Explore the vast range of titles available.

Background: 8-Hydroxyquinoline and phthalimide are two significant heterocyclic scaffolds in medicinal chemistry due to their pharmacological profiles. Hybridizing these pharmacophores and further modifying them via modified Mannich reactions provides a strategy to improve their physicochemical parameters and selectivity toward multidrug-resistant (MDR) cancer cells. Objectives: To synthesize a series of 8-hydroxyquinoline–phthalimide hybrids and their Mannich base derivatives and evaluate their cytotoxic activity and resistance-selective properties against sensitive Colo205 and resistant Colo320 cancer cell lines. Methods: Four hybrid compounds were synthesized by reacting 5-amino-8-hydroxyquinoline with different phthalic anhydride derivatives. Twelve fine-tuned derivatives were prepared by using the modified Mannich reaction. Cytotoxic activity was measured using the MTT assay, and relative resistance (RR) was calculated to determine selectivity toward the resistant cell line. P-glycoprotein (Pgp) ATPase activity was evaluated for the most active compounds. Results: All derivatives displayed cytotoxic activity, with higher potency toward the resistant Colo320 cell line. Compounds 2 and 4 showed the strongest activity against both cell lines (IC50 down to 4.88 µM). Compounds 5, 8a, 9a, and 9c retained potent activity against Colo320 (IC50 = 9.89–22.79 µM). Incorporating a CH2–N group at position C7 substantially enhanced the selectivity for MDR cells. Compounds 9c, 9a, and 8a exhibited the highest selectivity, with RR values of 0.29, 0.33, and 0.35, respectively. Compounds 2, 4, 5, 8a, and 9a showed inhibitory effects on Pgp ATPase activity. Conclusions: The newly synthesized HQ–phthalimide hybrids represent promising candidates for targeting MDR in colorectal cancer, with Mannich modification enhancing the selectivity toward resistant cells.

Background/Objectives: Urinary tract infections (UTIs) represent a major healthcare challenge due to antimicrobial resistance and biofilm formation. Our aim was to evaluate whether repurposed drugs and efflux pump inhibitors (EPIs) could provide alternative strategies by investigating their antibacterial, anti-biofilm, and resistance-modifying properties against Gram-negative uropathogens under varying pH conditions. Methods: Clinical isolates of Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis were tested. Minimum inhibitory concentrations (MICs) of thioridazine (TZ), promethazine (PMZ), fluoxetine (Fx), sertraline (Sr), phenylalanine arginine β-naphthylamide (PAβN), carbonyl cyanide m-chlorophenyl hydrazone (CCCP), and the glutamine uptake inhibitor V9302 were determined at pH 5–8. Biofilm inhibition was assessed by crystal violet staining, while MIC reduction assays tested antibiotic combinations. Efflux pump inhibition was examined using an ethidium bromide accumulation assay. Results: TZ reduced biofilm formation in sensitive K. pneumoniae at all pH levels and enhanced ciprofloxacin (CIP) activity, whereas PMZ showed a weaker effect, limited mainly to neutral pH. Fx and Sr exhibited pH-dependent anti-biofilm activity, with Fx particularly effective against P. mirabilis at alkaline pH. PAβN consistently decreased biofilm biomass in both sensitive and resistant K. pneumoniae and, at pH 7–8, potentiated CIP activity with a 16-fold MIC reduction in the sensitive strain. CCCP showed pH-dependent activity, with stronger effects under acidic conditions, notably in E. coli and P. mirabilis. V9302 was a potent biofilm inhibitor in K. pneumoniae and resistant E. coli and interfered with efflux activity, showing strong effects in acidic environments. Conclusions: Repurposed drugs and EPIs may be useful as antibiotic adjuvants or biofilm inhibitors in treating resistant UTIs.

Long-term treatment of cancer with chemotherapeutics leads to the development of resistant forms that reduce treatment options. The main associated mechanism is the overexpression of transport proteins, particularly P-glycoprotein (P-gp, ABCB1). In this study, we have tested the anticancer and multidrug resistance (MDR) modulation activity of 15 selenocompounds. Out of the tested compounds, K3 , K4 , and K7 achieved the highest sensitization rate in ovarian carcinoma cells (HOC/ADR) that are resistant to the action of the Adriamycin. These compounds induced oxidation stress, inhibited P-gp transport activity and altered ABC gene expression. To verify the effect of compounds, 3D cell models were used to better mimic in vivo conditions. K4 and K7 triggered the most significant ROS release. All selected selenoesters inhibited P-gp efflux in a dose-dependent manner while simultaneously altering the expression of the ABC genes, especially P-gp in paclitaxel-resistant breast carcinoma cells (MCF-7/PAX). K4 , and K7 demonstrated sensitization potential in resistant ovarian spheroids. Additionally, all selected selenoesters achieved a high cytotoxic effect in 3D breast and ovarian models, which was comparable to that in 2D cultures. K7 was the only non-competitive P-gp inhibitor, and therefore appears to have considerable potential for the treatment of drug-resistant cancer.

Multidrug resistance (MDR) is a major obstacle in the therapy of infectious diseases and cancer. One of the major mechanisms of MDR is the overexpression of efflux pumps (EPs) that are responsible for extruding antimicrobial and anticancer agents. EPs have additional roles of detoxification that may aid the development of bacterial infection and the progression of cancer. Therefore, targeting EPs may be an attractive strategy to treat bacterial infections and cancer. The development and discovery of a new drug require a long timeline and may come with high development costs. A potential alternative to reduce the time and costs of drug development is to repurpose already existing drugs. Antidepressants and antipsychotic agents are widely used in clinical practice in the treatment of psychiatric disorders and some somatic diseases. Antidepressants and antipsychotics have demonstrated various beneficial activities that may be utilized in the treatment of infections and cancer. This review aims to provide a brief overview of antibacterial and anticancer effects of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs) and phenothiazine antipsychotics, while focusing on EPs. However, it should be noted that the antimicrobial activity of a traditionally non-antibiotic drug may have clinical implications regarding dysbiosis and bacterial MDR.

Background/Objectives: Antimicrobial resistance (AMR) is an escalating global threat driven by antibiotic misuse and bacterial adaptation. Efflux pumps are major contributors to multidrug resistance in Escherichia coli, as they expel antibiotics and reduce their intracellular activity. This study examined efflux-mediated resistance in extended-spectrum beta-lactamase (ESBL)-producing E. coli and evaluated the potential of several efflux pump inhibitors (EPIs)—promethazine (PMZ), thioridazine (TZ), carbonyl cyanide m-chlorophenyl hydrazine (CCCP), reserpine (RES), and phenyl-arginine-β-naphthylamide (PAβN)—as therapeutic adjuncts. Methods: Antibacterial and anti-biofilm activities of EPIs were tested using broth microdilution, real-time fluorimetry, and crystal violet assays, while ceftriaxone–PMZ interactions were assessed by checkerboard analysis. Results: TZ and CCCP showed strain-specific antibacterial activity, whereas PMZ, RES, and PAβN did not exert any effect. PMZ, TZ, and especially CCCP effectively inhibited efflux pump function, while RES and PAβN were less active. Biofilm inhibition varied between strains, with PMZ and TZ producing moderate reductions. We observed a quite weak synergism between ciprofloxacin, ceftriaxone, and PMZ; however, the result was not significant. Conclusions: Overall, the results highlight the central role of efflux pumps in ESBL-producing E. coli and indicate that EPIs can reverse resistance (e.g., PMZ) and exhibit potent anti-biofilm activity and show additive interactions with antibiotics. However, further studies are needed to optimize their safety, pharmacokinetics, and antibiotic pairing for potential clinical use.

Grossheimin, a guaiane-type sesquiterpene lactone, displayed a diverse range of biological activities, including anticancer, anti-inflammatory and antimicrobial effects. Various amino analogues of grossheimin were prepared through a Michael addition at its highly active α-methylene-γ-lactone motif. On the other hand, grossheimin was reduced to diol, which was then subjected to nucleophilic addition or acetylation to introduce heteroatoms associated with oxygen, sulfur or nitrogen functionalities. All of the synthesised Michael and acetylated adducts were evaluated for their in vitro cytotoxic action on human colon adenocarcinoma lines, including Colo205 and Colo320. The bioassay results indicated that the acetylated adducts displayed a potent cytotoxic effect compared to grossheimin, the parent molecule. A docking study was also performed to exploit the observed results.

Multidrug resistance (MDR) has appeared in response to selective pressures resulting from the incorrect use of antibiotics and other antimicrobials. This inappropriate application and mismanagement of antibiotics have led to serious problems in the therapy of infectious diseases. Bacteria can develop resistance by various mechanisms and one of the most important factors resulting in MDR is efflux pump-mediated resistance. Because of the importance of the efflux-related multidrug resistance the development of new therapeutic approaches aiming to inhibit bacterial efflux pumps is a promising way to combat bacteria having over-expressed MDR efflux systems. The definition of an efflux pump inhibitor (EPI) includes the ability to render the bacterium increasingly more sensitive to a given antibiotic or even reverse the multidrug resistant phenotype. In the recent years numerous EPIs have been developed, although so far their clinical application has not yet been achieved due to their in vivo toxicity and side effects. In this review, we aim to give a short overview of efflux mediated resistance in bacteria, EPI compounds of plant and synthetic origin, and the possible methods to investigate and screen EPI compounds in bacterial systems.

Malignant diseases present a serious public health burden and their treatment with traditional chemotherapy cannot be considered an all-round solution, due to toxic side effects. Selenium compounds (Se-compounds) have received substantial attention in medicinal chemistry, especially in experimental chemotherapy, both as cytotoxic agents and adjuvants in chemotherapy. A checkerboard microplate method was applied to study the drug interactions of Se-compounds and clinically relevant chemotherapeutic drugs against the multidrug-resistant (MDR) subtype of mouse t-lymphoma cells overexpressing the ABCB1 transporter. Se-compounds showed synergistic interactions with chemotherapeutic agents targeting the topoisomerase enzymes or the microtubule apparatus. The ketone-containing selenoesters showed synergism at lower concentrations (1.25 µM). Most of the tested compounds interacted antagonistically with alkylating agents and verapamil. A thiophene-containing Se-compound showed synergism with all tested drugs, except cisplatin. While the exact mechanism of drug interactions is yet unknown, the potency of the selenocompounds as efflux pump inhibitors or the potentiation of their efficacy as reactive oxygen species modulators may play a role in their complementary activity against the tested MDR lymphoma cell line.

Multidrug (MDR) resistances against various classes of antibiotics used in and MRSA infections have emerged. With limited options for novel antibacterial compounds, there is a strong focus on finding agents against MDR phenomenon, namely causative efflux pumps. We synthesised novel benzo-annelated 1,4-dihydropyridines with various substitution patterns both at the 4- and -alkyl substituents and, additionally, at the annelated aromatic residues. MDR efflux pump-inhibiting activity was evaluated in strains including MRSA and was measured in a fluorescent assay system using ethidium bromide as the overall substrate of efflux pumps. Favourable substituents for inhibiting efflux pump activity in have been 4-methoxy and 4- and 3-chloro at the 4-phenyl position of the 1,4-dihydropyridine ring combined with an -benzyl residue. The most favourable substituents for the activity inMRSA strains have been those 4-phenyl chloro substituents combined with additional pyrido residues attached to the benzo substituent at the 1,4-dihydropyridine core. Benzo-annelated 1,4-dihydropyridines are a novel class of inhibitors of MDR relevant efflux pumps in strains including MRSA.

Anaerobic bacteria have pivotal roles in the microbiota of humans and they are significant infectious agents involved in many pathological processes, both in immunocompetent and immunocompromised individuals. Their isolation, cultivation and correct identification differs significantly from the workup of aerobic species, although the use of new technologies (e.g., matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, whole genome sequencing) changed anaerobic diagnostics dramatically. In the past, antimicrobial susceptibility of these microorganisms showed predictable patterns and empirical therapy could be safely administered but recently a steady and clear increase in the resistance for several important drugs (β-lactams, clindamycin) has been observed worldwide. For this reason, antimicrobial susceptibility testing of anaerobic isolates for surveillance purposes or otherwise is of paramount importance but the availability of these testing methods is usually limited. In this present review, our aim was to give an overview of the methods currently available for the identification (using phenotypic characteristics, biochemical testing, gas-liquid chromatography, MALDI-TOF MS and WGS) and antimicrobial susceptibility testing (agar dilution, broth microdilution, disk diffusion, gradient tests, automated systems, phenotypic and molecular resistance detection techniques) of anaerobes, when should these methods be used and what are the recent developments in resistance patterns of anaerobic bacteria.