A series of substituted pyrrolo[2,3-d]pyrimidines was designed, synthesized, and evaluated in vitro against two protozoan parasites: Plasmodium falciparum and Trypanosoma brucei brucei. Pharmacological studies revealed antiprotozoal activity with IC50 values in the submicromolar to micromolar range. Additionally, the in vitro cytotoxicity of these new compounds was assessed using human HepG2 cells. Among them, the pyrrolopyrimidine derivative 1d emerged as the most potent antimalarial compound, exhibiting a selectivity index (SI) of 600.81 against the P. falciparum chloroquine-resistant W2 strain. For the chloroquine-sensitive 3D7 strain, the most notable selectivity index (SI) was observed for pyrrolo[2,3-d]pyrimidine 1c, with a value of approximately 123. Furthermore, compound 1b demonstrated the most interesting activity against Trypanosoma brucei brucei, with an SI of 39.52, marking it as a promising trypanocidal agent. FRET melting assays confirmed that these nitrogen-containing heterocyclic compounds bind to telomeric G-quadruplexes in P. falciparum and Trypanosoma. However, no clear correlation was found between G-quadruplex binding and antiparasitic activity or selectivity, suggesting that G-quadruplex targeting is unlikely to be the main mechanism underlying cytotoxicity.

In this work, we demonstrate for the first time the antimicrobial activity of poly-Q binding peptide 1 (QBP1), an anti-amyloidogenic molecule previously identified by phage display for its ability to bind and inhibit the aggregation of polyglutamine proteins like Huntingtin, but also α-synuclein and prion models. Intriguingly, sequence analysis by the ADAPTABLE web server highlighted QBP1's potential antifungal and antibacterial activity, which we have now confirmed experimentally. A theoretical basis for the predicted mechanism of action was provided by molecular dynamics simulations revealing the role of QBP1 aggregates promoting membrane disruption and specific interactions between QBP1 and bacterial and fungal phospholipids, further substantiated by solid-state NMR studies. Using primary human cells, we demonstrated that QBP1 does not display toxicity at high concentrations. Finally, our data demonstrate QBP1's efficacy against some strains of Bacillus cereus, B. mojavensis, Staphylococcus aureus, S. epidermidis, Micrococcus luteus, Enterococcus faecalis, Escherichia coli, and Candida. This unexpected dual function of QBP1 opens new avenues for therapeutic development, potentially restoring the putative antimicrobial protection exerted by many amyloidogenic proteins.

Background: Based on our previously reported series of novel 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene and 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivatives, we have now designed, synthesized, and tested a new series of novel restricted and simplified structural analogues of these compounds against Plasmodium falciparum in vitro; i.e., the 1,3-bis[(4-(substituted-aminomethyl)phenyl)methyl]benzene and 1,3-bis[(4-(substituted-aminomethyl)phenoxy)methyl]benzene compounds. Methods & Results: The pharmacological results revealed significant antimalarial activity, with IC50 values in the submicromolar to micromolar range. Additionally, the in vitro cytotoxicity of these new nitrogen-containing polyphenyl- or -phenoxymethylbenzene compounds was evaluated on human HepG2 cells. The compound 1f, the 1,3-bis[(4-(3-(morpholin-1-yl)propyl)aminomethyl)phenoxy)methyl]benzene derivative, emerged as one of the most potent and promising antimalarial candidates, demonstrating a cytotoxicity/antiprotozoal activity ratio of 594 against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. Additionally, the 1,3-bis[((substituted aminomethyl)phenyl)methyl]benzene compound 1j and the 1,3-bis[((substituted aminomethyl)phenoxy)methyl]benzenes 2p and 2q also showed strong antimalarial potential, with selectivity indexes (SI) of over 303, 280, and 217, respectively, against the 3D7 strain, which has mefloquine-reduced sensitivity. Furthermore, the 1,3-bis[(4-(pyridin-2-ylethylaminomethyl)phenyl)methyl]benzene 2k was identified as the most noteworthy antimalarial compound, exhibiting a selectivity index (SI) that was superior to 178 against the chloroquine-resistant Plasmodium falciparum W2 strain. It has previously been suggested that the telomeres of P. falciparum may serve as potential targets for these polyaromatic compounds; thus, we assessed the ability of our novel derivatives to stabilize parasitic telomeric G-quadruplexes using a FRET melting assay. Conclusions: However, regarding the stabilization of the protozoan G-quadruplex, it was noted that the few substituted derivatives, which showed interesting stabilization profiles, were not necessarily the most effective antimalarial compounds against both Plasmodium strains. Moreover, these new compounds did not show promising stabilizing effects on the different G4 sequences. Therefore, no correlation arises between their antimalarial activity and the selectivity of their binding to G-quadruplexes.

Pseudomonas aeruginosa is one of world’s most threatening bacteria. In addition to the emerging prevalence of multi-drug resistant (MDR) strains, the bacterium also possesses a wide variety of virulence traits that worsen the course of the infections. Particularly, its ability to form biofilms that protect colonies from antimicrobial agents is a major cause of chronic and hard-to-treat infections in immune-compromised patients. This protective barrier also ensures cell growth on abiotic surfaces and thus enables bacterial survival on medical devices. Hence, as the WHO alerted to the need to develop new treatments, the use of anti-biofilm agents (ABAs) appeared as a promising approach. Given the selection pressure imposed by conventional antibiotics, a new therapeutic strategy has emerged that aims at reducing bacterial virulence without inhibiting cell growth. So-called anti-virulence agents (AVAs) would then restore the efficacy of conventional antibiotics (ATBs) or potentiate the effectiveness of the immune system. The last decade has seen the development of ABAs as AVAs against P. aeruginosa. This review aims to highlight the design strategy and critical features of these molecules to pave the way for further discoveries of highly potent compounds.

Worldwide, several million people are infected with mycobacteria such as Mycobacterium tuberculosis (M. tb) or non-tuberculous mycobacteria (NTM). In 2023, 10.8 million cases and 1.25 million deaths due to M. tb were recorded. In Europe and North America, the emergence of NTM is tending to outstrip that of M. tb. Among pulmonary NTM, Mycobacterium avium complex (MAC) is the most common, accounting for 80% of NTM infections. First-line treatment requires the combination of at least three antibiotics over a long period and with different mechanisms of action to limit cross-resistance. The challenge is to discover more effective new anti-MAC molecules to reduce the duration of treatment and to overcome resistant strains. The aim of this review is to present an overview of the challenges posed by MAC infection such as side effects, reinfections and resistance mechanisms. The latest therapeutic options such as the optimized combination therapy, drug repurposing and the development of new formulations, as well as new anti-MAC compounds currently in (pre)clinical trials will also be discussed.

By taking into account our previously described series of 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene compounds, we have now designed, prepared, and evaluated in vitro against Plasmodium falciparum a novel series of structural analogues of these molecules, i.e., the 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivatives. The pharmacological data showed antimalarial activity with IC50 values in the sub and μM range. The in vitro cytotoxicity of these new nitrogen polyphenoxymethylbenzene compounds was also evaluated on human HepG2 cells. The 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivative 1m was found as one of the most potent and promising antimalarial candidates with favorable cytotoxic to antiprotozoal properties in the P. falciparum strains W2 and 3D7. In conclusion, this 1,3,5-tris[(4-(pyridin-3-ylmethylaminomethyl)phenoxyl)methyl]benzene 1m (IC50 = 0.07 μM on W2, 0.06 μM on 3D7, and 62.11 μM on HepG2) was identified as the most promising antimalarial derivative with selectivity indexes (SI) of 887.29 on the W2 P. falciparum chloroquine-resistant strain, and of 1035.17 on the chloroquine-sensitive and mefloquine decreased sensitivity strain 3D7. It has been previously described that the telomeres of P. falciparum could represent potential targets for these types of polyaromatic compounds; therefore, the capacity of our novel derivatives to stabilize the parasitic telomeric G-quadruplexes was assessed using a FRET melting assay. However, with regard to the stabilization of the protozoal G-quadruplex, we observed that the best substituted derivatives 1, which exhibited some interesting stabilization profiles, were not the most active antimalarial compounds against the two Plasmodium strains. Thus, there were no correlations between their antimalarial activities and selectivities of their respective binding to G-quadruplexes.

Currently, artemisinin-based combination therapy is recommended as first-line treatment of uncomplicated falciparum malaria. Arylamino alcohols (AAAs) such as mefloquine (MQ) are the preferred partner drugs due to their longer half-life, reliable absorption and strong antimalarial activity. However, the mode of action of MQ remains poorly understood and its neurotoxicity limits its use. Furthermore, the emergence of drug-resistant parasites requires development of new antimalarial drugs. The aim of this study was to evaluate the β-hematin inhibition capacity of three pairs of enantiopure AAAs 1–3 (a/S and b/R) derived from MQ or enpiroline (ENP), a pyridine-based MQ analog with strong antimalarial activity. Inhibition of β-hematin—the synthetic counterpart of hemozoin formation—was determined for each compound. Antimalarial activity against W2 and 3D7 Plasmodium falciparum strains as well as percentages of inhibition of β-hematin formation were compared to those of reference molecules, i.e., chloroquine (CQ), MQ and ENP. Furthermore, a cytotoxicity study on the human-derived hepatocarcinoma cell line HepG2 was performed. With high antimalarial activity, stronger ability to inhibit β-hematin formation and low cytotoxicity, AAAs 1a-b and 2a are the most promising. These findings provide a better understanding of their potential mechanisms of action and may pave the way toward developing new lead compounds.

Polygalacturonases (PGs) can modulate chemistry and mechanical properties of the plant cell wall through the degradation of pectins, one of its major constituents. PGs are largely used in food, beverage, textile, and paper industries to increase processes ' performances. To improve the use of PGs, knowledge of their biochemical, structural and functional features is of prime importance. Our study aims at characterizing SmoPG1, a polygalacturonase from Selaginella moellendorffii, that belongs to the lycophytes. Transcription data showed that SmoPG1 was mainly expressed in S. moellendorffii shoots while phylogenetic analyses suggested that SmoPG1 is an exo -PG, which was confirmed by the biochemical characterization following its expression in heterologous system. Indeed, LC-MS/MS oligoprofiling using various pectic substrates identified galacturonic acid (GalA) as the main hydrolysis product. We found that SmoPG1 was most active on polygalacturonic acid (PGA) at pH 5, and that its activity could be modulated by different cations (Ca 2+ , Cu 2+ , Fe 2+ , Mg 2+ , Mn 2+ , Na 2+ , Zn 2+ ). In addition, SmoPG1 was inhibited by green tea catechins, including (-)-epigallocatechin-3-gallate (EGCG). Docking analyses and MD simulations showed in detail amino acids responsible for the SmoPG1-EGCG interaction. Considering its expression yield and activity, SmoPG1 appears as a prime candidate for the industrial production of GalA.

Herein, we report the design, synthesis, and characterisation of a new library of enantiopure aminoalcohol fluorenes, as well as their in vitro evaluation for biological properties, including activity against two strains of P. falciparum (3D7 and W2) and cytotoxicity on the HepG2 cell line. All tested compounds exhibited good to excellent antimalarial potency with IC50 values ranging from 0.7 to 70.2 nM whatever the strain. Interestingly, most compounds showed equal or better antimalarial activity compared to the reference drugs lumefantrine, mefloquine and chloroquine. Despite moderate cytotoxicity in the micromolar range, all aminoalcohol fluorenes displayed an excellent selectivity index higher than 100 due to strong antimalarial activity. Furthermore, we report in silico analyses of physicochemical and pharmacokinetic properties for all compounds, highlighting the drug-likeness of compound 10 and its promising potential for further studies.

Neglected tropical diseases (NTDs) pose a major threat in tropical zones for impoverished populations. Difficulty of access, adverse effects or low efficacy limit the use of current therapeutic options. Therefore, development of new drugs against NTDs is a necessity. Compounds containing an aminopyridine (AP) moiety are of great interest for the design of new anti-NTD drugs due to their intrinsic properties compared with their closest chemical structures. Currently, over 40 compounds with an AP moiety are on the market, but none is used against NTDs despite active research on APs. The aim of this review is to present the medicinal chemistry work carried out with these scaffolds, against protozoan NTDs: Trypanosoma cruzi, Trypanosoma brucei or Leishmania spp.

Antibiotic resistance is a critical public health issue. Among the multi-drug resistant microorganisms in question, Pseudomonas aeruginosa has been designated by the WHO as a priority threat. Its virulence is orchestrated through quorum sensing (QS). This sophisticated communication network relies on the release and perception of autoinducers acting as population density indicators. Therefore, the interest of a quorum silencing pharmacological approach has unfolded to quench bacterial pathogenicity without impairing growth. In this article, we reported the development of a family of indazole–quinolone hybrids as anti-virulence agents. These new biaromatic compounds were designed as potential specific QS quenchers against P. aeruginosa. Our transdisciplinary research methodology included their synthesis using palladocatalyzed cross-coupling reactions, as well as their in silico physicochemical and in vitro biological evaluation. The hit 7-chloro-2-indazolyl-4-quinolone Ie shows a promising anti-biofilm and anti-pyocyanin efficiency (35% inhibition at 25 µM and 35% inhibition at 100 µM, respectively) without an anti-pseudomonal bacteriostatic effect. It also demonstrated a moderate eukaryotic cytotoxicity. Its anti-QS properties have been investigated using metabolomic and molecular modelling studies.

The purpose of the current investigation is to evaluate the methanolic extract from Apium graveolens seeds for chemical composition and in vivo antimicrobial activity, supported by a histological study. The chemical profile of the methanolic extract was identified using high-performance liquid chromatography diode array detector analysis. The toxicity and antimicrobial effects of the methanolic extract were examined through in vivo experiments on rats weighing 220 ± 5 g. The histological study was conducted using the rats’ ileum. The methanolic extract (80%) contained sinapic acid (49.9%), ascorbic acid (25.4%), butylated hydroxyanisole acid (6.1%), and quercetin (8.2%), with a yield ratio of 11.74%. The dose of 50 mg/kg of the methanolic extract did not lead to animal lethality or toxicity symptoms. Two days after treatment, the blood cultures of all females treated with the methanolic extract at 50 mg/kg showed sterility (100%). The same result appeared on the fifth day after treatment in all males of the same group. Histopathological examination revealed normal and well-preserved architecture of the ileum in both sexes. The study concludes that the methanolic extract of Apium graveolens possesses significant antimicrobial capacity.

The treatment of Mycobacterium avium infections is still long, complex, and often poorly tolerated, besides emergence of resistances. New active molecules that are more effective and better tolerated are deeply needed. Mefloquine and its enantiomers ((+) Erythro-mefloquine ((+)-EMQ) and (-)-Erythro-mefloquine ((-)-EMQ)) have shown efficacy in both in vitro and in vivo, in a mouse model of M. avium intraveinous infection. However, no study reports aerosol model of infection or combination with gold standard treatment. That was the aim of our study. In an aerosol model of M. avium infection in BALB/c mice, we used five treatment groups as followed: Clarithromycin-Ethambutol-Rifampicin (CLR-EMB-RIF, standard of care, n = 15), CLR-EMB-MFQ (n = 15), CLR-EMB-(+)-EMQ (n = 15), CLR-EMB-(-)-EMQ (n = 15) and an untreated group (n = 25). To evaluate drug efficacy, we sacrificed each month over 3 months, 5 mice from each group. Lung homogenates were diluted and plated for colony forming unit count (CFU) expressed in Log10. At each time point, we found a significant difference between the untreated group and each of the treatment groups (p<0.005). The (+)-EMQ-CLR-EMB group was the group with the lowest CFU count at each time point but never reached statistical significance. The results of each group 3 months after treatment are: (+)-EMQ-CLR-EMB (4.43 ± 0.26), RIF-CLR-EMB (4.83 ± 0.37), (-)-EMQ-CLR-EMB (4.82 ± 0.18), MFQ-CLR-EMB (4.70 ± 0.21). In conclusion, MFQ and its enantiomers appear to be as effective as rifampicin in combination therapy. Further studies are needed to evaluate the ability of these drugs to prevent selection of clarithromycin resistant strains and potential for lung sterilization.

A series of new 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene compounds were designed, synthesized, and evaluated in vitro against two parasites (Plasmodium falciparum and Leishmania donovani). The biological results showed antimalarial activity with IC50 values in the sub and μM range. The in vitro cytotoxicity of these new aza polyaromatic derivatives was also evaluated on human HepG2 cells. The 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene 1m was found as one of the most potent and promising antimalarial candidates with a ratio of cytotoxic to antiprotozoal activities of 83.67 against the P. falciparum CQ-sensitive strain 3D7. In addition, derivative 1r was also identified as the most interesting antimalarial compound with a selectivity index (SI) of 17.28 on the W2 P. falciparum CQ-resistant strain. It was previously described that the telomeres of P. falciparum could be considered as potential targets of these kinds of aza heterocycles; thus, the ability of these new derivatives to stabilize the parasitic telomeric G-quadruplexes was measured through a FRET melting assay.

The objective of this study was to characterize the chemical composition of the essential oil of Curcuma longa L and its anti-oxidant, antimicrobial and physicochemical properties.The chemical composition of the hydrodistilled essential oils of Curcuma longa L was analysed by gas chromatography-mass spectrometry. Sixty five compounds representing 93 % of the total oil were identified; the major components were & alpha;-tumerone (28.02 %), 13-sesquiphellandrene(9,98%),Zingiberene(10,37),13-tumerone (9.85 %), ar-tumerone (2.61 %), and ar-curcumene (8.57 %), 13-curcumene (5.70 %).The antioxidant activities of the oil and various extracts of Curcuma longa L were evaluated by using 2,2-diphenyl-1-picrylhydrazyl and superoxide radical-scavenging assays in 100 g of Curcuma langa L powder The half-maximal inhibitory concentration of oil and methanol extract showed value (17.976 and 21.678 & mu;g/ml) respectively, ethanol extract (36.446 & mu;g/ml) showed moderate radical scavenging activity toward ascorbic acid (14.105 & mu;g/ml). The antimicrobial activity was carried using diffusion agar method against Staphylococcus aureus, Bacillus subtilis, Escherichia coli.The highest and broadest activity was shown on Staphylococcus aureus and Escherichia coli.

Currently artemisinin-based combination therapy is recommended as first-line treatment of uncomplicated falciparum malaria. Arylamino alcohols (AAAs) such as mefloquine (MQ) are the preferred partner drugs due to their longer half-life, reliable absorption and strong antimalarial activity. However, the mode of action of MQ remains poorly understood and its neurotoxicity limits its use. Furthermore, the emergence of drug-resistant parasites requires continuous research and development of new antimalarial drugs. In this context, the development of enantiopure AAAs derived from MQ, exhibiting strong activity against resistant strains, good pharmacokinetic profiles and with an identified mode of action seems particularly interesting. The aim of this study was to evaluate the β-hematin inhibition capacity of three pairs of enantiopure AAAs 1-3 (a/S and b/R) derived from MQ or enpiroline (ENP), a pyridine-based MQ analog with a strong antimalarial activity. Compounds 1-3 have a different aromatic core substituted by the same butyl chain: quinoline core for MQ-derived compounds 1a-b and pyridine core for ENP-derived compounds 2a-b and 3a-b. Inhibition of β-hematin (the synthetic counterpart of hemozoin) formation was determined for each compound at 2 mM. Antimalarial activity determined on W2 and 3D7 Plasmodium falciparum strains as well as percentages of inhibition of β-hematin formation were compared to that of reference molecules, i.e. chloroquine (CQ), MQ and ENP. Furthermore, a cytotoxicity study on the human-derived hepatocarcinoma cell line HepG2 was performed on the most active compounds to determine their selectivity index (SI). With high antimalarial activity, stronger ability to inhibit β-hematin formation and low cytotoxicity, AAAs 1a-b and 2a are the most promising. These findings provide a better understanding of potential mechanisms of action of these MQ and ENP analogs and may pave the way toward developing new lead compounds.

Antibacterial resistance is a healthcare burden. Among Gram-negative bacteria, Pseudomonas aeruginosa belongs to the first list of antibiotic-resistant "priority pathogens" described by the World Health Organization. Formerly Pseudomonas pseudomallei, Burkholderia pseudomallei, responsible for melioidosis, is considered as a potential bioterrorist weapon by the Centers of Diseases Control and Prevention. We are interested in the development of new ways to combat these bacteria, targeted due to their high level of resistance to antibiotics via a lack of membrane permeability or efflux. Using iron transport systems is a promising strategy to bypass the bacteria cell membrane and restore the activity of conventional antibiotics such as ciprofloxacin. Specific outer membrane receptors are necessary to most microbes as they allow iron uptake, essential for their survival through siderophore-dependent mechanisms. These systems may allow the introduction of antibacterial agents, chemically coupled to a natural or synthetic siderophore molecule to form siderophore-antibiotic conjugates. In this work, we describe the synthesis of six new siderophore analog-ciprofloxacin conjugates including cleavable linker or not. The siderophore analogs correspond to a mono-catechol or a hydroxypyridinone moiety recognized by both Pseudomonas and Burkholderia species. Physico-chemical studies showed that (i) conjugates were unable to interact or cross the membrane by passive diffusion and (ii) conjugates with cleavable linker are stable in physiologic environment. Biological evaluations have highlighted a promising compound 2d, bearing an hydroxypyridinone moiety with a cleavable linker, active on a large panel of strains of Pseudomonas aeruginosa, Burkholderia pseudomallei and Burkholderia thailandensis without toxicity observed in vitro.

Resistance to antimicrobial drugs is currently a serious threat to human health. Consequently, we are facing an urgent need for new antimicrobial drugs acting with original modes of action. The ubiquitous and widely conserved microbial fatty acid biosynthesis pathway, called FAS-II system, represents a potential target to tackle antimicrobial resistance. This pathway has been extensively studied, and eleven proteins have been described. FabI (or InhA, its homologue in mycobacteria) was considered as a prime target by many teams and is currently the only enzyme with commercial inhibitor drugs: triclosan and isoniazid. Furthermore, afabicin and CG400549, two promising compounds which also target FabI, are in clinical assays to treat Staphylococcus aureus. However, most of the other enzymes are still underexploited targets. This review, after presenting the FAS-II system and its enzymes in Escherichia coli, highlights the reported inhibitors of the system. Their biological activities, main interactions formed with their targets and structure–activity relationships are presented as far as possible.

A series of new 2,9-bis[(pyridinylalkylaminomethyl)phenyl]-1,10-phenanthroline compounds was considered, synthesized, and evaluated in vitro against three parasites (Plasmodium falciparum, Leishmania donovani and Trypanosoma brucei brucei).Pharmacological results showed antiparasitic activity with IC 50 values in the sub and µM range.The in vitro cytotoxicity of these novel aza derivatives was evaluated on human HepG2 cells.The phenanthroline 1f was noticed as the most potent antimalarial candidate with a ratio of cytotoxic to antiprotozoal activities of 912.4 against the P. falciparum CQ-resistant strain W2.In addition, the phenanthroline 1a was also identified as the most potent antiparasitic derivative with a selectivity index (SI) of 811.8 on P. falciparum CQ-sensitive strain 3D7.Against the promastigote forms of L. donovani, the same phenanthroline 1a was found the most active compounds with an IC 50 of 2.08 mM.In addition, the phenanthrolines 1f and 1i were also identified as the most promising trypanosomal candidates with selectivity index (SI) of 231.1 and 143.7, respectively on T. brucei brucei strain.As the telomeres of the parasites P. falciparum and Trypanosoma could be considered as possible targets of this kind of aza heterocyclic molecules, their ability to stabilize the parasitic telomeric G-quadruplexes have been measured through the FRET melting assay.