INTRODUCTION:The indole nucleus is considered a privileged pharmacophore in medicinal chemistry. Indole-2-carboxylic acid derivatives are valued for their antiproliferative and antibacterial properties, including the potential to overcome drug resistance. This study aimed to synthesize novel salicylidene hydrazones of indole-2-carboxylic acid and evaluate their potential as metallo-β-lactamase (NDM-1) inhibitors and antiproliferative agents alongside previously reported indole-2-carboxylic acid derivatives. METHODS:A novel series of salicylidene hydrazones of indole-2-carboxylic acid was synthesized with potential as metallo-β-lactamase inhibitors in mind. All compounds were evaluated for their inhibitory activity against NDM-1 and tested for antiproliferative potency against human chronic myelogenous leukemia K-562 cells and the multidrug-resistant (MDR) subline K- 562/4. Doxorubicin and previously reported indole derivatives (1, 5, 6) were used as reference compounds. RESULTS:Unlike the parent acid 1, the novel derivatives showed weak NDM-1 inhibition (IC50 > 50 μM). In contrast, salicylidene hydrazones 4a-g demonstrated strong antiproliferative activity (IC50 = 0.15-0.80 μM). This effect was particularly pronounced against the MDR subline K- 562/4. Notably, the IC50 values for several derivatives were up to 50-fold lower than that of doxorubicin against resistant cells. Hydrazide 3, hydrazones 4h and 4i, thiosemicarbazide 5, and hydroxamic acids 6a-c showed moderate antiproliferative activity (IC50 = 2.4-13.3 μM). DISCUSSION:The weak NDM-1 inhibition confirms that a free 2-carboxyl group is critical for binding within the enzyme's active site. However, converting this scaffold into salicylidene hydrazones significantly enhances antiproliferative potency. It also effectively enables the circumvention of P-glycoprotein (P-gp) mediated efflux in MDR leukemia cells. CONCLUSION:Indole-2-carboxylic acid salicylidene hydrazones emerged as promising scaffolds for developing new anticancer agents. They exhibit potent activity against leukemia cells, particularly against the P-gp-overexpressing MDR subline K-562/4.

Abstract Echinocandins are the preferred agents for treating invasive candidiasis; however, rising resistance in Candida species poses a significant challenge for patient care. This study aimed to improve the efficacy of echinocandins against clinical Candida isolates by enhancing their noncanonical membrane activity. The mechanisms of action of anidulafungin, caspofungin, and micafungin on lipid membranes were investigated using a range of biophysical methods and molecular dynamics approaches. Antifungal activity was assessed using a panel of clinical Candida isolates. The results indicated that echinocandins exhibit greater selectivity for ergosterol-containing membranes than for cholesterol-enriched membranes. Echinocandins caused differential phase disordering, leading to a significant increase in the size of sterol-rich ordered domains, induced membrane stress/perturbation, and promoted the formation of ion-permeable transmembrane pores. The membrane activity of echinocandins was enhanced upon incorporation into liposomes. Echinocandin liposomes exhibited reduced MICs against clinical Candida isolates (down to 0.002 µg/mL) compared with conventional echinocandins. This reduction in MIC was observed regardless of the strain’s susceptibility to standard echinocandins. Enhancing the membrane activity of echinocandins through their incorporation into liposomal formulations represents a promising strategy to improve antifungal efficacy and address the increasing resistance observed in clinical Candida isolates.

The rapid spread of metallo-β-lactamase (MBL)-mediated resistance, particularly by NDM- and VIM-type enzymes, poses a major threat to the clinical efficacy of β-lactam antibiotics. Building on our previous work, we report the design, synthesis, and evaluation of 4-substituted 3,5-diarylpyrrole-2-carboxylic acids as MBL inhibitors. Structure-activity relationship studies revealed that both the nature and position of substituents in the A and B rings, as well as functionalization at the C4 position, critically influence inhibitory activity. Notably, C4 halogenation, especially bromination, significantly enhanced inhibition of VIM-2 while maintaining activity against NDM-1. Molecular modelling supported these findings, indicating distinct binding modes and coordination patterns within the enzyme active sites. The most active compounds displayed nanomolar potency and effectively restored the activity of β-lactam antibiotics, including meropenem, against NDM- and VIM-producing resistant strains. Importantly, the compounds exhibited no detectable cytotoxicity and lacked intrinsic antibacterial activity. These results identify C4-functionalized pyrrole-2-carboxylic acids as promising dual-target MBL inhibitors for combination antibacterial therapy.

Microbial secondary metabolites continue to be used as scaffolds for the development of medications for treatment of infectious and oncological diseases. Among them, aromatic polyketides occupy a prominent place due to their structural originality and broad biological activities. Heliomycin (also known as resistomycin), an antibiotic with pentacyclic benzo[cd]pyrenequinone core, produced by Streptomyces species, represents a structurally unique member of this class. Although historically heliomycin applied as a topical antibacterial or antiviral agent, it has attracted renewed interest owing to its versatile biological profile, including, antibacterial, antifungal, and particularly anticancer activities. This review provides a comprehensive and systematic analysis of heliomycin and its analogues, covering microbial production, biosynthetic pathways, structural elucidation, total synthesis and chemical modifications. Special attention is focused on semisynthetic derivatives of heliomycin aimed for improved solubility, stability, and pharmacological properties. The biological section summarizes current knowledge on molecular targets and mechanisms of action, including interactions with DNA, topoisomerases, epigenetic regulators (HDACs, SIRT1), tumor-associated enzymes (tNOX), oxidative stress pathways, and key signaling cascades. In vivo antitumor studies and emerging structure-activity relationships are also critically discussed. Taken together the available evidence positions heliomycin not as a single-target antibiotic, but as a pleiotropic bioactive scaffold with significant potential for further drug development.

An access to new sulfonamide-containing 3-phenyl-quinoxaline 1,4-dioxides has been accomplished via the Beirut reaction of benzofuroxans with N-(tert-butyl)-2-oxo-2-phenylethane-1-sulfonamide. The reaction of 5-amino-benzofuroxan derivatives afforded 7-amino-2-sulfamoyl-quinoxaline 1,4-dioxides, whereas nucleophilic substitution of the chlorine atom in 6,7-dichloro-2-sulfamoylquinoxaline 1,4-dioxide gave the corresponding 6-amino-substituted analogs.

Quinazolinone derivatives are well-known anticancer agents; anticancer properties are also part of the broad spectrum of biological activity of coumarins. Conjugates containing quinazolin-4(3H)-one and coumarin fragments linked by polymethylene bridges of varying lengths were designed to improve properties of both parental compounds and create new anticancer or antibacterial agents. 3-{3-[(4-Methyl-2-oxo-2H-chromen-7-yl)oxy]propyl}quinazolin-4(3H)-one was synthesized as the base compound. It demonstrated moderate cytotoxicity against leukemia (K562 and HL60) and neuroblastoma (SH-SY5Y) cells in vitro, combined with relatively low acute, subacute, and chronic toxicity in vivo. Conjugates with various substituents and linkers were then synthesized to evaluate the structure-activity relationship. A study of the synthesized compounds on cell cultures showed that the introduction of a methyl substituent into the benzene ring of the coumarin fragment led to both an increase in cytotoxicity and expansion of its spectrum of action. Testing of the hybrids against Gram-positive and Gram-negative bacteria revealed that the introduction of halogens into the quinazoline fragment in the compounds or the elongation of the linker led to the emergence of pronounced antibacterial properties, which were most clearly manifested against Acinetobacter baumanii. The possibility of directing activity of quinazoline-4(3H)-one-coumarin hybrids by varying the substituents and the length of the linker was shown.

The clinical utility of anthracyclines is limited by severe cardiotoxicity and multidrug resistance (MDR) necessitates the development of improved analogues and new chemotherapeutics. In this work a series of 2-substituted 4,11-diaminoanthra[2,3-b]furan-5,10-diones (anthrafurans) was synthesized via Pd-catalyzed cross-coupling/heterocyclization followed by the amination reaction. Several derivatives demonstrated low submicromolar cytotoxicity against five tumor cell lines comparable to doxorubicin and reduced cytotoxicity toward non-cancerous cells. Structure-activity relationship analysis demonstrated that hydrophobic 2-substituents (phenyl, trimethylsilyl) and N-methylated aminoalkyl side chains at the 4,11-positions enhanced potency and effectively circumvented Pgp- and p53-mediated MDR, while hydrophilic groups (hydroxymethyl, aminomethyl) decreased activity. Mechanistic studies showed that the 2-phenyl derivative 2b acts as a DNA-intercalating dual topoisomerase I and II inhibitor, causing DNA damage and apoptosis in leukemia cells, whereas the 2-aminomethyl analog 2j displayed weaker cellular activity due to poor intracellular accumulation despite similar in vitro DNA and topoisomerase interactions. None of the tested compounds generated significant reactive oxygen species, suggesting low oxidative stress and potentially reduced cardiotoxicity. Overall, the 4,11-diaminoanthra[2,3-b]furan-5,10-dione scaffold represents a promising and tunable platform for next-generation anthraquinone-based anticancer agents, offering potent antiproliferative activity, improved safety profile, and the ability to overcome MDR mechanisms.

The rapid increase in antimicrobial resistance underscores the urgent need for new antibacterial agents. One promising strategy involves designing novel compounds through targeted chemical modifications of existing antibiotics. Azithromycin (AZI), a widely used macrolide, has served as a versatile scaffold for developing numerous antibacterial candidates. However, the mechanistic consequences of such modifications remain largely unexplored. Here, we characterize the activity and mechanism of action of three AZI-benzoxaborole (AZI-BB) conjugates. We show that these compounds inhibit bacterial translation in vitro and remain active against a model Escherichia coli strain carrying an inducible ermCL-ermC operon, which confers resistance to macrolide antibiotics. Unlike erythromycin, these derivatives, along with AZI itself, exhibit minimal induction of ErmC expression. Structural analysis reveals that the benzoxaborole moiety of AZI-BB2 forms additional interactions with nucleotides C2441 and C2586 of 23S rRNA, likely contributing to premature ribosome stalling at the ermCL regulatory sequence and thereby preventing ErmC expression. Furthermore, high-throughput toeprinting analysis combined with deep sequencing (Toe-seq) demonstrates that AZI-BB2 exhibits reduced sequence specificity for canonical macrolide-sensitive stalling motifs. Altogether, these findings demonstrate that targeted chemical modification of AZI can reshape its context-specific interaction with the ribosome and attenuate the induction of macrolide resistance mechanisms.

G-quadruplexes (G4s) are non-canonical nucleic acid structures involved in transcription, genome stability, and telomere maintenance, and represent attractive targets for anticancer therapy. Anthraquinone derivatives are privileged G4 ligands owing to their rigid planar π-conjugated cores, which promote end-stacking interactions with G-tetrads and confer selectivity over duplex DNA. In this study, we synthesized a series of indole-, thiazole-, quinoline-, and quinoxaline-fused anthraquinones bearing three terminal cationic side chains to investigate structure-activity relationships. FRET-melting and fluorescence assays showed that the heterocyclic core critically determines G4 stabilization and selectivity. Thiazole-fused derivatives exhibited the strongest stabilization of telomeric and c-Myc promoter G-quadruplexes while showing minimal interaction with duplex DNA and imperfect G4 structures, whereas the other scaffolds were less effective. These compounds also displayed the highest antiproliferative activity against K562 leukemia and HCT116 colon carcinoma cells with favorable selectivity toward cancer cells. Molecular modelling revealed preferential binding of the thiazole ligands to G-quadruplex DNA over duplex DNA, and confocal fluorescence microscopy confirmed efficient cellular uptake and nuclear accumulation. Moreover, compounds 7b and 9b significantly downregulated c-Myc expression, supporting G4-mediated modulation of oncogene transcription as a contributor to their antiproliferative activity.

Anthraquinone-based intercalating compounds, such as doxorubicin and mitoxantrone, have long been used clinically due to their ability to induce DNA damage. More recently, heteroarene-fused anthraquinones have been developed to further enhance their anticancer activity. Among these compounds, 4,11-bis(2-(2-chloroacetamidine)ethylamino)anthra[2,3-b]thiophene-5,10-dione dihydrochloride (designated as derivative a) was identified as a potent apoptotic inducer. Based on this scaffold, two additional derivatives were synthesized by replacing the sulfur atom within the heterocyclic ring with nitrogen (derivative b) or oxygen (derivative c). Building upon our previous identification of ENOX2 as the primary target of this scaffold, the present study investigated the anti-proliferative effects and underlying mechanisms of these derivatives in colon cancer cells with varying p53 statuses. Derivatives a and b effectively induced apoptosis and suppressed proliferation in p53 wild-type HCT116 cells, which was concomitantly accompanied by significant ENOX2 downregulation and the activation of intrinsic apoptotic signaling. In contrast, p53-null HCT116 cells exhibited reduced sensitivity, attenuated apoptotic responses, and minimal ENOX2 downregulation. Notably, derivative c primarily induced G2/M arrest rather than apoptosis regardless of p53 status, indicating a predominantly cytostatic mechanism. Collectively, these findings suggest that the degree of ENOX2 modulation is linked to the distinct anti-proliferative responses induced by heteroarene-fused anthraquinones, and that p53 status serves as a critical molecular switch influencing the transition between cytostatic growth arrest and apoptotic cell death.

The rise of multidrug-resistant Gram-positive pathogens and the persistence of biofilm-associated infections present major challenges for current antimicrobial therapies. In response, we developed a novel series of eremomycin derivatives by introducing ω-guanidine-containing alkyl substituents at the C-terminal carboxyl group. N-(2-Guanidinoethyl)amide of eremomycin (12a) exhibited superior in vitro activity against both vancomycin-sensitive and -resistant strains, including VRE and MRSE, and showed enhanced potency compared to vancomycin, telavancin, and previously reported eremomycin analogs without hemolytic or cytotoxic effects. The compound retained its bactericidal activity in biofilms and, unlike vancomycin, did not stimulate biofilm formation at subinhibitory concentrations. Physicochemical characterization was performed by 2D NMR and high-resolution mass spectrometry, verifying the integrity and proposed chemical structures of the new derivatives. In vivo evaluation in a murine sepsis model demonstrated that compound 12a had an ED50 value 14 times lower than that of vancomycin, highlighting its strong therapeutic potential. These findings suggest that guanidine-functionalized eremomycin amides represent a promising new class of glycopeptide antibiotics capable of addressing both resistance and biofilm-related challenges.

Gramicidin S (GS) is a potent cyclic decapeptide antibiotic produced by Bacillus brevis, exhibiting strong activity against Gram-positive bacteria and remaining in clinical use for the topical treatment of skin and throat infections. Despite its efficacy, GS's clinical application is restricted due to significant hemolytic toxicity associated with its membranolytic mechanism of action. This review summarizes over 80 years of structure-activity relationship (SAR) studies on GS and its analogues, highlighting key strategies to enhance antibacterial activity while reducing cytotoxicity. Particular focus is given to the influence of amino acid substitutions, stereochemistry, sequence modifications, and the incorporation of peptidomimetic fragments. Additionally, we discuss GS-based oligo- and polymers, as well as analogues with expanded or contracted macrocycles, emphasizing their effects on biological activity and conformational stability. Collectively, these insights underscore the value of GS as a resilient scaffold for next-generation antimicrobial peptide design with improved therapeutic indices and potency towards resistant pathogens.

Background . Neurotoxicity is a side effect of anthracycline antibiotics that has been identified during clinical use. while this type of toxicity may not be limiting, it can significantly affect the quality of life for patients. In the Gause Institute of New Antibiotics an antitumor compound called anthrafuran has developed, that is similar in structure to anthracyclines. This compound has shown high activity in experiments using mouse models of transplanted tumors when administered orally. Anthrafuran has the ability to penetrate the blood-brain barrier, so a study of its neurotoxicity was previously conducted at the maximum tolerated dose. Aim . To experimentally evaluate the neurotoxicity of anthrafuran when it is administered orally at both a therapeutic dose and three times the therapeutic dose. Materials and methods . Female Albino rats were used in the experiment. The animals were kept under conditions accordance to GOST 33044–2014 “Principles of good laboratory practice”. Anthrafuran substance was administered orally as a 1,2 % solution in 5 % glucose for injection at doses of 20 and 60 mg/kg once. Motor and research activity of the animals was evaluated in an Open Field test setting 4 hours, one day, and one month after administration. To detect cognitive dysfunction, rats were trained in a T-maze with food reward 3–5 days after drug administration. Results . Administration of the drug at a therapeutic dose of 20 mg/kg did not cause any abnormal behavior in animals in the Open Field or affect the ability to learn in the T-maze. However, at a dose three times higher than the therapeutic dose (60 mg/kg), anthrafuran decreased the research activity of rats in the Open Field 4 and 24 hours after administration and inhibited the ability to acquire learning in T-maze. Conclusion . The use of anthrafuran in a therapeutic dose did not cause pronounced neurotoxic reactions. In order to further promote the drug, it is necessary to conduct an in-depth study on the effect of the substance and dosage forms on the behavioral responses and cognitive abilities of rats.

Fascaplysins form a group of marine natural products with unique cationic five-ring coplanar backbone. Native fascaplysin exhibits a broad spectrum of bioactivities, among which the cytotoxic activity has been the most investigated. Several fascaplysin derivatives have more selective biological effects and are promising as lead compounds. Thus, the introduction of a substituent at C-9 of fascaplysin leads to a strong increase in its antimicrobial properties. Here, a comparative assessment of the antimicrobial activity of synthetic analogs of the marine alkaloids 3-bromofascaplysin, 10-bromofascaplysin, and 3,10-dibromofascaplysin, along with some of their isomers and analogs, was carried out against a panel of Gram-positive bacteria in vitro. For the first time, a significant increase in the antimicrobial activity of fascaplysin was observed when a substituent was introduced at C-3. The introduction of two bromine atoms at C-2 and C-9 enhances the antimicrobial properties by 4 to 16 times, depending on the tested strain. Evaluation of the antimicrobial potential in vivo showed that fascaplysin and 3,10-dibromofascaplysin had comparable efficacy in the mouse staphylococcal sepsis model. Additionally, 3,10-dibromofascaplysin demonstrated a strong and reliable antitumor effect in vivo on the Ehrlich carcinoma inoculated subcutaneously, with a value of tumor growth inhibition by 49.2% 20 days after treatment. However, further studies on alternative chemical modifications of fascaplysin are needed to improve its chemotherapeutic properties.

Gossypol has been shown to be a promising natural product for the anticancer drug development for treating leukemia, lymphoma, colon carcinoma, breast cancer, and other malignant disease. It is known that the conversion of aldehyde groups of gossypol into iminofragments by the treatment of various amines can reduce the toxicity of the derivative and simultaneously increase their pharmacological efficacy. This article describes the preparation and screening of antiproliferative properties of a conjugate of gossypol with antitumor antibiotic doxorubicin. It has been shown that the reaction of the amino group of doxorubicin with the aldehyde groups of gossypol gives the condensation product in which two pharmacophores are linked via enamine– enamine moieties. However, this conjugation decreased the antiproliferative activity of paternal doxorubicin and gossypol against chronic myeloid leukemia cells K562 and led to dramatic loss of potency against MDRsubline K-562/4 with expression of Р-glycoprotein (Р-gp).

Here, we show that the aureolic acid-class antibiotic, olivomycin A, exerts potent anticancer activity in renal cell carcinoma (RCC) by disrupting both cell survival and metastatic programs. In A-498 (wild-type p53) and 786-O (loss-of-function in p53 and PTEN) cells, olivomycin A markedly inhibited migratory capacity and reversed epithelial–mesenchymal transition (EMT), as shown by downregulation of nuclear Snail and the mesenchymal marker N-cadherin, restoration of the epithelial markers, E-cadherin and ZO-1. In parallel, olivomycin A induced apoptosis through distinct p53-dependent mechanisms: In A-498 cells, apoptosis was primarily mediated via the intrinsic pathway, characterized by upregulation of Puma, and Bak, activated caspase-9. In 786-O cells, in contrast, both intrinsic and extrinsic cascades were engaged, as evidenced by caspase-8 activation, Bid truncation, and concurrent mitochondrial involvement. Notably, in p53-mutant 786-O cells, treatment with olivomycin A elicited severe genotoxic stress accompanied by robust DNA damage signaling, excessive reactive oxygen species (ROS) accumulation, and lysosomal activation, culminating in extensive mitochondrial clearance through mitophagy. Such changes were weaker in p53-wild-type A-498 cells, suggesting that the altered p53 context sensitizes RCC cells to olivomycin A-mediated mitochondrial quality control mechanisms. Collectively, our findings delineate a multifaceted mechanism whereby olivomycin A coordinates EMT suppression, apoptotic induction, and mitophagy. Thus, olivomycin A has potential as a therapeutic candidate that can target both survival and metastatic pathways in heterogeneous genetic backgrounds.

The increasing threat of antimicrobial resistance (AMR) has driven the need for novel antibacterial agents. Conjugating antibiotics with siderophores may expand their spectrum of activity or enhance their efficacy against AMR strains. In this study, we developed a synthetic route for azithromycin derivatives bound with siderophore moieties containing one or two 2,3-dihydroxybenzamide residues, yielding two series of hybrid molecules (5a-b, 6a-b, 7a-b, and 8a-b, 9a-b, 10a-b). Derivatives 5a, 6a-b, and 7a-b, which bear a single siderophore fragment, exhibited MIC values comparable to those of azithromycin against the majority of tested pathogens. Notably, compounds 7a-b demonstrated increased activity under iron-deficient conditions against Gram-negative Pseudomonas aeruginosa and Escherichia coli strains. In contrast, azotochelin-containing conjugates (9a-b and 10a-b) were found to be completely inactive. Although the introduction of a siderophore did not significantly enhance the potency of macrolides in this study, further optimization of the conjugation strategy, linker structure, or chelating moieties may lead to more effective siderophore-macrolide antibiotics.

Antimicrobial resistance mediated by metallo-β-lactamases (MBLs) represents a critical challenge for the efficacy of β-lactam antibiotics. Here, we report the design, synthesis, and evaluation of a novel class of 3,5-diaryl-1H-pyrrole-2-carboxylic acids as potent New Delhi metallo-β-lactamase (NDM)-type MBL inhibitors. Guided by molecular modeling and structure-activity relationship studies, the pyrrole scaffold was optimized through systematic modifications of the phenyl rings at position 3 and 5 of pyrrole core, yielding derivatives with low-nanomolar IC50 values against NDM-1. Key interactions involve coordination of the pyrrole carboxyl groups with Zn2+ ions and hydrogen bonding with active-site residues, supporting enhanced binding and inhibitory potency. Lead compounds restored the activity of cefepime and meropenem against NDM-positive E. coli and K. pneumoniae strains, while triple combinations with serine β-lactamase inhibitors further enhanced antimicrobial efficacy. These results highlight 1H-pyrrole-2-carboxylic acids as a versatile scaffold for MBL inhibition and provide a rational framework for the development of therapeutics against multidrug-resistant pathogens.

Natural products remain to be an important source for the development of antibacterial agents. In this study, we isolated and evaluated the key biological properties of minor components of the gramicidin S (GS) antibiotic complex produced by Bacillus brevis var. G-B R+. Using HPLC techniques, we obtained highly pure samples of GS and its five major related components in individual form. Structures of isolated compounds were assigned as GS homologues, featuring several amino acid residue substitutions, two of which are previously undescribed. Antibacterial activity of new cyclic decapeptides was close to GS, while two of five isolated compounds demonstrated up to 4 times reduced haemolysis. Circular dichroism spectra of GS homologues and the parental antibiotic exhibited the same β-structure conformation. Taken together, this study demonstrates that analysis of minor components of antibiotic complexes could result in the discovery of new antibacterial compounds with better efficacy or favourable therapeutic profile.