Search Results (22)

Efflux is one of the key mechanisms used by Gram-negative bacteria to reduce internal antibiotic concentrations. These active transport systems recognize and expel a wide range of toxic molecules, including antibiotics, thereby contributing to reduced antibiotic susceptibility and allowing the bacteria to acquire additional resistance mechanisms. To date, unlike other resistance mechanisms such as enzymatic modification or target mutations/masking, efflux is challenging to detect and counteract in clinical settings, and no standardized methods are currently available to diagnose or inhibit this mechanism effectively. This review first outlines the structural and functional features of major efflux pumps in Gram-negative bacteria and their role in antibiotic resistance. It then explores various strategies used to curb their activity, with a particular focus on efflux pump inhibitors under development, detailing their structural classes, modes of action, and pharmacological potential. We discuss the main obstacles to their development, including the structural complexity and substrate promiscuity of efflux mechanisms, the limitations of current screening methods, pharmacokinetic and tissue distribution issues, and the risk of off-target toxicity. Overcoming these multifactorial barriers is essential to the rational development of less efflux-prone antibiotics or of efflux pump inhibitors. Full article

Malaria remains a major global health problem that has been exacerbated by the impact of the COVID-19 pandemic on health systems. To combat this, the World Health Organization (WHO) has set a target of driving forward research into innovative treatment methods such as new drugs and vaccines. Quinones, particularly 1,4-naphthoquinones, have been identified as promising candidates for the development of antiprotozoal drugs. Herein, we report several methods for the preparation of 2-benzyl-1,4-naphthoquinones. In particular, the silver-catalyzed Kochi–Anderson radical decarboxylation is well suited for the preparation of these compounds. The antiprotozoal activity of all synthesized compounds was evaluated against Plasmodium falciparum NF54 and Trypanosoma brucei rhodesiense STIB900. Cytotoxicity towards L6 cells was also determined, and the respective selectivity indices (SI) were calculated. The synthesized compounds exhibited good antiplasmodial activity against the P. falciparum (NF54) strain, particularly (2-fluoro-5-trifluoromethylbenzyl)-menadione 2e, which showed strong efficacy and high selectivity (IC₅₀ = 0.006 µM, SI = 7495). In addition, these compounds also displayed favorable physicochemical properties, suggesting that the benzylnaphthoquinone scaffold may be a viable option for new antiplasmodial drugs. Full article

Background/Objectives: Leishmaniasis is one of the 20 Neglected Tropical Diseases according to the WHO, affecting approximately 12 million people in four continents, generating serious public health problems. The lack of therapeutic options, associated with toxicity and the emergence of resistance to the few available drugs, makes it urgent to develop new drug options. In this context, the aims of this work are to expand the knowledge about the pharmacophore group responsible for the antileishmanial potential of 2-aminothiophene derivatives. Thus, new compounds were synthesized containing chemical modifications at the C-3, C-4, and C-5 positions of the 2-aminothiophene ring, in addition to the S-Se bioisosterism. Methods: Dozens of 2-AT and 2-aminoselenophen (2-AS) derivatives were sequentially synthesized through applications of the Gewald reaction and were then evaluated in vitro for their activities against L. amazonensis and for cytotoxicity against macrophages. Results: Several series of compounds were synthesized, and it was possible to identify some substitution patterns favorable to the activity generating compounds with IC₅₀ values below 10 µM, such as the non-essentiality of the presence of a carbonitrile group at C-3; the importance of the presence and size of cycloalkyl/piperidinyl chains at C-4 and C-5 in modulating the activity; and the increase in activity without affecting the safety of the S/Se bioisosteric substitution. Conclusions: Taken together, these findings reaffirm the great potential of 2-aminothiophenes to generate antileishmanial drug candidates and offers contributions to the drug design of compounds with an even more promising profile for the problem of leishmaniasis. Full article

Leishmaniasis, a protozoan disease affecting humans, exposes significant shortcomings in current treatments. In continuation to our previous findings on amidoxime-based antileishmanial compounds bearing a 4,5-dihydrofuran scaffold, twelve new amidoxime derivatives substituted at position 3 with an amide bearing a nitrogen heterocycle were synthesized. This series was designed to replace the sulfone and aryl group on a previously reported HIT. The synthesis of these compounds involved the following three-step pathway: manganese (III) acetate-based cyclization of a β-ketoester, followed by amidation with LiHMDS and a final reaction with hydroxylamine. Three of them, containing either bromine, chlorine, or methyl substitutions and featuring a pyridine moiety, showed an interesting toxicity–activity relationship in vitro. They exhibited IC₅₀ values of 15.0 µM, 16.0 µM, and 17.0 µM against the promastigote form of the parasite and IC₅₀ values of 0.5 µM, 0.6 µM, and 0.3 µM against the intracellular amastigote form, respectively. A selectivity index (SI) greater than 300 was established between the cytotoxic concentrations (in murine macrophages) and the effective concentrations (against the intracellular form of Leishmania amazonensis). This SI is at least seventy times higher than that observed for Pentamidine and twenty-five times higher than that observed for the reference HIT, as previously reported. Full article

This review collects the synthetic modifications performed on andrographolide, a natural molecule derived from Andrographis paniculata, for oncology applications. Various pharmacomodulations were carried out, and the products were tested on different cancer cell lines. The impact of these modifications was analyzed with the aim of mapping the positions essential for activity to facilitate future research in this field. However, this study makes it clear that, in addition to structural modifications of the molecule, which can result in varying degrees of effectiveness in targeting interactions, the lipophilic capacity of the structures obtained through hemisynthesis is of significant importance. Full article

Here we have chosen to highlight the main natural molecules extracted from Camellia sinensis, Andrographis paniculata, and Curcuma longa that may possess antioxidant activities of interest for skin protection. The molecules involved in the antioxidant process are, respectively, catechins derivatives, in particular, EGCG, andrographolide, and its derivatives, as well as various curcuminoids. These plants are generally used as beverages for Camellia sinensis (tea tree), as dietary supplements, or as spices. The molecules they contain are known for their diverse therapeutic activities, including anti-inflammatory, antimicrobial, anti-cancer, antidiabetic, and dermatological treatment. Their common antioxidant activities and therapeutic applications are widely documented, but their use in cosmetics is more recent. We will see that the use of pharmacomodulated derivatives, the addition of co-antioxidants, and the use of various formulations enable better skin penetration and greater ingredient stability. In this review, we will endeavor to compile the cosmetic uses of these natural molecules of interest and the various structural modulations reported with the aim of improving their bioavailability as well as establishing their different mechanisms of action. Full article

Malaria is an infectious disease caused by a Plasmodium genus parasite that remains the most widespread parasitosis. The spread of Plasmodium clones that are increasingly resistant to antimalarial molecules is a serious public health problem for underdeveloped countries. Therefore, the search for new therapeutic approaches is necessary. For example, one strategy could consist of studying the redox process involved in the development of the parasite. Regarding potential drug candidates, ellagic acid is widely studied due to its antioxidant and parasite-inhibiting properties. However, its low oral bioavailability remains a concern and has led to pharmacomodulation and the synthesis of new polyphenolic compounds to improve antimalarial activity. This work aimed at investigating the modulatory effect of ellagic acid and its analogues on the redox activity of neutrophils and myeloperoxidase involved in malaria. Overall, the compounds show an inhibitory effect on free radicals as well as on the enzyme horseradish peroxidase- and myeloperoxidase (HRP/MPO)-catalyzed oxidation of substrates (L-012 and Amplex Red). Similar results are obtained with reactive oxygen species (ROS) produced by phorbol 12-mystate acetate (PMA)-activated neutrophils. The efficiency of ellagic acid analogues will be discussed in terms of structure–activity relationships. Full article

In the context of a continuously increasing global cancer risk, the search for new effective and affordable anticancer drugs remains a constant demand. This study describes chemical experimental drugs able to destroy cancer cells by arresting their growth. New hydrazones with quinoline, pyridine, benzothiazole and imidazole moieties have been synthesized and evaluated for their cytotoxic potential against 60 cancer cell lines. 7-Chloroquinolinehydrazones were the most active in the current study and exhibited good cytotoxic activity with submicromolar GI₅₀ values on a large panel of cell lines from nine tumor types (leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer). This study provided consistent structure-activity relationships in this series of experimental antitumor compounds. Full article

Pharmacomodulation of membrane channels is an essential topic in the study of physiological conditions and disease status. Transient receptor potential (TRP) channels are one such family of nonselective cation channels that have an important influence. In mammals, TRP channels consist of seven subfamilies with a total of twenty-eight members. Evidence shows that TRP channels mediate cation transduction in neuronal signaling, but the full implication and potential therapeutic applications of this are not entirely clear. In this review, we aim to highlight several TRP channels which have been shown to mediate pain sensation, neuropsychiatric disorders, and epilepsy. Recent findings suggest that TRPM (melastatin), TRPV (vanilloid), and TRPC (canonical) are of particular relevance to these phenomena. The research reviewed in this paper validates these TRP channels as potential targets of future clinical treatment and offers patients hope for more effective care. Full article

This study tested the hypothesis that intrarenal arterial transfusion of oxidized low-density lipoprotein (ox-LDL) jeopardized the residual renal function and kidney architecture in rat chronic kidney disease ((CKD), i.e., induced by 5/6 nephrectomy) that was reversed by rosuvastatin. Cell culture was categorized into A1 (NRK-52E cells), A2 (NRK-52E + TGF-β), A3 (NRK-52E + TGF-β + ox-LDL) and A4 (NRK-52E + TGF-β + ox-LD). The result of in vitro study showed that cell viability (at 24, 48 and 72 h), NRK-52E ox-LDL-uptake, protein expressions of epithelial–mesenchymal–transition (EMT) markers (i.e., p-Smad2/snail/α-SMA/FSP1) and cell migratory and wound healing capacities were significantly progressively increased from A1 to A4 (all p < 0.001). SD rats were categorized into group 1 (sham-operated control), group 2 (CKD), group 3 (CKD + ox-LDL/0.2 mg/rat at day 14 after CKD induction) and group 4 (CKD + ox-LDL-treated as group 3+ rosuvastatin/10 mg/kg/day by days 20 to 42 after CKD induction) and kidneys were harvested at day 42. The circulatory levels of BUN and creatinine, ratio of urine-protein to urine-creatinine and the protein expressions of the above-mentioned EMT, apoptotic (cleaved-caspase3/cleaved-PARP/mitochondrial-Bax) and oxidative-stress (NOX-1/NOX-2/oxidized-protein) markers were lowest in group 1, highest in group 3 and significantly higher in group 4 than in group 2 (all p < 0.0001). Histopathological findings demonstrated that the kidney injury score, fibrotic area and kidney injury molecule-1 (KIM-1) displayed an identical pattern, whereas the cellular expression of podocyte components (ZO-1/synaptopodin) exhibited an opposite pattern of EMT markers (all p < 0.0001). In conclusion, ox-LDL damaged the residual renal function and kidney ultrastructure in CKD mainly through augmenting oxidative stress, EMT and fibrosis that was remarkably reversed by rosuvastatin. Full article

Medicinal plants are known as sources of potential antimicrobial compounds belonging to different classes. The aim of the present work was to evaluate the antimicrobial potential of the crude extract, fractions, and some isolated secondary metabolites from the leaves of Macaranga occidentalis, a Cameroonian medicinal plant traditionally used for the treatment of microbial infections. Repeated column chromatography of the ethyl acetate and n-butanol fractions led to the isolation of seventeen previously known compounds (1−17), among which three steroids (1−3), one triterpene (4), four flavonoids (5−8), two stilbenoids (9 and 10) four ellagic acid derivatives (11−14), one geraniinic acid derivative (15), one coumarine (16), and one glyceride (17). Their structures were elucidated mainly by means of extensive spectroscopic and spectrometric (1D and 2D NMR and, MS) analysis and comparison with the published data. The crude extract, fractions, and isolated compounds were all screened for their antimicrobial activity. None of the natural compounds was active against Candida strains. However, the crude extract, fractions, and compounds showed varying levels of antibacterial properties against at least one of the tested bacterial strains, with minimal inhibitory concentrations (MICs) ranging from 250 to 1000 μg/mL. The n-butanol (n-BuOH) fraction was the most active against Escherichia coli ATCC 25922, with an MIC value of 250 μg/mL. Among the isolated compounds, schweinfurthin B (10) exhibited the best activity against Staphylococcus aureus NR 46003 with a MIC value of 62.5 μg/mL. In addition, schweinfurthin O (9) and isomacarangin (6) also exhibited moderate activity against the same strain with a MIC value of 125 μg/mL. Therefore, pharmacomodulation was performed on compound 6 and three new semisynthetic derivatives (6a–c) were prepared by allylation and acetylation reactions and screened for their in vitro antimicrobial activity. None of the semisynthetic derivatives showed antimicrobial activity against the same tested strains. The chemophenetic significance of the isolated compounds is also discussed in this paper. Full article

Chlamydia trachomatis causes the most common sexually transmitted bacterial infection and trachoma, an eye infection. Untreated infections can lead to sequelae, such as infertility and ectopic pregnancy in women and blindness. We previously enhanced the antichlamydial activity of the fluoroquinolone ciprofloxacin by grafting a metal chelating moiety onto it. In the present study, we pursued this pharmacomodulation and obtained nanomolar active molecules (EC₅₀) against this pathogen. This gain in activity prompted us to evaluate the antibacterial activity of this family of molecules against other pathogenic bacteria, such as Neisseria gonorrhoeae and bacteria from the ESKAPE group. The results show that the novel molecules have selectively improved activity against C. trachomatis and demonstrate how the antichlamydial effect of fluoroquinolones can be enhanced. Full article

Insulin-degrading enzyme (IDE) is a multifunctional protease due to the variety of its substrates, its various cellular locations, its conservation between species and its many non-proteolytic functions. Numerous studies have successfully demonstrated its implication in two main therapeutic areas: metabolic and neuronal diseases. In recent years, several reports have underlined the overexpression of this enzyme in different cancers. Still, the exact role of IDE in the physiopathology of cancer remains to be elucidated. Known as the main enzyme responsible for the degradation of insulin, an essential growth factor for healthy cells and cancer cells, IDE has also been shown to behave like a chaperone and interact with the proteasome. The pharmacological modulation of IDE (siRNA, chemical compounds, etc.) has demonstrated interesting results in cancer models. All these results point towards IDE as a potential target in cancer. In this review, we will discuss evidence of links between IDE and cancer development or resistance, IDE’s functions, catalytic or non-catalytic, in the context of cell proliferation, cancer development and the impact of the pharmacomodulation of IDE via cancer therapeutics. Full article

Flavonoids are polyphenols with broad known pharmacological properties. A series of 2,3-dihydroflavanone derivatives were thus synthesized and investigated for their anti-inflammatory activities. The target flavanones were prepared through cyclization of 2′-hydroxychalcone derivatives, the later obtained by Claisen–Schmidt condensation. Since nitric oxide (NO) represents an important inflammatory mediator, the effects of various flavanones on the NO production in the LPS-induced RAW 264.7 macrophage were assessed in vitro using the Griess test. The most active compounds were flavanone (4G), 2′-carboxy-5,7-dimethoxy-flavanone (4F), 4′-bromo-5,7-dimethoxy-flavanone (4D), and 2′-carboxyflavanone (4J), with IC50 values of 0.603, 0.906, 1.030, and 1.830 µg/mL, respectively. In comparison, pinocembrin achieved an IC₅₀ value of 203.60 µg/mL. Thus, the derivatives synthesized in this work had a higher NO inhibition capacity compared to pinocembrin, demonstrating the importance of pharmacomodulation to improve the biological potential of natural molecules. SARs suggested that the use of a carboxyl-group in the meta-position of the B-ring increases biological activity, whereas compounds carrying halogen substituents in the para-position were less active. The addition of methoxy-groups in the meta-position of the A-ring somewhat decreased the activity. This study successfully identified new bioactive flavanones as promising candidates for the development of new anti-inflammatory agents. Full article

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystemic disorder responsible for significant disability. Although a unifying etiology for ME/CFS is uncertain, impaired natural killer (NK) cell cytotoxicity represents a consistent and measurable feature of this disorder. Research utilizing patient-derived NK cells has implicated dysregulated calcium (Ca²⁺) signaling, dysfunction of the phosphatidylinositol-4,5-bisphosphate (PIP₂)-dependent cation channel, transient receptor potential melastatin (TRPM) 3, as well as altered surface expression patterns of TRPM3 and TRPM2 in the pathophysiology of ME/CFS. TRPM7 is a related channel that is modulated by PIP₂ and participates in Ca²⁺ signaling. Though TRPM7 is expressed on NK cells, the role of TRPM7 with IL-2 and intracellular signaling mechanisms in the NK cells of ME/CFS patients is unknown. This study examined the effect of IL-2 stimulation and TRPM7 pharmacomodulation on NK cell cytotoxicity using flow cytometric assays as well as co-localization of TRPM7 with PIP₂ and cortical actin using confocal microscopy in 17 ME/CFS patients and 17 age- and sex-matched healthy controls. The outcomes of this investigation are preliminary and indicate that crosstalk between IL-2 and TRMP7 exists. A larger sample size to confirm these findings and characterization of TRPM7 in ME/CFS using other experimental modalities are warranted. Full article