Triazoles and Other N‐Containing Metabolites from the Marine‐Derived Endophytic Fungus Penicillium chrysogenum EN‐118

Two new triazoles, chrysotriazoles A and B ( 1 and 2 , resp.), along with two known quinazolinones, 3 and 4 , two known 2‐(4‐hydroxyphenyl)acetamides, 5 and 6 , and two known N‐(4‐hydroxystyryl)formamides, 7 and 8 , were isolated and identified from the culture extract of Penicillium chrysogenum EN‐118, an endophytic fungus obtained from the marine brown alga Sargassum pallidium. The structures of the isolated compounds were elucidated by NMR‐spectroscopic analysis, and that of compound 1 was confirmed by X‐ray crystallographic analysis of its p‐bromobenzoate derivative. Compounds 4, 5 , and 7 showed moderate cytotoxicities against Du145, A‐549, and HeLa cell lines.     

Biosynthesis of Bromoroquefortines in a High Saline Medium by Penicillium chrysogenum,a Terrestrial Endophyte Collected from Coffea arabica

Roquefortine C ( 1 ) and 11‐bromoroquefortine C ( 4 ) were isolated from Penicillium chrysogenum, an endophyte obtained from green leaves of Coffea arabica, during induction experiments by adding halide salts to the culture media. In our studies, 11‐bromoroquefortine D and 11‐bromo‐17‐hydroxybromoroquefortine C were identified by LC/HR‐MS. It is the first time that bromoroquefortine C and D are described as halogenated natural products. These halo alkaloids were shown to be biosynthesized from brominated tryptophan as the biosynthetic precursor. Cytotoxic and antibiotic assays using roquefortine C and 11‐bromoroquefortine C showed that the presence of the 11‐Br substituent impairs some biological activities of this alkaloid.     

Lobularia libyca: Phytochemical Profiling,Antioxidant and Antimicrobial Activity Using In Vitro and In Silico Studies

Lobularia libyca (L. libyca) is a traditional plant that is popular for its richness in phenolic compounds and flavonoids. The aim of this study was to comprehensively investigate the phytochemical profile by liquid chromatography, electrospray ionization and tandem mass spectrometry (LC-ESI-MS), the mineral contents and the biological properties of L. libyca methanol extract. L. libyca contains significant amounts of phenolic compounds and flavonoids. Thirteen compounds classified as flavonoids were identified. L. libyca is rich in nutrients such as Na, Fe and Ca. Moreover, the methanol extract of L. libyca showed significant antioxidant activity without cytotoxic activity on HCT116 cells (human colon cancer cell line) and HepG2 cells (human hepatoma), showing an inhibition zone of 13 mm in diameter. In silico studies showed that decanoic acid ethyl ester exhibited the best fit in β-lactamase and DNA gyrase active sites; meanwhile, oleic acid showed the best fit in reductase binding sites. Thus, it can be concluded that L. libyca can serve as a beneficial nutraceutical agent, owing to its significant antioxidant and antibacterial potential and due to its richness in iron, calcium and potassium, which are essential for maintaining a healthy lifestyle.     

Potential Anticancer Activity of the Furanocoumarin Derivative Xanthotoxin Isolated from Ammi majus L. Fruits: In Vitro and In Silico Studies

Ammi majus L., an indigenous plant in Egypt, is widely used in traditional medicine due to its various pharmacological properties. We aimed to evaluate the anticancer properties of Ammi majus fruit methanol extract (AME) against liver cancer and to elucidate the active compound(s) and their mechanisms of action. Three fractions from AME (Hexane, CH₂Cl₂, and EtOAc) were tested for their anticancer activities against HepG2 cell line in vitro (cytotoxicity assay, cell cycle analysis, annexin V-FITC apoptosis assay, and autophagy efflux assay) and in silico (molecular docking). Among the AME fractions, CH₂Cl₂ fraction revealed the most potent cytotoxic activity. The structures of compounds isolated from the CH₂Cl₂ fraction were elucidated using ¹H- and ¹³C-NMR and found that Compound 1 (xanthotoxin) has the strongest cytotoxic activity against HepG2 cells (IC₅₀ 6.9 ± 1.07 µg/mL). Treating HepG2 cells with 6.9 µg/mL of xanthotoxin induced significant changes in the DNA-cell cycle (increases in apoptotic pre-G1 and G2/M phases and a decrease in the S-phase). Xanthotoxin induced significant increase in Annexin-V-positive HepG2 cells both at the early and late stages of apoptosis, as well as a significant decrease in autophagic flux in cancer compared with control cells. In silico analysis of xanthotoxin against the DNA-relaxing enzyme topoisomease II (PDB code: 3QX3) revealed strong interaction with the key amino acid Asp479 in a similar fashion to that of the co-crystallized inhibitor (etoposide), implying that xanthotoxin has a potential of a broad-spectrum anticancer activity. Our results indicate that xanthotoxin exhibits anticancer effects with good biocompatibility toward normal human cells. Further studies are needed to optimize its antitumor efficacy, toxicity, solubility, and pharmacokinetics.     

Berberine Derivatives as Pseudomonas aeruginosa MexXY-OprM Inhibitors: Activity and In Silico Insights

The natural alkaloid berberine has been demonstrated to inhibit the Pseudomonas aeruginosa multidrug efflux system MexXY-OprM, which is responsible for tobramycin extrusion by binding the inner membrane transporter MexY. To find a structure with improved inhibitory activity, we compared by molecular dynamics investigations the binding affinity of berberine and three aromatic substituents towards the three polymorphic sequences of MexY found in P. aeruginosa (PAO1, PA7, and PA14). The synergy of the combinations of berberine or berberine derivatives/tobramycin against the same strains was then evaluated by checkerboard and time-kill assays. The in silico analysis evidenced different binding modes depending on both the structure of the berberine derivative and the specific MexY polymorphism. In vitro assays showed an evident MIC reduction (32-fold and 16-fold, respectively) and a 2–3 log greater killing effect after 2 h of exposure to the combinations of 13-(2-methylbenzyl)- and 13-(4-methylbenzyl)-berberine with tobramycin against the tobramycin-resistant strain PA7, a milder synergy (a 4-fold MIC reduction) against PAO1 and PA14, and no synergy against the ΔmexXY strain K1525, confirming the MexY-specific binding and the computational results. These berberine derivatives could thus be considered new hit compounds to select more effective berberine substitutions and their common path of interaction with MexY as the starting point for the rational design of novel MexXY-OprM inhibitors.     

Oxalactam A,a Novel Macrolactam with Potent Anti-Rhizoctonia solani Activity from the Endophytic Fungus Penicillium oxalicum

A novel macrolactam named oxalactam A (1), three known dipeptides (2–4) as well as other known alkaloids (5–7) were obtained from the endophytic fungus Penicillium oxalicum, which was derived from the tuber of Icacina trichantha (Icacinaceae). All chemical structures were established based on spectroscopic data, chemical methods, ECD calculations, and ¹³C-DP4+ analysis. Among them, oxalactam A (1) is a 16-membered polyenic macrolactam bearing a new skeleton of 2,9-dimethyl-azacyclohexadecane core and exhibited potent anti-Rhizoctonia solani activity with a MIC value of 10 μg/mL in vitro. The plausible biosynthetic pathway of 1 was also proposed via the alanyl protecting mechanism. Notably, three dipeptides (2–4) were first identified from the endophytic fungus P. oxalicum and the NMR data of cyclo(L-Trp-L-Glu) (2) was reported for the first time. In addition, the binding interactions between compound 1 and the sterol 14α-demethylase enzyme (CYP51) were studied by molecular docking and dynamics technologies, and the results revealed that the 16-membered polyenic macrolactam could be a promising CYP51 inhibitor to develop as a new anti-Rhizoctonia solani fungicide.     

The Hydrolysis Rate of Paraoxonase-1 Q and R Isoenzymes: An In Silico Study Based on In Vitro Data

Human serum paraoxonase-1 (PON1) is an important hydrolase-type enzyme found in numerous tissues. Notably, it can exist in two isozyme-forms, Q and R, that exhibit different activities. This study presents an in silico (QSAR, Docking, MD and QM/MM) study of a set of compounds on the activity towards the PON1 isoenzymes (QPON1 and RPON1). Different rates of reaction for the Q and R isoenzymes were analyzed by modelling the effect of Q192R mutation on active sites. It was concluded that the Q192R mutation is not even close to the active site, while it is still changing the geometry of it. Using the combined genetic algorithm with multiple linear regression (GA-MLR) technique, several QSAR models were developed and relative activity rates of the isozymes of PON1 explained. From these, two QSAR models were selected, one each for the QPON1 and RPON1. Best selected models are four-variable MLR models for both Q and R isozymes with squared correlation coefficient R² values of 0.87 and 0.83, respectively. In addition, the applicability domain of the models was analyzed based on the Williams plot. The results were discussed in the light of the main factors that influence the hydrolysis activity of the PON1 isozymes.     

In Vitro Anti-Inflammatory Activity of Cotula anthemoides Essential Oil and In Silico Molecular Docking of Its Bioactives

The genus Cotula (Asteraceae) comprises about 80 species, amongst them Cotula anthemoides L. It is a wild plant growing in Egypt that possesses many traditional uses as a headache, colic, and chest cold remedy. In our study, the chemical composition of C. anthemoides essential oils was analyzed using GC-MS spectroscopy. Sixteen components of leave and stem oils and thirteen components of flower oils were characterized. The main components in both essential oil parts were camphor (88.79% and 86.45%) and trans-thujone (5.14% and 10.40%) in the leaves and stems and the flowers, respectively. The anti-inflammatory activity of the oils in lipopolysaccharide-stimulated RAW 264.7 macrophage cells was evaluated. The flower oil showed its predominant effect in the amelioration of proinflammatory cytokines and tumor necrosis factor-α, as well as cyclooxygenase-2. The bornyl acetate showed the highest affinity for the cyclooxygenase-2 receptor, while compound cis-p-menth-2-ene-1-ol had the best affinity for the tumor necrosis factor receptor, according to the results of molecular docking. In addition, the molecule cis-β-farnesene showed promising dual affinity for both studied receptors. Our findings show that essential oils from C. anthemoides have anti-inflammatory properties through their control over the generation of inflammatory mediators. These findings suggest that C. anthemoides essential oils could lead to the discovery of novel sources of anti-inflammatory treatments.     

In Vitro and In Silico Investigation of Diterpenoid Alkaloids Isolated from Delphinium chitralense

This study reports the isolation of three new C₂₀ diterpenoid alkaloids, Chitralinine A–C (1–3) from the aerial parts of Delphinium chitralense. Their structures were established on the basis of latest spectral techniques and single crystal X-rays crystallographic studies of chitralinine A described basic skeleton of these compounds. All the isolated Compounds (1–3) showed strong, competitive type inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in comparison to standard allanzanthane and galanthamine however, chitralinine-C remained the most potent with IC₅₀ value of 11.64 ± 0.08 μM against AChE, and 24.31 ± 0.33 μM against BChE, respectively. The molecular docking reflected a binding free energy of −16.400 K Cal-mol⁻¹ for chitralinine-C, having strong interactions with active site residues, TYR334, ASP72, SER122, and SER200. The overall findings suggest that these new diterpenoid alkaloids could serve as lead drugs against dementia-related diseases including Alzheimer’s disease.     

α-Glucosidase Inhibitory and Antimicrobial Benzoylphloroglucinols from Garcinia schomburgakiana Fruits: In Vitro and In Silico Studies

α-Glucosidase plays a role in hydrolyzing complex carbohydrates into glucose, which is easily absorbed, causing postprandial hyperglycemia. Inhibition of α-glucosidase is therefore an ideal approach to preventing this condition. A novel polyprenylated benzoylphloroglucinol, which we named schomburgkianone I (1), was isolated from the fruit of Garcinia schomburgkiana, along with an already-reported compound, guttiferone K (2). The structures of the two compounds were determined using NMR and HRESIMS analysis, and comparisons were made with previous studies. Compounds 1 and 2 exhibited potent α-glucosidase inhibition (IC_50s of 21.2 and 34.8 µM, respectively), outperforming the acarbose positive control. Compound 1 produced wide zones of inhibition against Staphylococcus aureus and Enterococcus faecium (of 21 and 20 mm, respectively), compared with the 19 and 20 mm zones of compound 2, at a concentration of 50 µg/mL. The MIC value of compound 1 against S. aureus was 13.32 µM. An in silico molecular docking model suggested that both compounds are potent inhibitors of enzyme α-glucosidase and are therefore leading candidates as therapies for diabetes mellitus.     

In Vitro and In Silico Anti-Acetylcholinesterase Activity from Macaranga tanarius and Syzygium jambos

Macaranga tanarius (MT) and Syzygium jambos (SJ) are pharmacologically reported to have anti-oxidant, anti-inflammatory, and anti-diabetic effects, and can be neuroprotective agents. Our previous work revealed that MT and SJ exhibited 76.32% and 93.81% inhibition against acetylcholinesterase (AChE) at 50 μg/mL final concentration in their ethyl acetate and hexane fractions, respectively. This study was aimed to investigate the bioactive constituents of MT and SJ and their molecular mechanism toward AChE inhibition. Bioassay-guided isolation afforded prenylflavonoids 1–3 from MT and anacardic acid derivatives 4 and 5 from SJ that were confirmed by NMR and MS data. Compound 5 exerted the strongest anti-AChE potential (IC₅₀: 0.54 μM), followed by 1, 4, 3, and 2 (IC₅₀: 1.0, 2.4, 6.8, and 33 μM, respectively). In silico molecular docking revealed 5 formed stronger molecular interactions including three H-bonds than its derivative 4 based on the saturation of their alkyl chains. The addition of a five carbon-prenyl chain in 1 increased the number of binding interactions, justifying its greater activity than derivatives 2 and 3. This research reflects the first report of AChE inhibitors from these species, thereby adding pharmacological values to MT and SJ as potential remedies in neuroprotection.     

Biological Efficacy of Compounds from Stingless Honey and Sting Honey against Two Pathogenic Bacteria: An In Vitro and In Silico Study

Honey inhibits bacterial growth due to the high sugar concentration, hydrogen peroxide generation, and proteinaceous compounds present in it. In this study, the antibacterial activity of stingless and sting honey against foodborne pathogenic bacteria isolated from spoiled milk samples was examined. The isolated bacterial strains were confirmed as Bacillus cereus and Listeria monocytogenes through morphological, biochemical, and 16 s RNA analysis. Physiochemical characterizations of the honey samples revealed that both of the honey samples had an acidic pH, low water content, moderate reducing sugar content, and higher proline content. Through the disc diffusion method, the antibacterial activities of the samples were assayed and better results were observed for the 50 mg/disc honey. Both stingless and sting honey showed the most positive efficacy against Bacillus cereus. Therefore, an in silico study was conducted against this bacterium with some common compounds of honey. From several retrieved constituents of stingless and sting honey, 2,4-dihydroxy-2,5-dimethyl 3(2H)-furan-3-one (furan) and 4H-pyran-4-one,2,3-dihydro of both samples and beta.-D-glucopyranose from the stingless revealed high ligand-protein binding efficiencies for the target protein (6d5z, hemolysin II). The root-mean-square deviation, solvent-accessible surface area, the radius of gyration, root-mean-square fluctuations, and hydrogen bonds were used to ensure the binding stability of the docked complexes in the atomistic simulation and confirmed their stability. The combined effort of wet and dry lab-based work support, to some extent, that the antimicrobial properties of honey have great potential for application in medicine as well as in the food industries.     

In Silico Screening and In Vitro Assessment of Natural Products with Anti-Virulence Activity against Helicobacter pylori

Helicobacter pylori is one of the most frequent human pathogens and a leading etiological agent of various gastric diseases. As stringent response, coordinated by a SpoT protein, seems to be crucial for the survivability of H. pylori, the main goal of this article was to use in silico computational studies to find phytochemical compounds capable of binding to the active site of SpoT from H. pylori and confirm the ability of the most active candidates to interfere with the virulence of this bacterium through in vitro experiments. From 791 natural substances submitted for the virtual screening procedure, 10 were chosen and followed for further in vitro examinations. Among these, dioscin showed the most interesting parameters (the lowest MIC, the highest anti-biofilm activity in static conditions, and a relatively low stimulation of morphological transition into coccoids). Therefore, in the last part, we extended the research with a number of further experiments and observed the ability of dioscin to significantly reduce the formation of H. pylori biofilm under Bioflux-generated flow conditions and its capacity for additive enhancement of the antibacterial activity of all three commonly used antibiotics (clarithromycin, metronidazole, and levofloxacin). Based on these results, we suggest that dioscin may be an interesting candidate for new therapies targeting H. pylori survivability and virulence.     

A New Cyclic Peptide and a New Steroid from the Fungus Penicillium sp. GD6 Isolated from the Mangrove Bruguiera gymnorrhiza

A rare new cyclic tetrapeptide, 5,5′‐epoxy‐MKN‐349A ( 1 ), featured by a MKN‐349A ( 5 ) skeleton and containing an uncommon ether bridge between C(5) and C(5′), and a new steroid, named 11‐O‐acetyl‐NGA0187 ( 2 ), together with two known steroids, 3 and 4 , were isolated from an endophytic fungus Penicillium sp. GD6 associated with the Chinese mangrove Bruguiera gymnorrhiza. The structures of the new compounds were elucidated on the basis of extensive spectroscopic analyses and by comparison with the data of related compounds reported in literature. Neither of the compounds 3 and 4 , isolated in this study, showed obvious bioactivities in the antibacterial bioassay experiments.     

Thiazolidinedione Derivatives: In Silico,In Vitro,In Vivo,Antioxidant and Anti-Diabetic Evaluation

This work aimed to synthesize a new antihyperglycemic thiazolidinedione based on the spectral data. The DFT\B3LYP\6-311G** level of theory was used to investigate the frontier molecular orbitals (FMOs), chemical reactivity and map the molecular electrostatic potentials (MEPs) to explain how the synthesized compounds interacted with the receptor. The molecular docking simulations into the active sites of PPAR-γ and α-amylase were performed. The in vitro potency of these compounds via α-amylase and radical scavenging were evaluated. The data revealed that compounds (4–6) have higher potency than the reference drugs. The anti-diabetic and anti-hyperlipidemic activities for thiazolidine-2,4-dione have been investigated in vivo using the alloxan-induced diabetic rat model along with the 30 days of treatment protocol. The investigated compounds didn’t show obvious reduction of blood glucose during pre-treatments compared to diabetic control, while after 30 days of treatments, the blood glucose level was lower than that of the diabetic control. Compounds (4–7) were able to regulate hyperlipidemia levels (cholesterol, triglyceride, high-density lipoproteins and low- and very-low-density lipoproteins) to nearly normal value at the 30th day.     

Exploring Natural Product Activity and Species Source Candidates for Hunting ABCB1 Transporter Inhibitors: An In Silico Drug Discovery Study

The P-glycoprotein (P-gp/ABCB1) is responsible for a xenobiotic efflux pump that shackles intracellular drug accumulation. Additionally, it is included in the dud of considerable antiviral and anticancer chemotherapies because of the multidrug resistance (MDR) phenomenon. In the search for prospective anticancer drugs that inhibit the ABCB1 transporter, the Natural Product Activity and Species Source (NPASS) database, containing >35,000 molecules, was explored for identifying ABCB1 inhibitors. The performance of AutoDock4.2.6 software to anticipate ABCB1 docking score and pose was first assessed according to available experimental data. The docking scores of the NPASS molecules were predicted against the ABCB1 transporter. Molecular dynamics (MD) simulations were conducted for molecules with docking scores lower than taxol, a reference inhibitor, pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. On the basis of MM-GBSA calculations, five compounds revealed promising binding affinities as ABCB1 inhibitors with ΔG_binding < −105.0 kcal/mol. The binding affinity and stability of the identified inhibitors were compared to the chemotherapeutic agent. Structural and energetical analyses unveiled great steadiness of the investigated inhibitors within the ABCB1 active site throughout 100 ns MD simulations. Conclusively, these findings point out that NPC104372, NPC475164, NPC2313, NPC197736, and NPC477344 hold guarantees as potential ABCB1 drug candidates and warrant further in vitro/in vivo tests.     

Novel Thiosemicarbazone Derivatives: In Vitro and In Silico Evaluation as Potential MAO-B Inhibitors

MAO-B inhibitors are frequently used in the treatment of neurodegenerative diseases such as Parkinson’s and Alzheimer’s. Due to the limited number of compounds available in this field, there is a need to develop new compounds. In the recent works, it was shown that various thiosemicarbazone derivatives show hMAO inhibitory activity in the range of micromolar concentration. It is thought that benzofuran and benzothiophene structures may mimic structures such as indane and indanone, which are frequently found in the structures of such inhibitors. Based on this view, new benzofuran/benzothiophene and thiosemicarbazone hybrid compounds were synthesized, characterized and screened for their hMAO-A and hMAO-B inhibitory activity by an in vitro fluorometric method. The compounds including methoxyethyl substituent (2b and 2h) were found to be the most effective agents in the series against MAO-B enzyme with the IC₅₀ value of 0.042 ± 0.002 µM and 0.056 ± 0.002 µM, respectively. The mechanism of hMAO-B inhibition of compounds 2b and 2h was investigated by Lineweaver–Burk graphics. Compounds 2b and 2h were reversible and non-competitive inhibitors with similar inhibition features as the substrates. The K_i values of compounds 2b and 2h were calculated as 0.035 µM and 0.046 µM, respectively, with the help of secondary plots. The docking study of compound 2b and 2h revealed that there is a strong interaction between the active sites of hMAO-B and analyzed compound.     

Hepatoprotective Effect of Millettia dielsiana: In Vitro and In Silico Study

In silico docking studies of 50 selected compounds from Millettia dielsiana Harms ex Diels (family Leguminosae) were docked into the binding pocket of the PI3K/mTOR protein. In there, compounds trans−3−O-p-hydroxycinnamoyl ursolic acid (1) and 5,7,4′−trihydroxyisoflavone 7−O−β−D−apiofuranosyl−(1→6)−β−D−glucopyranoside (2) are predicted to be very promising inhibitors against PI3K/mTOR. They direct their cytotoxic activity against Hepatocellular carcinoma with binding affinity (BA) values, the pulling work spent to the co-crystallized ligand from the binding site of PI3K/mTOR (W and F_max), and the non-equilibrium binding free energy (∆G_neq^Jar) as BA values = −9.237 and −9.083 kcal/mol, W = 83.5 ± 10.6 kcal/mol with F_max = 336.2 ± 45.3 pN and 126.6 ± 21.7 kcal/mol with F_max = 430.3 ± 84.0 pN, and ∆G_neq^Jar = −69.86074 and −101.2317 kcal/mol, respectively. In molecular dynamic simulation, the RMSD value of the PI3K/mTOR complex with compounds (1 and 2) was in the range of 0.3 nm to the end of the simulation. Therefore, the compounds (1 and 2) are predicted to be very promising inhibitors against PI3K/mTOR. The crude extract, ethyl acetate fraction and compounds (1 and 2) from Millettia dielsiana exhibited moderate to potent in vitro cytotoxicity on Hepatocellular carcinoma cell line with IC₅₀ values of 81.2 µg/mL, 60.4 µg/mL, 23.1 μM, and 16.3 μM, respectively, and showed relatively potent to potent in vitro antioxidant activity on mouse hepatocytes with ED₅₀ values of 24.4 µg/mL, 19.3 µg/mL, 30.7 μM, and 20.5 μM, respectively. In conclusion, Millettia dielsiana and compounds (1 and 2) are predicted to have very promising cytotoxic activity against Hepatocellular carcinoma and have a hepatoprotective effect.     

Holospiniferoside: A New Antitumor Cerebroside from The Red Sea Cucumber Holothuria spinifera: In Vitro and In Silico Studies

Chemical investigation of the methanolic extract of the Red Sea cucumber Holothuria spinifera led to the isolation of a new cerebroside, holospiniferoside (1), together with thymidine (2), methyl-α-d-glucopyranoside (3), a new triacylglycerol (4), and cholesterol (5). Their chemical structures were established by NMR and mass spectrometric analysis, including gas chromatography–mass spectrometry (GC–MS) and high-resolution mass spectrometry (HRMS). All the isolated compounds are reported in this species for the first time. Moreover, compound 1 exhibited promising in vitro antiproliferative effect on the human breast cancer cell line (MCF-7) with IC₅₀ of 20.6 µM compared to the IC₅₀ of 15.3 µM for the drug cisplatin. To predict the possible mechanism underlying the cytotoxicity of compound 1, a docking study was performed to elucidate its binding interactions with the active site of the protein Mdm2–p53. Compound 1 displayed an apoptotic activity via strong interaction with the active site of the target protein. This study highlights the importance of marine natural products in the design of new anticancer agents.     

Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design,Synthesis, In Vitro,and In Silico Study

Breast cancer is the most common cancer in women, responsible for over half a million deaths in 2020. Almost 75% of FDA-approved drugs are mainly nitrogen- and sulfur-containing heterocyclic compounds, implying the importance of such compounds in drug discovery. Among heterocycles, thiazole-based heterocyclic compounds have demonstrated a broad range of pharmacological activities. In the present study, a novel set of 1,3-thiazole derivatives was designed and synthesized based on the coupling of acetophenone derivatives, and phenacyl bromide was substituted as a key reaction step. The activity of synthesized compounds was screened against the proliferation of two breast cancer cell lines (MCF-7 and MDA-MB-231). Almost all compounds exhibited a considerable antiproliferative activity toward the breast cancer cells as compared to staurosporine, with no significant cytotoxicity toward the epithelial cells. Among the synthesized compounds, compound 4 exhibited the most potent antiproliferative activity, with an IC₅₀ of 5.73 and 12.15 µM toward MCF-7 and MDA-MB-231 cells, respectively, compared to staurosporine (IC₅₀ = 6.77 and 7.03 µM, respectively). Exploring the mechanistic insights responsible for the antiproliferative activity of compound 4 revealed that compound 4 possesses a significant inhibitory activity toward the vascular endothelial growth factor receptor-2 (VEGFR-2) with (IC₅₀ = 0.093 µM) compared to Sorafenib (IC₅₀ = 0.059 µM). Further, compound 4 showed the ability to induce programmed cell death by triggering apoptosis and necrosis in MCF-7 cells and to induce cell cycle arrest on MCF-7 cells at the G1 stage while decreasing the cellular population in the G2/M phase. Finally, detailed in silico molecular docking studies affirmed that this class of compounds possesses a considerable binding affinity toward VEGFR2 proteins. Overall, these results indicate that compound 4 could be a promising lead compound for developing potent anti-breast cancer compounds.