Synthesis, Docking, and Machine Learning Studies of Some Novel Quinolinesulfonamides–Triazole Hybrids with Anticancer Activity
Ontology highlight
ABSTRACT:
SUBMITTER: Marciniec K
PROVIDER: S-EPMC11243625 | biostudies-literature | 2024 Jul
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:In an attempt to develop natural product-based anticancer agents, a series of novel piperazine-linked bergenin heterocyclic hybrids bearing arylthiazolyl (5a-e), benzothiazolyl (10a-i), and arylsulfonyl (13a-o) were synthesized using the classical Mannich reaction and evaluated for their anticancer activity. All the synthesized derivatives were assessed for in vitro cytotoxic activity against a panel of human cancer and normal cell lines and the results showed that most of the compounds exhibited significant cytotoxic activity against cancer cells and mild cytotoxicity against normal cells. In particular, the compounds 5a, 5c, 10f, and 13o showed potent cytotoxic activity against tongue and oral cancer cell lines compared to the parent compound (<100 μM). Considering the efficacy, the compounds 5a, 5c, 10f, and 13o were subjected to cell cycle analysis and the results indicated that the compounds mitigated the cell cycle progression at the G0/G1 phase in the tongue and oral cancer cell lines. Subsequently, the annexin V/PI staining assay demonstrated that the compounds 5a, 5c, 10f, and 13o induced early and late apoptosis against tongue cancer and necrosis against oral cancer. Further, gene expression analysis revealed that 5a, 5c, and 13o treatment regulated the BAX and BcL-2 expression and also the selected compounds significantly reduced the expression level of vimentin, oct-4, and nanog. In addition, molecular docking studies revealed that the selected derivatives have strong binding energy with the BcL2 protein and downregulates the expression. Taken together, the study results implied that these compounds are promising anticancer candidates by modulating the epithelial to mesenchymal transition axis and could be considered for further development of novel anticancer drugs.
| S-EPMC9383709 | biostudies-literature
Project description:To increase the antitubercular potency, we synthesized a series of novel pyrazolylpyrazoline derivatives (9a-p) using the one-pot multicomponent reaction of the substituted heteroaryl aldehyde (3a,b), 2-acetyl pyrrole/thiazole (4a,b), and substituted hydrazine hydrates (5-8) in the presence of base NaOH as a catalyst in ethanol as the solvent at room temperature. Substituted heteroaryl aldehyde (3a,b) was synthesized from 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-methyl-carbaldehyde on protection with ethylene glycol followed by treatment with 4-amino triazole/5-amino tetrazole and then deprotection using acid. The salient features of the green protocol are the one-pot reaction, shorter reaction time, and straightforward workup procedure. All of the compounds were tested against Mycobacterium tuberculosis H37Rv, wherein compounds 9i, 9k, 9l, 9o, and 9p were found to be most effective. The structures of newly synthesized compounds were determined using spectral methods. Furthermore, molecular docking investigations into the active site of mycobacterial InhA yielded well-clustered solutions for these compounds' binding modalities producing a binding affinity in the range from -8.884 to -7.113. Theoretical results were in good accord with the observed experimental values. The docking score of the most active compound 9o was found to be -8.884, and the Glide energy was -61.144 kcal/mol. and it was found to accommodate well into the active site of InhA, engaging in a network of bonded and nonbonded interactions.
| S-EPMC10268283 | biostudies-literature
Project description:The newly synthesized quinoline-benzimidazole hybrids containing two types of triazole-methyl-phenoxy linkers were characterized via NMR and elemental analysis. Additional derivatization was achieved by introducing bromine at the C-2 position of the phenoxy core. These novel hybrids were tested for their effects on the growth of the non-tumor cell line MRC-5 (human fetal lung fibroblasts), leukemia and lymphoma cell lines: Hut78, THP-1 and HL-60, and carcinoma cell lines: HeLa and CaCo-2. The results obtained, presented as the concentration that achieves 50% inhibition of cell growth (IC50 value), show that the compounds tested affect tumor cell growth differently depending on the cell line and the dose applied (IC50 ranged from 0.2 to >100 µM). The quinoline-benzimidazole hybrids tested, including 7-chloro-4-(4-{[4-(5-methoxy-1H-1,3-benzo[d]imidazol-2-yl)phenoxy]methyl}-1H-1,2,3-triazol-1-yl)quinoline 9c, 2-(3-bromo-4-{[1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methoxy}phenyl)-N-propyl-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride 10e, 2-{4-[(1-{2-[(7-chloroquinolin-4-yl)amino]ethyl}-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-N-propyl-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride 14e and 2-{3-bromo-4-[(1-{2-[(7-chloroquinolin-4-yl)amino]ethyl}-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-N-propyl-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride 15e, arrested the cell cycle of lymphoma (HuT78) cells. The calculated ADMET properties showed that the synthesized compounds violated at most two of Lipinski's rules, making them potential drug candidates, but mainly for parenteral use due to low gastrointestinal absorption. The quinoline-benzimidazole hybrid 14e, which was shown to be a potent and selective inhibitor of lymphoma cell line growth, obtained the highest binding energy (-140.44 kcal/mol), by docking to the TAO2 kinase domain (PDB: 2GCD).
| S-EPMC10574761 | biostudies-literature
Project description:The synthesis of hybrid molecules is one of the current strategies of drug discovery for the development of new lead compounds. The 1,2,3-triazole moiety represents an important building block in Medicinal Chemistry, extensively present in recent years. In this paper, we presented the design and the synthesis of new 1,2,3-triazole hybrids, containing both an isatine and a phenolic core. Firstly, the non-commercial azide and the alkyne synthons were prepared by different isatines and phenolic acids, respectively. Then, the highly regioselective synthesis of 1,4-disubstituted triazoles was obtained in excellent yields by a click chemistry approach, catalyzed by Cu(I). Finally, a molecular docking study was performed on the hybrid library, finding four different therapeutic targets. Among them, the most promising results were obtained on 5-lipoxygenase, an enzyme involved in the inflammatory processes.
| S-EPMC11013233 | biostudies-literature
Project description:Betulin derivatives containing a 1,2,3-triazole ring possess a wide spectrum of biological activities, including antiviral, anticancer, and antibacterial activity. A series of novel triazoles were prepared by the 1,3-dipolar cycloaddition reaction between the alkyne derivatives of betulin and organic azides. The chemical structures of the obtained compounds were defined by ¹H and 13C NMR, IR, and high-resolution mass spectrometry (HR-MS) analysis. The target triazoles were screened for their antiviral activity against DNA and RNA viruses. The cytotoxic activity of the obtained compounds 5a-k and 6a-h was determined using five human cancer cell lines (T47D, MCF-7, SNB-19, Colo-829, and C-32) by a WST-1 assay. The bistriazole 6b displayed a promising IC50 value (0.05 μM) against the human ductal carcinoma T47D (500-fold higher potency than cisplatin). The microdilution method was applied for an evaluation of the antimicrobial activity of all of the compounds. The triazole 5e containing a 3'-deoxythymidine-5'-yl moiety exhibited antibacterial activity against two gram-negative bacteria vz. Klebsiellapneumoniae and Escherichia coli (minimal inhibitory concentration (MIC) range of 0.95-1.95 μM).
| S-EPMC6150379 | biostudies-literature
Project description:A series of novel benzofuran-triazole hybrids was designed and synthesized by click chemistry, and their structures were characterized by HRMS, FTIR and NMR. The in vitro antifungal activity of target compounds was evaluated using the microdilution broth method against five strains of pathogenic fungi. The result indicated that the target compounds exhibited moderate to satisfactory activity. Furthermore, molecular docking was performed to investigate the binding affinities and interaction modes between the target compound and N-myristoyltransferase. Based on the results, preliminary structure activity relationships (SARs) were summarized to serve as a foundation for further investigation.
| S-EPMC6274255 | biostudies-literature
Project description:A series of novel 1,2,3-triazole and chiral Schiff base hybrids 2-6 were synthesized by Schiff base condensation reaction from pre-prepared parent component of the hybrids (1,2,3-triazole 1) and series of primary chiral amines and their chemical structure were confirmed using NMR and FTIR spectroscopies, and CHN elemental analysis. Compounds 1-6 were evaluated for their anticancer activity against two cancer PC3 (prostate) and A375 (skin) and MRC-5 (healthy) cell lines by Almar Blue assay method. The compounds exhibited significant cytotoxicity against the tested cancer cell lines. Among the tested compounds 3 and 6 showed very good activity for the inhibition of the cancer cell lines and low toxicity for the healthy cell lines. All the compounds exhibited high binding affinity for Androgen receptor modulators (PDB ID: 5t8e) and Human MIA (PDB ID: 1i1j) inhibitors compared to the reference anticancer drug (cisplatin). Structure activity relationships (SARs) of the tested compounds is in good agreement with DFT and molecular docking studies. The compounds exhibited desirable physicochemical properties for drug likeness.
| S-EPMC10960833 | biostudies-literature
Project description:Podophyllotoxin, along with its numerous derivatives and related compounds, is well known for its broad-spectrum pharmacological activity, especially for anticancer potential. In this study, several isatin-podophyllotoxin hybrid compounds were successfully synthesized with good yields through microwave-prompted three-component reactions of 2-amino-1,4-naphthoquinone, various substituted isatins, and tetronic acid. Their cytotoxicity was assessed against four types of human cancer cell lines, HepG2 (hepatoma carcinoma), MCF7 (breast cancer), A549 (non-small lung cancer), and KB (epidermoid carcinoma), alongside nontumorigenic HEK-293 human embryonic kidney cells. Among 14 compounds screened, 7f possessed the strongest cytotoxicity to KB and A549 cell lines, with IC50 values of 1.99 ± 0.22 and 0.90 ± 0.09 μM, respectively. Further studies revealed that product 7f could arrest the cell cycle of A549 cells at S phase and induce apoptosis of A549 cells. This compound was examined for its binding ability against cyclin-dependent kinases (CDKs) and procaspase/caspase systems. The results indicated that 7f exhibited significant interactions with the residues of the ATP binding sites of CDK2/cyclin A and CDK5/p25 and also activated procaspase 6 through stable zinc chelation. Additionally, physicochemical and pharmacokinetic properties related to drug-likeness, in parallel with toxicity, were computationally assessed to identify the main issues that need to be addressed in structural optimization. Taken together, compound 7f was identified as a potent cytotoxic agent that could be considered for anticancer drug discovery and development.
| S-EPMC11774189 | biostudies-literature
Project description: Not available
| S-EPMC11242894 | biostudies-literature
Project description: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.
| S-EPMC9458111 | biostudies-literature