Search Results (19)

Tyrosyl-DNA phosphodiesterase 1 (TDP1) represents a compelling pharmacological target for the development of agents designed to circumvent tumor resistance to topoisomerase 1 (TOP1) inhibitors, a major class of clinically relevant antineoplastic drugs. This paper describes the design and synthesis of novel hybrid TDP1 inhibitors combining coumarin and monoterpene moieties via rigid isoxazole and 1,2,3-triazole heterocyclic linkers. The synthesis was accomplished via [3 + 2] cycloaddition of nitrile oxides to alkynes and copper-catalyzed click chemistry. Biological tests have demonstrated the crucial role of linker nature in the activity of the compounds. Isoxazole-linked conjugates showed strong inhibitory effects on TDP1, with IC₅₀ values in the submicromolar to low micromolar range (0.8–3.2 μM). Overall, these values slightly surpassed those of the triazole-linked analogues, whose IC₅₀ values ranged from 1.1 to 23.3 μM. At noncytotoxic doses, compounds 26e and 16b enhanced the sensitivity of human cervical cancer (HeLa) cells to the antitumor agent topotecan, a TOP1 inhibitor, thereby supporting the promise of this structural class as components of combination chemotherapy. Full article

A new series of tacrine–coumarin hybrids (compounds 15a–18b) linked by 1,2,3-triazole had been designed and synthesized as multifunctional ligands for the treatment of Alzheimer’s disease (AD). The inhibitory effects of the synthesized compounds on AChE and BuChE, their ability to inhibit Aβ aggregation, and their MAO inhibitory activities were evaluated. In vitro studies showed that some of the hybrids (compounds 17a–18b) exhibited significant abilities to inhibit both AChE and BuChE, self-induced Aβ aggregation, and MAO-B. In particular, compound 17d showed a well-balanced inhibitory profile against AChE and BuChE (IC₅₀ = 0.080 ± 0.007 μM for AChE, IC₅₀ = 0.044 ± 0.004 μM for BuChE), self-induced Aβ aggregation (58.4% ± 2.1% at 20 μM), and MAO-B (IC₅₀ = 0.18 ± 0.01 μM), suggesting that 17d might be an excellent multifunctional agent for AD treatment. In addition, compounds 15a and 15b were identified as selective inhibitors of BuChE at micromolar concentrations. Full article

Coumarin derivatives constitute a versatile small-molecule chemotype with broad anticancer potential. This narrative review synthesizes recent in vitro and in vivo evidence on coumarin-based scaffolds, emphasizing breast cancer and covering lung, prostate, and colorectal models. We summarize major mechanisms of action—including induction of apoptosis (caspase activation and BAX/BCL-2 balance), modulation of PI3K/Akt/mTOR signaling, inhibition of angiogenesis (VEGFR-2), interference with estrogen biosynthesis (aromatase/ER axis), chaperone targeting (Hsp90), and attenuation of multidrug resistance (efflux pumps/autophagy)—and highlight representative chemotypes (e.g., benzimidazole, triazole, furocoumarins, topoisomerase- and CDK-oriented hybrids). Where available, we contrast potency and selectivity across models (e.g., MCF-7 vs. MDA-MB-231; A549; PC-3; colon lines) and discuss structure–activity trends linking substituent patterns (heteroaryl linkers, judicious halogenation, polar handles) to pathway engagement. We also delineate translational gaps limiting clinical progress—selectivity versus non-malignant cells, incomplete pharmacokinetic and safety characterization, and limited validation beyond xenografts. Finally, we outline priorities for preclinical optimization: biology-aligned target selection with biomarkers, resistance-aware combinations (e.g., PI3K/mTOR ± autophagy modulation; MDR mitigation), and early integration of ADME/tox and PK/PD to confirm on-target exposure. Collectively, the evidence supports coumarins as adaptable, multi-target anticancer leads, particularly promising in hormone-dependent breast cancer while remaining relevant to other tumor types. Full article

A series of 21 novel coumarin–triazole–isatin hybrids was synthesized and evaluated for their potential as multitarget agents in Alzheimer’s disease (AD). The compounds featured variations in alkyl linker length that connects coumarin and triazole and substitution at the 5-position of the isatin ring. Several derivatives showed potent butyrylcholinesterase (BChE) inhibition with selectivity over acetylcholinesterase (AChE). The lead compound, 6c1, exhibited strong BChE inhibition (IC₅₀ = 1.74 μM), surpassing donepezil. Enzyme kinetics revealed a mixed-type mechanism, while molecular docking studies confirmed dual binding at catalytic and peripheral sites. Structure–activity relationship (SAR) analysis highlighted the influence of linker flexibility and steric/electronic effects of substituents. The observed BChE selectivity, combined with favorable in vitro profiles, identifies these hybrids as promising leads for AD drug development. Full article

Although the present use of pesticides in plant protection has limited the occurrence and development of plant diseases and pests, resistance to pesticides and their environmental and health hazards indicates an urgent need for new active ingredients in plant protection products. Recently synthesized coumarin-1,2,4-triazole hybrid compounds have been proven effective against plant pathogenic fungi and safe for soil-beneficial bacteria. Drosophila melanogaster, the common fruit fly, has been used as a model organism for scientific research. Additionally, it is considered a pest since it damages fruits and serves as a carrier for various plant diseases. On the contrary, Orius laevigatus is a beneficial true bug that biologically controls harmful arthropods in agricultural production. In the present study, we performed an adulticidal bioassay against D. melanogaster and O. laevigatus using coumarin-1,2,4-triazole hybrids. Quantitative structure–activity relationship studies (QSARs) and in silico ecotoxicity evaluation elucidated the structural features underlying the compounds’ insecticidal activity. The derivative of 4-methylcoumarin-1,2,4-triazole with a 3-bromophenyl group showed great insecticidal potential. A molecular docking study indicated that the most active compound probably binds to glutamate-gated chloride channels. Full article

A new series of compounds planned by molecular hybridization of the nucleobases uracil and thymine, or the xanthine theobromine, with coumarins, and linked through 1,2,3-triazole heterocycles were evaluated for their in vitro anticancer activity against the human tumor cell lines: colon carcinoma (HCT116), laryngeal tumor cells (Hep-2), and lung carcinoma cells (A549). The hybrid compound 9a exhibited better activity in the series, showing an IC50 of 24.19 ± 1.39 μM against the HCT116 cells, with a selectivity index (SI) of 6, when compared to the cytotoxicity against the non-tumor cell line HaCat. The in silico search for pharmacological targets was achieved through molecular docking studies on all active compounds, which suggested that the synthesized compounds possess a high affinity to the Topoisomerase 1–DNA complex, supporting their antitumor activity. The in silico toxicity prediction studies suggest that the compounds present a low risk of causing theoretical mutagenic and tumorigenic effects. These findings indicate that molecular hybridization from natural derivative molecules is an interesting approach to seek new antitumor candidates. Full article

Inhibitors of monoamine oxidases (MAOs) are of interest for the treatment of neurodegenerative disorders and other human pathologies. In this frame, the present work describes different synthetic strategies to obtain MAO inhibitors via the coupling of the aminocoumarin core with arylsulfonyl chlorides followed by copper azide-alkyne cycloaddition, leading to coumarin–sulfonamide–nitroindazolyl–triazole hybrids. The nitration position on the coumarin moiety was confirmed through nuclear magnetic resonance spectroscopy and molecular electron density theory in order to elucidate the molecular mechanism and selectivity of the electrophilic aromatic substitution reaction. The coumarin derivatives were evaluated for their inhibitory potency against monoamine oxidases and cholinesterases. Molecular docking calculations provided a rational binding mode of the best compounds in the series with MAO A and B. The work identified hybrids 14a–c as novel MAO inhibitors, with a selective action against isoform B, of potential interest to combat neurological diseases. Full article

The tyrosinase enzyme has a vital role in the browning of vegetables and fruits and the biosynthesis of melanin. In this work, we synthesized a diverse library of coumarin–triazole hybrids, and these compounds were characterized by using suitable analytical techniques. Our research work extends beyond the synthetic effort to explore the therapeutic potential of these compounds. We put the synthesized compounds through meticulous in vitro screening against the tyrosinase enzyme, and these coumarin derivatives evinced good IC₅₀ values in the range of 0.339 ± 0.25 µM to 14.06 ± 0.92 µM. In the library of synthesized compounds, six compounds were found to be more potent than standard ascorbic acid (IC₅₀ = 11.5 ± 1.00), and among them, 17e and 17f, being the most active, exhibited remarkable anti-tyrosinase potential, with IC₅₀ values of 0.339 ± 0.25 μM and 3.148 ± 0.23 μM, respectively. Furthermore, an in silico modeling study was carried out to determine the key interactions of these compounds with the tyrosinase protein (PDB ID: 2Y9X) and thus to authenticate our experimental findings. The quantitative SAR studies exhibited a good correlation between the synthesized derivatives of coumarin and their anti-tyrosinase activity. The docking studies verified the experimental results, and ligand 17e showed good interaction with the core residues of tyrosinase. This study not only expands the field of coumarin–triazole hybrid synthesis but also provides valuable insights for the development of novel tyrosinase inhibitors. Full article

Molecular hybridization represents a new approach in drug discovery in which specific chromophores are strategically combined to create novel drugs with enhanced therapeutic effects. This innovative strategy leverages the strengths of individual chromophores to address complex biological challenges, synergize beneficial properties, optimize pharmacokinetics, and overcome limitations associated with single-agent therapies. Coumarins are documented to possess several bioactivities and have therefore been targeted for combination with other active moieties to create molecular hybrids. This review summarizes recent (2013–2023) trends in the synthesis of coumarins, as well as coumarin–chalcone and coumarin–triazole molecular hybrids. To cover the wide aspects of this area, we have included differently substituted coumarins, chalcones, 1,2,3– and 1,2,4–triazoles in this review and considered the point of fusion/attachment with coumarin to show the diversity of these hybrids. The reported syntheses mainly relied on well-established chemistry without the need for strict reaction conditions and usually produced high yields. Additionally, we discussed the bioactivities of the reported compounds, including antioxidative, antimicrobial, anticancer, antidiabetic, and anti-cholinesterase activities and commented on their IC₅₀ where possible. Promising bioactivity results have been obtained so far. It is noted that mechanistic studies are infrequently found in the published work, which was also mentioned in this review to give the reader a better understanding. This review aims to provide valuable information to enable further developments in this field. Full article

Metastasis, the dissemination of tumor cells, stands as the second most prominent contributor to mortality arising from breast cancer. To counteract this phenomenon, the molecular markers associated with angiogenesis, particularly vascular endothelial growth factor (VEGF) and its receptor (VEGFR), have emerged as promising strategies for impeding the progression of tumor cells. Compounds like pyrimidines, coumarins, oxadiazoles, and triazoles have undergone comprehensive investigations due to their notable anticancer potential, highlighting their encouraging capacities in inhibiting VEGFR-2, an essential mediator of angiogenesis signaling. Herein, we have synthesized pyrimidine–triazoles and oxadiazole–triazoles using electrochemical and conventional methods. The newly synthesized compounds were evaluated for anticancer activity against MCF-7 breast cancer cells, and it was found that the compounds 8a and 8b showed IC₅₀ values of 5.29 and 15.54 μM, respectively. Our in silico mode of action revealed that these compounds could target VEGFR-2, which was further evidenced by our in silico structure-based bioinformatic analysis. In conclusion, we reported an electrochemical method to prepare novel drug-like compounds, based on triazole and other heterocyclic hybrids, that could be used to design VGFR-targeting drugs. Full article

Bacterial infections have attracted the attention of researchers in recent decades, especially due to the special problems they have faced, such as their increasing diversity and resistance to antibiotic treatment. The emergence and development of the SARS-CoV-2 infection stimulated even more research to find new structures with antimicrobial and antiviral properties. Among the heterocyclic compounds with remarkable therapeutic properties, benzimidazoles, and triazoles stand out, possessing antimicrobial, antiviral, antitumor, anti-Alzheimer, anti-inflammatory, analgesic, antidiabetic, or anti-ulcer activities. In addition, the literature of the last decade reports benzimidazole-triazole hybrids with improved biological properties compared to the properties of simple mono-heterocyclic compounds. This review aims to provide an update on the synthesis methods of these hybrids, along with their antimicrobial and antiviral activities, as well as the structure–activity relationship reported in the literature. It was found that the presence of certain groups grafted onto the benzimidazole and/or triazole nuclei (-F, -Cl, -Br, -CF₃, -NO₂, -CN, -CHO, -OH, OCH₃, COOCH₃), as well as the presence of some heterocycles (pyridine, pyrimidine, thiazole, indole, isoxazole, thiadiazole, coumarin) increases the antimicrobial activity of benzimidazole-triazole hybrids. Also, the presence of the oxygen or sulfur atom in the bridge connecting the benzimidazole and triazole rings generally increases the antimicrobial activity of the hybrids. The literature mentions only benzimidazole-1,2,3-triazole hybrids with antiviral properties. Both for antimicrobial and antiviral hybrids, the presence of an additional triazole ring increases their biological activity, which is in agreement with the three-dimensional binding mode of compounds. This review summarizes the advances of benzimidazole triazole derivatives as potential antimicrobial and antiviral agents covering articles published from 2000 to 2023. Full article

Toxicity and resistance to newly synthesized anticancer drugs represent a challenging phenomenon of intensified concern arising from variation in drug targets and consequently the prevalence of the latter concern requires further research. The current research reports the design, synthesis, and anticancer activity of new 1,2,3-triazole-coumarin-glycosyl hybrids and their 1,2,4-triazole thioglycosides as well as acyclic analogs. The cytotoxic activity of the synthesized products was studied against a panel of human cancer cell lines. Compounds 8, 10, 16 and 21 resulted in higher activities against different human cancer cells. The impact of the hybrid derivative 10 upon different apoptotic protein markers, including cytochrome c, Bcl-2, Bax, and caspase-7 along with its effect on the cell cycle was investigated. It revealed a mitochondria-apoptotic effect on MCF-7 cells and had the ability to upregulate pro-apoptotic Bax protein and downregulate anti-apoptotic Bcl-2 protein and thus implies the apoptotic fate of the cells. Furthermore, the inhibitory activities against EGFR, VEGFR-2 and CDK-2/cyclin A2 kinases for 8, 10 and 21 were studied to detect the mechanism of their high potency. The coumarin-triazole-glycosyl hybrids 8 and 10 illustrated excellent broad inhibitory activity (IC₅₀= 0.22 ± 0.01, 0.93 ± 0.42 and 0.24 ± 0.20 μM, respectively, for compound 8), (IC₅₀ = 0.12 ± 0.50, 0.79 ± 0.14 and 0.15± 0. 60 μM, respectively, for compound 10), in comparison with the reference drugs, erlotinib, sorafenib and roscovitine (IC₅₀ = 0.18 ± 0.05, 1.58 ± 0.11 and 0.46 ± 0.30 μM, respectively). In addition, the docking study was simulated to afford better rationalization and put insight into the binding affinity between the promising derivatives and their targeted enzymes and that might be used as an optimum lead for further modification in the anticancer field. Full article

Cancer is a complex disease, and its treatment is a big challenge, with variable efficacy of conventional anticancer drugs. A two-drug cocktail hybrid approach is a potential strategy in recent drug discovery that involves the combination of two drug pharmacophores into a single molecule. The hybrid molecule acts through distinct modes of action on several targets at a given time with more efficacy and less susceptibility to resistance. Thus, there is a huge scope for using hybrid compounds to tackle the present difficulties in cancer medicine. Recent work has applied this technique to uncover some interesting molecules with substantial anticancer properties. In this study, we report data on numerous promising hybrid anti-proliferative/anti-tumor agents developed over the previous 10 years (2011–2021). It includes quinazoline, indole, carbazole, pyrimidine, quinoline, quinone, imidazole, selenium, platinum, hydroxamic acid, ferrocene, curcumin, triazole, benzimidazole, isatin, pyrrolo benzodiazepine (PBD), chalcone, coumarin, nitrogen mustard, pyrazole, and pyridine-based anticancer hybrids produced via molecular hybridization techniques. Overall, this review offers a clear indication of the potential benefits of merging pharmacophoric subunits from multiple different known chemical prototypes to produce more potent and precise hybrid compounds. This provides valuable knowledge for researchers working on complex diseases such as cancer. Full article

This study represents the design and synthesis of a new set of triazole-coumarin-glycosyl hybrids and their tetrazole hybrid analogues possessing various sugar moieties and modified analogues. All the newly synthesized derivatives were screened for their cytotoxic activities against a panel of human cancer cell lines. The coumarin derivatives 10, 13 and 15 derivatives revealed potent cytotoxic activities against Paca-2, Mel-501, PC-3 and A-375 cancer cell lines. These promising analogues were further examined for their inhibitory assessment against EGFR, VEGFR-2 and CDK-2/cyclin A2 kinases. The coumarin-tetrazole 10 displayed broad superior inhibitory activity against all screened enzymes compared with the reference drugs, erlotinib, sorafenib and roscovitine, respectively. The impact of coumarin-tetrazole 10 upon cell cycle and apoptosis induction was determined to detect its mechanism of action. Additionally, it upregulated the levels of casp-3, casp-7 and cytochrome-c proteins and downregulated the PD-1 level. Finally, molecular docking study was simulated to afford better rationalization and gain insight into the binding affinity between the promising derivatives and their targeted enzymes, which could be used as an optimum lead for further modification in the anticancer field. Full article

As cancer remains one of the major health burdens worldwide, novel agents, due to the development of resistance, are needed. In this work, we designed and synthesized harmirins, which are hybrid compounds comprising harmine and coumarin scaffolds, evaluated their antiproliferative activity, and conducted cell localization and cell cycle analysis experiments. Harmirins were prepared from the corresponding alkynes and azides under mild reaction conditions using Cu(I) catalyzed azide–alkyne cycloaddition, leading to the formation of the 1H-1,2,3-triazole ring. Antiproliferative activity of harmirins was evaluated in vitro against four human cancer cell lines (MCF-7, HCT116, SW620, and HepG2) and one human non-cancer cell line (HEK293T). The most pronounced activities were exerted against MCF-7 and HCT116 cell lines (IC₅₀ in the single-digit micromolar range), while the most selective harmirins were 5b and 12b, substituted at C-3 and O-7 of the β-carboline core and bearing methyl substituent at position 6 of the coumarin ring (SIs > 7.2). Further experiments demonstrated that harmirin 12b is localized exclusively in the cytoplasm. In addition, it induced a strong G1 arrest and reduced the percentage of cells in the S phase, suggesting that it might exert its antiproliferative activity through inhibition of DNA synthesis, rather than DNA damage. In conclusion, harmirin 12b is a novel harmine and coumarin hybrid with significant antiproliferative activity and warrants further evaluation as a potential anticancer agent. Full article