythematosus and rheumatoid arthritis. There is growing interest in chloroquine as a therapeutic alternative in the treatment of HIV, Q fever, Whipple’s disease, fungal, Zika, Chikungunya infections, Sjogren’s syndrome, porphyria, chronic ulcerative stomatitis, polymorphic light eruption, and different types of cancer. HPLC coupled to UV detectors is the most employed method to quantify chloroquine in pharmaceutical products and biological samples. The main chromatographic conditions used to identify and quantify chloroquine from tablets and injections, degradation products, and metabolites are presented and discussed.ConclusionResearch findings reported in this article may facilitate the repositioning, quality control, and biological monitoring of chloroquine in modern pharmaceutical dosage forms and treatments.Graphical abstract      

Semisynthesis and Biological Evaluation of Platencin Thioether Derivatives: Dual FabF and FabH Inhibitors against MRSA

The discovery and clinical use of multitarget monotherapeutic antibiotics is regarded as a promising approach to reduce the development of antibiotic resistance. Platencin (PTN), a potent natural antibiotic initially isolated from a soil actinomycete, targets both FabH and FabF, the initiation and elongation condensing enzymes for bacterial fatty acid biosynthesis. However, its further clinical development has been hampered by poor pharmacokinetics. Herein we report the semisynthesis and biological evaluation of platencin derivatives 1–15 with potent antibacterial activity against methicillin-resistant Staphylococcus aureus in vitro. Some of these PTN analogues showed similar yet distinct interactions with FabH and FabF, as shown by molecular docking, differential scanning fluorometry, and isothermal titration calorimetry. Compounds 3, 8, 10, and 14 were further evaluated in a mouse peritonitis model, among which 8 showed in vivo antibacterial activity comparable to that of PTN. Our results suggest that semisynthetic modification of PTN is a rapid route to obtain active PTN derivatives that might be further developed as promising antibiotics against drug-resistant major pathogens.     

Dioxane-Linked Amide Derivatives as Novel Bacterial Topoisomerase Inhibitors against Gram-Positive Staphylococcus aureus

In recent years, novel bacterial topoisomerase inhibitors (NBTIs) have been developed as future antibacterials for treating multidrug-resistant bacterial infections. A series of dioxane-linked NBTIs with an amide moiety has been synthesized and evaluated. Compound 3 inhibits DNA gyrase, induces the formation of single strand breaks to bacterial DNA, and achieves potent antibacterial activity against a variety of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Optimization of this series of analogues led to the discovery of a subseries of compounds (22–25) with more potent anti-MRSA activity, dual inhibition of DNA gyrase and topoisomerase IV, and the ability to induce double strand breaks through inhibition of S. aureus DNA gyrase.     

Identification of Piperidine-3-carboxamide Derivatives Inducing Senescence-like Phenotype with Antimelanoma Activities

This study evaluated the potential use of senescence-inducing small molecules in the treatment of melanoma. We screened commercially available small-molecule libraries with high-throughput screening and high-content screening image-based technology. Our findings showed an initial hit with the embedded N-arylpiperidine-3-carboxamide scaffold-induced senescence-like phenotypic changes in human melanoma A375 cells without serious cytotoxicity against normal cells. A focused library containing diversely modified analogues were constructed and examined to evaluate the structure–activity relationship of N-arylpiperidine-3-carboxamide derivatives starting from hit 1. This work identified a novel compound with remarkable antiproliferative activity in vitro and demonstrated the key structural moieties within.     

Design,Synthesis, and Antiplasmodial Activity of Hybrid Compounds Based on (2R,3S)-N-Benzoyl-3-phenylisoserine

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Discovery and Characterization of ML398, a Potent and Selective Antagonist of the D4 Receptor with in Vivo Activity

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In vitro antiplasmodial and antimicrobial potential of Tagetes erecta roots

Context: Among strategies to combat malaria, the search for newer antimalarial compounds is a priority. Traditionally, Tagetes erecta Linn. (Compositae) has been used for the treatment of various diseases and ailments including malaria.

Objective: Five successive extracts (petroleum ether, chloroform, ethyl acetate, methanol and aqueous) of the roots of T. erecta and a new bithienyl compound, 2-hydroxymethyl-non-3-ynoic acid 2-[2,2']-bithiophenyl-5-ethyl ester from the roots of the plant, were evaluated for in vitro antiplasmodial activity against chloroquine sensitive and resistant strains of Plasmodium falciparum. The extracts were also tested for in vitro antimicrobial activity against seven microbial strains.

Materials and methods: The antiplasmodial screening was carried out using the schizont maturation inhibition assay. Preliminary antimicrobial screening was carried out using the agar well assay followed by determination of minimum inhibitory concentration (MIC) using two-fold serial dilutions.

Results: Among all the extracts tested, the ethyl acetate fraction exhibited significant antiplasmodial efficacy with the 50% inhibitory concentrations (IC₅₀) of 0.02 and 0.07?mg/mL against the chloroquine sensitive and resistant strains of Plasmodium falciparum respectively. The new bithienyl compound also showed significant schizonticidal activity against both chloroquine sensitive and resistant strains of Plasmodium falciparum with the IC₅₀ values of 0.01 and 0.02?mg/mL. Additionally, all extracts exhibited significant antimicrobial activity against three Gram-positive and two Gram-negative bacterial and two fungal strains with MIC values ranging between 12.5-100 µg/mL.

Discussion: The new bithienyl compound was profoundly able to arrest the ring stages of the malarial parasites thereby exerting its antiplasmodial effect.

Conclusion: The observations provide support for the ethnobotanical use of the plant.     

Thiophene-Pyrazolourea Derivatives as Potent,Orally Bioavailable,and Isoform-Selective JNK3 Inhibitors

Potent JNK3 isoform selective inhibitors were developed from a thiophenyl-pyrazolourea scaffold. Through structure activity relationship (SAR) studies utilizing enzymatic and cell-based assays, and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies, potent and highly selective JNK3 inhibitors with oral bioavailability and brain penetrant capability were developed. Inhibitor 17 was a potent and isoform selective JNK3 inhibitor (IC₅₀ = 35 nM), had significant inhibition to only JNK3 in a panel profiling of 374 wild-type kinases, had high potency in functional cell-based assays, had high stability in human liver microsome (t_1/2 = 66 min) and a clean CYP-450 inhibition profile, and was orally bioavailable and brain penetrant. Moreover, cocrystal structures of compounds 17 and 27 in human JNK3 were solved at 1.84 Å, which showed that these JNK3 isoform selective inhibitors bound to the ATP pocket, had interactions in both hydrophobic pocket-I and hydrophobic pocket-II.