Chronic myeloid leukemia (CML) is driven by the BCR-ABL1 fusion oncoprotein and is managed with tyrosine kinase inhibitors (TKIs). However, resistance and persistence of leukemic stem/progenitor cells remain major clinical challenges. Autophagy-mediated survival signaling contributes to therapeutic resistance in CML. We hypothesized that histone deacetylase 6 (HDAC6), a key regulator of protein homeostasis and autophagic flux, is a therapeutic target in this context. Transcriptomic analysis of CML bone marrow datasets revealed enrichment of HDAC6-associated autophagy and stress-response gene programs. The selective HDAC6 inhibitor 7b induced sustained α-tubulin acetylation at lower concentrations than ricolinostat or nexturastat A. 7b reduced primary CML PBMC viability while sparing healthy PBMCs and was active in vivo. Combining 7b with the allosteric BCR-ABL1 inhibitor asciminib synergistically suppressed cell viability and clonogenic growth. A tandem mCherry-GFP-LC3 reporter showed that 7b blocks autophagosome maturation, thereby decreasing autophagic degradation. Cotreatment engaged a maladaptive integrated stress response (ISR), characterized by eIF2α phosphorylation, ATF4 and CHOP induction, MCL-1 suppression, PUMA and NOXA upregulation, and BCL-xL-dependent mitochondrial apoptosis, accompanied by caspase-2 activation. ISR activation occurred downstream of the autophagy disruption: rapamycin attenuated ISR activation, whereas ATG7 silencing intensified ISR signaling and apoptosis. CHOP knockdown blunted the BCL-xL/PUMA/NOXA shift and caspase-3 cleavage, establishing CHOP as required. Caspase-10 acted upstream of caspases-9, -7, and -3. The combination elicited immunogenic cell death markers: calreticulin exposure, ATP and HMGB1 release, elevated TNF-α, and reduced IL-8. These findings identify HDAC6-driven autophagy as a therapeutically exploitable vulnerability in CML that, when combined with asciminib, triggers ISR-dependent immunogenic apoptosis.

Thiazoles and rhodanines present interesting biological and photophysical properties, and merging both structures could give rise to antioxidant-luminescent dyads. Here, a practical synthesis of thiazolylidenthiazolidinones via one-pot reaction is reported, giving access to a large family in good yields (78-93 %) after simple purification. The compounds were fully characterized by NMR, FT-IR, HRMS, and their photophysical properties were studied. One of them was characterized by single-crystal X-ray diffraction, crystallizing in the monoclinic space group P2(1) with a = 8.1772(14) A degrees, b = 22.564(4) A degrees, c = 12.939(2) A degrees, alpha= 90 degrees, beta= 95.154 degrees (5) and gamma= 90 degrees. It was used as a model for computational studies, which served to rationalize the properties of the compounds. The DFT computations, performed using the DFT/ B3LYP/6-311G+ (d,p) level basis set, showed a good agreement with the experimental data (XRD, H-1 and C-13 NMR, FTIR, absorption and emission spectra). In addition, these compounds were tested for their antioxidant activity, studying their DPPH radical scavenging capacity. Interestingly, the compounds showed an antioxidant activity ranging from low (IC50 = 763.61 mu M) to good(IC50 = 11.96 mu M), the later being comparable to the capacity of ascorbic acid. (IC50=13.71 mu M). All compounds emit faintly in solution (quantum yield < 1 %), with an absorption maximum around 430 nm and an emission around 480 nm, these results being rationalized through td-DFT calculations. The luminescence combined with the antioxidant activity of these compounds makes them a promising scaffold to develop biologically relevant molecules.

Chronic myeloid leukemia (CML) remains a therapeutic challenge, particularly in patients who develop resistance to standard tyrosine kinase inhibitors (TKIs) such as imatinib. Here, we present the first demonstration of the potent anti-leukemic activity of the histone deacetylase (HDAC) inhibitor martinostat in both TKI-sensitive and TKI-resistant CML. Structural and biochemical analyses confirmed the efficient and selective binding of martinostat to HDAC isoenzyme ligand-binding pockets, resulting in histone and tubulin hyperacetylation in both imatinib-sensitive and resistant CML cells, outperforming vorinostat, a clinically used HDAC inhibitor (HDACi). It selectively impaired CML cell proliferation and viability and induced apoptosis across various CML models, including resistant cell models and patient blasts, with minimal toxicity to healthy cells and low developmental toxicity in zebrafish. In addition to its single-agent efficacy, martinostat demonstrated enhanced anticancer effects when combined with imatinib, both in vitro and in vivo, significantly reducing tumor growth in resistant CML xenograft models. Mechanistically, mRNA-seq data showed that martinostat disrupted key survival signaling pathways and amplified apoptotic responses, contributing to its anticancer activity. These findings highlight the potential of martinostat as a selective, low-toxicity HDACi that, combined with TKIs, could provide an effective strategy to overcome drug resistance in CML and improve therapeutic outcomes.

This study focuses on the green synthesis of novel Spirooxindole derivatives featuring indoline and pyrano[2,3-c] pyrazole or pyrimidine moieties. These derivatives were synthesized via a one-pot reaction using isatin, active methylene compounds, malononitrile, and MTPPBr as an eco-friendly catalyst. Their structural integrity was confirmed through 1H NMR, 13C NMR, and MS analyses. The in vitro antibacterial and antifungal activities of these compounds were evaluated, revealing that their biological efficacy is strongly influenced by their chemical structures and functional groups. Among the derivatives, compound 7l exhibited the strongest antibacterial activity, particularly against Escherichia coli (MIC = 1.25 mg/ml). Its potent activity was attributed to the synergistic effects of chlorophenyl, thioketone, and dioxo functional groups, which enhance membrane penetration and enzyme binding. Compound 7k showed broad-spectrum antibacterial activity, especially against Klebsiella pneumoniae (MIC = 1.25 mg/ml). In contrast, compounds 7c and 7f displayed weaker activity due to the absence of additional reactive groups necessary for effective bacterial targeting. In antifungal evaluations, spiro[indolinepyrano-pyrazolo] derivatives outperformed spiro[indoline-pyrano-pyrimidine] compounds. Notably, 7l exhibited the highest antifungal activity against Candida albicans (MIC = 10 mg/ml), driven by the combined effects of thioketone, dioxo, and diethyl groups, which enhanced lipophilicity and enzyme interactions. Compounds 7i and 7k also demonstrated moderate antifungal potential due to their hydrophilic and hydrophobic balance. DFT studies supported these findings by analyzing electronic structures, highlighting the role of HOMO-LUMO energies and charge transfer dynamics in determining biological activity. Molecular docking revealed key interactions with bacterial (3UDI) and fungal (1DI8) enzymes, while drug-likeness evaluations and toxicity predictions confirmed their therapeutic potential. This study identifies 7l and 7k as promising agents for combating bacterial and fungal infections.

A biofilm is a community of microorganisms that are capable of living and reproducing as a collective entity known as a colony. The biofilm structure shields and enables colony expansion. Biofilms often lead to chronic infections in clinical settings. Because bacteria in biofilms continuously develop resistance to antibiotics, using antibiotics alone to treat infections caused by biofilms is ineffective. Quorum sensing (QS) is a means of communication between bacterial cells and is a key factor in the formation of mature biofilms. Therefore, disrupting this process is one of the most important ways to eliminate biofilms. Triazoles are an important class of nitrogen heterocyclic compounds with a wide spectrum of bioactivities and extensive applications. Additionally, triazoles are capable of QS rewiring and biofilm formation inhibition, leading to higher susceptibility to antimicrobial agents and less antibiotic resistance. The present study aimed to investigate the potential of triazole antimicrobial agents to inhibit biofilm development in infectious microorganisms. This study was designed to assess how effectively triazole antimicrobial compounds can suppress biofilm formation in pathogenic microorganisms.

Dehydroacetic acid (DHA) is a significant heterocyclic molecule whose derivatives are highly prevalent. Thus, a new series of heterocyclic derivatives starting from dehydroacetic acid were synthesized and investigated for their antimicrobial and antioxidant activities. The antimicrobial activity of the twenty-one new compounds was determined against S. aureus ATCC 6538-P, E. coli ATCC 25922, C. albicans ATCC 10231, and A. niger NRRL A326. Out of twenty one compounds, 7a, 8a, 9, 10d and 14 showed promising in vitro antimicrobial activity. Compounds 7a, 8a, and 10d were equipotent to ciprofloxacin reference drug against S. aureus, while compounds 9 and 14 were 4-fold and 2-fold higher than ciprofloxacin, respectively. For E. coli, compounds 9 and 10d were equipotent to ciprofloxacin whereas compounds 7a, 8a, and 14 were 4-fold, 8-fold, and 2-fold higher than ciprofloxacin, respectively. Regarding C. albicans, 7a showed moderate activity with 2-fold lower than nystatin (reference drug). To further analyze the antimicrobial potential of the compounds (7a, 8a, 9, 10d, and 14), their in vitro inhibitory activity against E. coli DNA gyrase was evaluated. The results revealed that compound 8a showed the lowest IC50 required for DNA gyrase inhibition almost similar IC50 to ciprofloxacin. A molecular docking study was established to assess the binding mode of 8a, the most active derivative, with the crystal structure of DNA gyrase B (PDB: 5MMN). 8a demonstrated a good binding mode inside the active pocket of the DNA gyrase B with good binding energy value. Additionally, 8a displayed the highest antioxidant activity compared with ascorbic acid. Collectively, the compound 8a is a highly promising antimicrobial candidate for further studies.

Natural products, with their various sources from plants, marine organisms, and microorganisms, are considered a key source and inspiration for medicines and continue to be so. Indole alkaloids are a class of alkaloids and represent a large subunit of natural products. Indole alkaloids of biological importance are numerous and cover a wide range of pharmaceutical applications, including anticancer, antiviral, antimicrobial, anti-inflammatory, and antioxidant. Obtaining natural, biologically active indole compounds involves isolating them from their natural sources or preparing them synthetically. 3-Substituted indoles represent an emerging structural class of marine alkaloids based on their high degree of biological activity. 3-Acetyl indole is an important core used as a starting material for synthesizing many bioactive indole alkaloids. (5-Indole)oxazole alkaloids, β-carboline alkaloids, bis-indole alkaloids, chuangxinmycin, meridianine, and (±) indolemycin are the most important indole alkaloids that are prepared starting from 3-acety indole. The present review provides comprehensive information on the structures and the synthesis of bioactive indole alkaloids utilizing 3-acetyl indole and its derivatives as starting compounds. Additionally, it also spotlights the diverse biological activities of these compounds.

Quorum sensing (QS) is a bacterial cell-to-cell communication mechanism that plays an essential role in bacterial pathogenesis. QS governs bacterial behavior and controls biofilm formation, which in turn contributes to antibiotic resistance. Therefore, identifying and synthesizing novel compounds to overcome QS and inhibit biofilm formation are essential. Coumarins are important plant-derived natural products with wide-ranging bioactivities and extensive applications, including antibacterial, antifungal, anticoagulant, antioxidant, anticancer, and anti-inflammatory properties. Additionally, coumarins are capable of QS rewiring and biofilm formation inhibition, leading to higher susceptibility to antimicrobial agents and less antibiotic resistance. Therefore, in this review, we aim to provide an overview of QS and biofilm formation. This review also discusses the role of natural and synthesized coumarins in controlling QS, inhibiting biofilm formation, and inducing synergy in antibiotic–coumarin combinations. Hence, this review emphasizes the potential of coumarin compounds to act as antibacterial agents and demonstrates their ability to alleviate antibiotic resistance.

Marine products are among the most promising sources of biologically active molecules. Aplysinopsins, tryptophan-derived marine natural products, were isolated from different natural marine sources including sponges, stony corals (hard corals) especially genus scleractinian, as well as sea anemone, in addition to one nudibranch. Aplysinopsins were reported to be isolated from different marine organisms related to various geographic areas such as Pacific, Indonesia, Caribbean, and Mediterranean regions. This review gives an up-to-date overview of marine alkaloid aplysinopsins: their various sources, their synthesis, and the fact that many aplysinopsin derivatives are biologically active compounds.

Asteltoxins belong to a group of polyene pyrone mycotoxins that are known to be potent inhibitors of mitochondrial ATP synthesis and ATP hydrolysis. Asteltoxin A was first isolated from the toxic maize cultures of Aspergillus stellatus. Several attempts have been made to synthesize asteltoxin A, starting with the synthesis of a bis(tetrahydrofuran) moiety that has been demonstrated previously in biosynthetic studies. This review highlights the fungal sources of asteltoxins, similar asteltoxins, biosynthetic pathways, their synthetic trials, and their biological activities. This review is the first of its kind covering the periods from 1979 to 2023.

Fungal bioactive secondary metabolites are considered promising sources for the production of unique compounds with exceptional chemical structures. Of these bioactive secondary metabolites, meleagrins are prenylated indole alkaloids characterized by a triazaspirocyclic skeleton that is generally obtained from Penicillium species. Meleagrins are alkaloids with promising biological activities. Here is a survey of previously published research on meleagrins: their sources, biosynthetic pathways, synthesis, and bioactivities.

Cdc25 phosphatases have been considered promising targets for anticancer development due to the correlation of their overexpression with a wide variety of cancers. In the last two decades, the interest in this subject has considerably increased and many publications have been launched concerning this issue. An overview is constructed based on data analysis of the results of the previous publications covering the years from 1992 to 2021. Thus, the main objective of the current review is to report the chemical structures of Cdc25s inhibitors and answer the question, how to design an inhibitor with better efficacy and lower toxicity?

In consideration of green and efficient organic chemical methodology, we reported here a green, an efficient and convenient procedure for synthesis of 3-aryl-2,3-dihydro-1,3,4-thiadiazoles based on benzofuran as well as chromone moieties, using the grinding technique. Condensation of 1-(4,7-dimethoxybenzofuran-5-yl)ethan-1-ones 2, 3; 7-hydroxy-5-methoxy-2-methyl-4-oxo-4H-chromene-6-carbaldehyde (4); and 4-oxo-4H-chromene-3-carbaldehydes 10a–c with alkyl hydrazine carbodithioates followed with some hydrazonoyl halides 7a–g under grinding and solvent-free condition led to the formation of the targeted 3-aryl-2,3-dihydro-1,3,4-thiadiazoles 8a–g, 9a,b, and 12a–f, correspondingly. Structures of the synthesized compounds were clarified based on their elemental analyses and spectral data. Eleven of the entire target compounds were selected for anticancer activity against 60 human cancer cell lines at a single dose (10‾5 M) by the National Cancer Institute (NCI, Bethesda, USA).

Given the diverse pharmacological attributes possessed by the curcumin and its analogs, quinazolinethione 3, thiazoloquinazolinone 4, and thiazolylidene thiazoloquinazolinone hybrids D1-D12 were synthesized from α, α' Bis(arylidene)Cyclohexanone (BAC) as starting material. The proposed structures of all synthesized compounds were confirmed by 1H, 13CNMR, and elemental analysis. The newly synthesized hybrids were screened in vitro for their antimicrobial and antioxidant activities. Preliminary studies showed that compounds D4, D5, D10, D11, and D12 exhibited superior inhibitory behaviors against some microorganisms in comparison with standard drugs. In addition, DPPH radical scavenging assay was used to evaluate their antioxidant property. Accordingly, compound D11 was found to be a more powerful antioxidant than the other compounds. Furthermore, the HOMO–LUMO energy values and some chemical parameters indicate that the synthesized hybrid D11 is more reactive than D7. These results were consistent with our experimental data on antioxidants. Moreover, molecular electrostatic potential (MEP) maps were computed in order to predict the reactive sites for nucleophilic and electrophilic attacks of the synthesized hybrids D7 and D11.

Aplysinopsins are a class of indole alkaloids that possess various pharmacological activities. Although their action has been studied in regard to many diseases, their effect on prostate cancer has not yet been examined. Therefore, we synthesized a new series of aplysinopsin analogs and investigated their cytotoxic activity against prostate cancer. Five analogs showed high antitumor activity via suppressing the expression of the anti-apoptotic gene Bcl2, simulationously increasing the expression of the pro-apoptotic genes p53, Bax and Caspase 3. The inhibition of BCL2 led to the activation of BAX, which in turn activated Caspase 3, leading to apoptosis. This dual mechanism of action via apoptosis and cell cycle arrest induction is responsible for aplysinopsin analogs antitumor activity. Hence, our newly synthesized analogs are highly promising candidates for further preclinical studies against prostate cancer.

During a previous study that identified plants used in traditional medicine in Togo to treat infectious diseases, Daniellia oliveri was specifically reported to treat intertrigo and candidiasis. Consequently, to explore the anti-infective potential of this plant, we investigated the antibacterial and the antifungal activity of the plant’s parts, as well as the cytotoxic activities of raw extracts and subsequent fractions, and the chemical composition of the most active fractions. In order to evaluate the antimicrobial activity, MICs were determined using the broth dilution method. Then, the most active fractions were evaluated for cytotoxicity by using normal human cells (MRC-5 cells) via the MTT assay. Finally, the most active and not toxic fractions were phytochemically investigated by GC-MS. Interestingly, all the raw extracts and fractions were active against the bacteria tested, with MICs ranging from 16 µg/mL to 256 µg/mL, while no antifungal activity was observed at 256 µg/mL, the highest tested concentration. Moreover, no toxicity was observed with most of the active fractions. The subsequent chemical investigation of the most interesting fractions led to identifying terpenes, phytosterols, phenolic compounds, and fatty acids as the main compounds. In conclusion, this study demonstrated that D. oliveri possesses valuable antibacterial activities in accordance with traditional use.

Mercapto (or sulfanyl)-coumarins are heterocycles of great interest in the development of valuable active structures in material and biological domains. They represent a highly exploitable class of compounds that open many possibilities for further chemical transformations. The present review aims to draw focus toward the synthetic applicability of various forms of mercapto-coumarins and their representations in pharmaceuticals and industries. This work covers the literature issued from 1970 to 2021.

Cancer is one of the main causes of human mortality worldwide and novel chemotherapeutics are required due to the limitations of conventional cancer therapies. For example, using redox selenium compounds as novel chemotherapeutics seem to be very promising. The objective of this study was to explore if folate could be used as a carrier to deliver a newly synthesised selenium derivative selenofolate into cancer cells. Particularly, the cytotoxic effects of this selenofolate compound were investigated in a variety of cancer cell types including lung, liver, and cervical cancers and specifically IGROV1 cells. Our results showed that selenofolate inhibits the growth of cancer cells in-vitro. However, despite the expectations, folate receptor alpha (FRα) was not involved in the transportation of selenofolate compound into the cells i.e. growth inhibition was independent of FRα, suggesting that multiple transporters (e.g. reduced folate carrier-1) are possibly involved in the delivery and internalisation of folate in IGROV1 cells. Additionally, selenofolate did not exert cell death through apoptosis. Instead, anti-proliferative activity showed to be the main cause of growth inhibition of selenolofate in the IGROV1 cell line. In conclusion, selenofolate inhibits the growth of cancer cells and thus, may be explored further as a potential chemotherapeutic agent.