Chalcone Derivatives Research Articles

New Fluoro‐ and Trifluoromethyl‐Substituted Trimethoxychalcones as Anticancer Agents: Synthesis, Bio‐evaluation, and Computational Studies

AbstractWe designed and synthesized a novel series of trimethoxy chalcones with CF3 or F substituents at various positions of ring B, characterized using IR, NMR spectral data, and elemental analyses, based on the fact that methoxy and fluoro‐substituted chalcones are included in the literature as a pharmacophore due to their anticancer activities. All compounds (12‐21) were tested for cytotoxicity against A549, HEPG2, MCF7, and normal mouse fibroblasts (L929) using the XTT assay. The most active compound, 13, was also shown to induce MCF7 cell cycle arrest at the G0/G1 phase, indicating that they exert their antitumor potency via MCF7 cell apoptosis. The mechanisms involved in apoptotic cell death induced by compound 13 were also investigated to see if apoptotic proteins such as Bax, Bcl‐2, and p53 were involved. In addition, the compounds with the strongest apoptotic effects against human EGFR and VEGFR‐2 receptors were studied in silico. Finally, methoxy and fluoro‐substituted chalcones derivatives have been shown to have potent anticancer properties.

A novel chalcone derivative exerts anticancer effects by promoting apoptotic cell death of human pancreatic cancer cells

Aggressive pancreatic cancer is typically treated using chemotherapeutics to reduce the tumor pre-operatively and prevent metastasis post-operatively, as well as surgical approaches. In the present study, we synthesized a hydroxyl group-introduced chalcone derivative (1, IC50 = 32.1 μM) and investigated its potential as an anticancer drug candidate by evaluating its apoptosis-promoting effects on BXPC-3 cancer cells. The viability of BXPC-3 cells treated with 1 was measured using the water-soluble tetrazolium 1 reagent. BXPC-3 cells induced by 1 were stained with diverse probes or antibodies, such as ethidium homodimer-1, Hoechst, anti-Ki67, and MitoTracker. Protein expression was measured using an immunoblotting assay, and mRNA expression was determined using real-time polymerase chain reaction. Apoptotic molecular features, such as lipid accumulation and protein degradation, were monitored directly using stimulated Raman scattering microspectroscopy. Through incubation time- and concentration-dependent studies of 1, we found that it significantly reduced the proliferation and increased the number of apoptotic BXPC-3 cells. Compound 1 induced mitochondrial dysfunction, phosphorylation of p38, and caspase 3 cleavage. These results indicate that 1 is a potential therapeutic agent for pancreatic cancer, providing valuable insights into the development of new anticancer drug candidates.

Furan based synthetic chalcone derivative functions against gut inflammation and oxidative stress demonstrated in in-vivo zebrafish model

Inflammatory Bowel Disease (IBD) is a group of persistent intestinal illnesses resulting from bowel inflammation unrelated to infection. The prevalence of IBD is rising in industrialized countries, increasing healthcare costs. Whether naturally occurring or synthetic, chalcones possess a broad range of biological properties, including anti-inflammatory, anti-microbial, and antioxidant effects. This investigation focuses on DKO7 (E)-3-(4-(dimethylamino)phenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one, a synthesized chalcone with potential anti-inflammatory effects in a zebrafish model of intestinal inflammation induced by Dextran sodium sulfate (DSS). The in vitro study displayed dose-dependent anti-inflammatory as well as antioxidant properties of DKO7. Additionally, DKO7 protected zebrafish larvae against lipid peroxidation, reactive oxygen stress (ROS), and DSS-induced inflammation. Moreover, DKO7 reduced the expression of pro-inflammatory genes, including TNF-α, IL-1β, IL-6, and iNOS. Further, it reduced the levels of nitric oxide (NO) and lactate dehydrogenase (LDH) in the intestinal tissues of adult zebrafish and increased the levels of antioxidant enzymes such as Catalase (CAT) and superoxide dismutase (SOD). The protective effect of DKO7 against chemically (or DSS) induced intestinal inflammation was further verified using histopathological techniques in intestinal tissues. The furan-based chalcone derivative, DKO7, displayed antioxidant and anti-inflammatory properties. Also, DKO7 successfully reverses the DSS-induced intestinal damage in zebrafish. Overall, this study indicates the ability of DKO7 to alleviate DSS-induced gut inflammation in an in-vivo zebrafish.

In silico Molecular Docking Study of Some Novel Chalcone Derivatives as Anticancer Agents

In silico Molecular Docking Study of Some Novel Chalcone Derivatives as Anticancer Agents

Curcumin Chalcone Derivatives Database (CCDD): a Python framework for natural compound derivatives database.

We built the Curcumin Chalcone Derivatives Database (CCDD) to enable the effective virtual screening of highly potent curcumin and its analogs. The two-dimensional (2D) structures were drawn using the ChemBioOffice package and converted to 3D structures using Discovery Studio Visualizer V 2021 (DS). The database was built using different Python modules. For the 3D structures, different Python packages were used to obtain the data frame of compounds. This framework is also used to visualize the compounds. The webserver enables the users to screen the compounds according to Lipinski's rule of five. The structures can be downloaded in .sdf and .mol format. The data frame (df) can be downloaded in .csv format. Our webserver can help computational drug discovery researchers find new therapeutics and build new webservers. The CCDD is freely available at: https://srampogu-ccdd-ccdd-8uldk8.streamlit.app/.

A convenient method for the construction of triazole-bonded chalcone derivatives from acetophenone: Synthesis and free radical scavenging investigation

The substituted 1,2,3-triazole core is prevalent in numerous commercially available drugs utilized for a wide range of clinical applications. Simultaneously, chalcone represents a privileged framework discovered in natural products exhibiting intriguing bioactivities. In this study, we synthesized triazole-bonded chalcone compounds (4ax-4by), starting from a simple aromatic ketone, acetophenone, which underwent aldol condensation to give hydroxychalcone intermediate. In the second step, the hydroxyl group of chalcone compound was adducted with propargyl moiety through propargylation reaction. Then, the propargylated products underwent smooth copper-mediated azide-alkyne cyclization to give the triazole-bonded chalcones as the final products. They were characterized by IR, NMR and HRMS, and evaluated their radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH). Among the tested products, compound 4by was denoted as the most potent derivative which can inhibit DPPH radical in 91.62 ± 0.10% at 500 ppm.•Acetophenone as a simple ketone was modified to triazole-bonded chalcones.•Modification was performed through three steps reaction.•Final products exhibited free radical scavenging activity.

Unraveling the structure–property relationship of a chalcone-based push–pull molecule for optical limiting application in high-powered laser

In this work, the optical limiting response of a highly π-conjugated push–pull chalcone derivative (2E)-3-(2,3-dimethoxyphenyl)-1-(3-nitrophenyl)prop-2-en-1-one (abbreviated as 3DPNP) has been investigated. The structure–property relationship of 3DPNP was explored through spectroscopic investigation and quantum chemical computations. The existence of weak-non-covalent interactions and charge transfer species that responsible for the chemical stability of 3DPNP were studied by AIM and NBO analyses. The quantitative and qualitative analysis of vibrational and electronic contribution to non-linear optical (NLO) response of 3DPNP were discussed in detail. The normal vibrational modes associated with a change in the dipole moment, polarizability, first- and second-order hyperpolarizabilities of 3DPNP were identified using DFT calculations followed by potential energy distribution (PED) analysis using Gaussian 09 W software and Gar2ped program, respectively. The changes in the NLO parameters with respect to the varying frequencies and electric dipole fields were studied. The abrupt changes in the NLO properties were noticed when the frequency doubled, confirming the second harmonic generation (SHG) efficiency of 3DPNP. From the non-linear absorption and refraction studies through the z-scan experiment, the optical limiting threshold value of 3DPNP is determined to be 3.26 kJ/cm2, which shows the suitability of the material for optical limiting applications in the continuous wave (CW) laser regime.

Design, synthesis and biological evaluation of chalcone derivatives as potent and orally active hCYP3A4 inhibitors

Human cytochrome P450 3A4 (hCYP3A4), one of the most important drug-metabolizing enzymes, catalyze the metabolic clearance of ∼50% therapeutic drugs. CYP3A4 inhibitors have been used for improving the in vivo efficacy of hCYP3A4-substrate drugs. However, most of existing hCYP3A4 inhibitors may trigger serious adverse effects or undesirable effects on endogenous metabolism. This study aimed to discover potent and orally active hCYP3A4 inhibitors from chalcone derivatives and to test their anti-hCYP3A4 effects both in vitro and in vivo. Following three rounds of screening and structural optimization, the isoquinoline chalcones were found with excellently anti-hCYP3A4 effects. SAR studies showed that introducing an isoquinoline ring on the A-ring significantly enhanced anti-CYP3A4 effect, generating A10 (IC50 = 102.10 nM) as a promising lead compound. The 2nd round of SAR studies showed that introducing a substituent group at the para position of the carbonyl group on B-ring strongly improved the anti-CYP3A4 effect. As a result, C6 was identified as the most potent hCYP3A4 inhibitor (IC50 = 43.93 nM) in human liver microsomes (HLMs). C6 also displayed potent anti-hCYP3A4 effect in living cells (IC50 = 153.00 nM), which was superior to the positive inhibitor ketoconazole (IC50 = 251.00 nM). Mechanistic studies revealed that C6 could potently inhibit CYP3A4-catalyzed N-ethyl-1,8-naphthalimide (NEN) hydroxylation in a competitive manner (Ki = 30.00 nM). Moreover, C6 exhibited suitable metabolic stability in HLMs and showed good safety profiles in mice. In vivo tests demonstrated that C6 (100 mg/kg, orally administration) significantly increased the AUC(0-inf) of midazolam by 3.63-fold, and strongly prolonged its half-life by 1.66-fold compared with the vehicle group in mice. Collectively, our findings revealed the SARs of chalcone derivatives as hCYP3A4 inhibitors and offered several potent chalcone-type hCYP3A4 inhibitors, while C6 could serve as a good lead compound for developing novel, orally active CYP3A4 inhibitors with improved druglikeness properties.

Discovery of Novel Tetramethylpyrazine Containing Chalcone Derivatives as Anti-Inflammatory Agents.

Chalcones are precursors of flavonoids and exhibit a broad spectrum of pharmacological activity. As anti-inflammatory agents, two series of chalcone derivatives and chalcone-based oximes were synthesized and characterized. To integrate the tetramethylpyrazine moiety into these novel molecules, the multifunctional natural chemical ligustrazine was employed. A variety of newly synthesized ligustrazine-based chalcones were utilized as precursors for the synthesis of new oximes and their inhibitory activity against COX-1, COX-2, and LOX-5 enzymes were compared. The conversion of ketones to their oxime derivatives increased the effectiveness of COX-1 and COX-2 inhibition. Due to the substituted ether groups, oxime derivative 5d had the lowest IC50 values of 0.027 ± 0.004 μM and 0.150 ± 0.027 μM for COX-1 and COX-2 isoenzymes, respectively. Notably, the oxime derivative's highest effectiveness is conferred by the presence of methoxymethoxy or hydroxy groups at the C-3 and C-4 positions on the phenyl ring. The 6b derivative with a long alkyl chain ether group was shown to be the most powerful 5-LOX inhibitor. All compounds were also assessed for their ability to inhibit nitric oxide generation and LPS-induced IL-6, IL-1β, and TNF-α production in RAW 264.7 macrophages. Finally, in order to determine the structural effects responsible for the binding mechanism of compounds, they were docked into the binding sites of COX-1, COX-2, and 5-LOX, which revealed an inhibitory mechanism of action and demonstrated the relevance of various types of interactions. The findings showed that these novel compounds had a significant impact on antiinflammatory actions.

Anti-Breast Cancer Activity of Some Synthesized Pyrazole Derivatives Bearing Imidazo[1,2a]pyridine Moiety

A novel series of pyrazole derivatives containing imidazo[1,2-a]pyridine D1-D8 moiety has been synthesized. The reaction of 2-aminopyridine with 4-phenylphenacyl bromide and 4-bromophenacyl bromide gave the products A and A1, respectively. These products then reacted with DMF and POCl3 to obtain new aldehyde derivatives B and B1. These two aldehydes were condensed with various acetophenone substitutes to yield the corresponding chalcone derivatives C1-C10. Following this, the cycloaddition reaction with hydrazine hydrate provided new pyrazole derivatives D1-D8. The prepared compounds were verified by FT-IR, 1H NMR, and 13C NMR spectroscopy. Two of these derivatives (C5 and D1) were chosen to investigate their cytotoxic efficacy against breast cancer using the MTT assay.

Synthesis, anticancer for prostate cancer cells and antibacterial activity of new diazepine derivatives

In the current study, four new benzodiazepine derivatives were synthesized via a reaction of o-phenylenediamine with some chalcone derivatives. The synthesized compounds were characterized by 1H NMR and FT-IR spectroscopies. The antibacterial activity of the obtained diazepines was screened against E. coli, Bacillus subtilis, and Staphylococcus aureus. The results showed that compound 8 had the highest activity toward Bacillus subtilis and Staphylococcus aureus, while compounds 5 and 7 showed the highest activity toward E. coli. To support in vitro studies, docking studies have been performed to determine whether the title compounds (5–8) are inhibitors of the androgen receptor prostate cancer mutant H874Y ligand binding domain bound with testosterone and an AR 20–30 peptide (2Q7K), and the relationship between calculated energies and docking studies has been investigated. Among the synthesized diazepines, compound 5 was subjected to anticancer screening, where its activity against human prostate cancer (PC3) was tested. According to the obtained results, compound 5 has good anticancer activity against PC3.

Nanographene‐Doped Chalcone Derivatives of Dioxybiphenyl‐Bridged Dispirocyclotriphosphazenes: Synthesis, Electrical Properties, and DFT Calculations

AbstractThe cyclotriphosphazenes, which constitute an important class of inorganic compounds, can show new properties in the medical or technological fields depending on the properties of the substituted organic/inorganic groups. Herein, we aimed to determine electrical and theoretical properties of the nanographene‐doped chalcone derivatives of dioxybiphenyl‐bridged dispiro‐cyclotriphosphazenes. For this aim, a new series of chalcone substituted spiro‐cyclotriphosphazenes (3 a–g) have been synthesized by the reaction of dioxybiphenyl‐bridged dispiro‐cyclotriphosphazene (3) with chalcone derivatives (1 a–g), respectively. Then, nanographene was doped to these spiro‐cyclotriphosphazene 3 a–g using a hydrothermal system. The dielectric constant and loss factor of 4 % graphene‐doped chalcone‐substituted spiro‐cyclotriphosphazene 3 g were determined as 167 and 2147 at 1 kHz, respectively, showing a significant increase compared to compound 3 g. The energy values of HOMO and LUMO orbitals are computed using DFT theory's level of B3LYP/6‐31G(d,p). The FMO's energy gap values for 3 a–g were found to be 7.92, 3.48, 3.26, 3.33, 3.53, 4.03 and 3.75 eV, respectively. Especially at frequencies below 10 kHz, the most striking result was observed for the nanographene‐doped 3 d. While the AC conductivity of 3 d at 1 kHz was 3.87×10−9 S cm−1, the conductivity of the graphene‐doped 3 d was calculated as 5.00×10−6 S cm−1. In addition, DC conductivity measurements were completed as a function of temperature and linearly increasing graphs were obtained with temperature. The activation energies calculated from the slopes of these graphs were 0.293, 0.305, 0.364 and 0.920 eV for 3 c, 3 d, 3 e and 3 g, respectively.

Studies on the Nonalkaloidal Secondary Metabolites of Hippeastrum vittatum (L'Her.) Herb. Bulbs.

Sixteen chemically varied metabolites were isolated from the bulbs of Hippeastrum vittatum (L'Her.) Herb., including eight flavonoids [3'-methyl isoliquiritigenin (2), 7-hydroxyflavan (8), 7-hydroxyflavanone (9), 7-hydroxyflavan-3-ol (10), 7-methoxy-3',4'-methylenedioxyflavan-3-ol (11), 7-hydroxy-3',4'-methylenedioxy flavan (12), 2',4'-dihydroxy-3'-methyl-3,4-methylenedioxychalcone (13), and isoliquiritigenin (14)], four acetophenones [2,6-dimethoxy-4-hydroxyacetophenone (3), 2,4-dihydroxyacetophenone (4), 2,4-dihydroxy-6-methoxy-3-methylacetophenone (6), and 2,4,6-trimethoxyacetophenone (7)], two alkaloids [lycorine (1) and narciprimine (15)], one phenol derivative [p-nitrophenol (5)], and one steroid [β-sitosterol 3-O-β-glucopyranoside (16)]. Their structures were elucidated by combining one- and two-dimensional NMR and ESI-MS techniques and by comparison with the reported literature data and some authentic samples. Except for lycorine (1), the isolated metabolites were obtained herein for the first time from Hippeastrum plants, among which compound 13 was identified as a new chalcone derivative. Additionally, the total phenolic and flavonoid contents of the total ethanol extract and different fractions of the bulbs were determined by the Folin-Ciocalteu and aluminum chloride colorimetric methods, respectively, whereas their antioxidant potential was compared using the phosphomolybdenum and 2,2'-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assays. Finally, the binding affinities of compounds 1-16 to some key target proteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), namely, main protease (Mpro), papain-like protease (PLpro), and RNA-dependent RNA polymerase (RdRp), were screened and compared using molecular docking analysis. The possible chemotaxonomic significance of the identified metabolites was also discussed.

Substituent and solvent effects on UV‐visible absorption spectra of chalcones derivatives: Experimental and computational studies

The electronic spectra of the title compounds were measured in ethanol and cyclohexane. Three band systems are distinguished in the spectra of which the first and second band systems are attributed to local excitation of PhCH and PhCO rings. The third absorption band is assigned to a charge transfer (CT) band and is associated with the CO−CH=CH moiety. The solvent plays an important role in the absorption spectra and causes the CT band to consist of two electronic transitions. The effect of substituents on the phenyl rings on the charge transfer band of chalcone derivatives was also established in the two solvents.The converged gas-phase geometries of the studied chalcones was optimized using the DFT PBE0 functional with the basis set 6-311++G**. DFT calculations has been performed for an ethanol solution (using TD-PBE0/6-311++G**) level to understand electronic transitions on terms of energies and oscillator strengths to study the substituent effect on the electronic transitions of the chalcone derivatives. To consider the solvation effect of ethanol on the absorptions, the integral equation formalism variant of the polarizable continuum model (IEFPCM) was used. The calculated energies were in good agreement with experiment results.The molecular modelling technique was followed to monitor the effect of substitutions on the HOMO/LUMO energy and total dipole moment. Transitions between natural transition orbitals are also described as part of this study.

Cyclization of Chalcone Derivatives: Design, Synthesis, In Silico Docking Study, and Biological Evaluation of New Quinazolin-2,4-diones Incorporating Five-, Six-, and Seven-Membered Ring Moieties as Potent Antibacterial Inhibitors.

Four novel series of quinazolin-2,4-diones bearing five-, six-, and seven-membered heterocyclic moieties 2-14 (such as pyrazole, oxazole, pyrimidine, and azepines) through the 1,4-phenyl linkage were designed, synthesized, and evaluated in terms of their antibacterial activities. Analytical and spectral techniques (FT-IR, 1H NMR, 13C NMR, and Mass) were utilized for the structural elucidation of all of the synthesized compounds 2-14. Furthermore, the potential antibacterial activity of the thirteen compounds was further evaluated in vitro against two different Gram-negative G-ve bacterial strains (named Escherichia coli ATCC 25955, Pseudomonas aeruginosa ATCC 10145) and two Gram-positive G+ve bacterial strains (named Bacillus subtilis ATCC 6633 and Staphylococcus aureus NRRL B-767). Investigation of the antibacterial potential indicated that the newly synthesized compounds, especially 13, exhibited remarkable antibacterial activity against pathogens, comparable to the standard drug ciprofloxacin (a known potent antibacterial agent). Additionally, compounds 2-14 and ciprofloxacin were assessed in silico using molecular docking studies against the target thymidine phosphorylase enzyme (PDB ID: 4EAD). Moreover, the structure activity relationship (SAR) for these compounds was also described to give guidance about the effective molecules that could play an important role in identifying potential antibacterial agents. Finally, the drug-likeness and physicochemical parameters of the newly synthesized molecules 2-14 were in silico investigated. Among them, we found that the compound 3-[4-(6-phenyl-6,7-dihydro-5-oxa-9-aza-benzocyclohepten-8-yl)-phenyl]-1H-quinazolin-2,4-dione 13 with the highest binding affinity showed a strong fit to the active site of the tested enzyme, indicating 13 as a promising drug candidate for designing and developing novel classes of antibiotics.

Synthesis, characterization, molecular docking, in silico ADME study, and in vitro cytotoxicity evaluation of new pyridine derivatives of nabumetone.

New pyridine derivatives of nabumetone containing 2-amino 3-cyano moieties were synthesized and aimed to introduce new EGFR kinase inhibitors through two methods either by synthesis of chalcone derivatives initially (1a-d)
 followed by reacting it with malononitrile and ammonium acetate to form (2a-d) or from a one-pot synthesis of all reactants together to synthesis compounds (2a-e). Melting point, and FT-IR spectra were used to characterize all the synthesized compounds and were confirmed by 1H-NMR, and 13C-NMR spectroscopy. The final compounds (2a-e) were investigated in vitro against A549 (lung cancer cell line) and WRL68 (human normal cell line). compounds (2a, 2b, and 2e) produced marked cytotoxic activity with IC50 (24.62, 23.43, and 24.06 μg/ml) respectively, higher than what obtained from erlotinib with IC50 (25 μg/ml) as a reference drug. Measuring the selectivity index (SI) reveals that all the compounds have high selectivity especially compound (2a) being the most selective towards cancerous cells rather than normal cells with SI two folds higher than erlotinib. The molecular docking study reveals good binding to the EGFR kinase that has a good correlation to the MTT Assay results. In silico ADME study exposes that this synthesized series not only have interesting activity but also shows promised pharmacokinetic properties.

A sulfonamide chalcone AMPK activator ameliorates hyperglycemia and diabetic nephropathy in db/db mice

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus (DM), which currently lacks effective treatments. AMP-activated protein kinase (AMPK) stimulation by chalcones, a class of polyphenols abundantly found in plants, is proposed as a promising therapeutic approach for DM. This study aimed to identify novel chalcone derivatives with improved AMPK-stimulating activity in human podocytes and evaluate their mechanisms of action as well as in vivo efficacy in a mouse model of DN. Among 133 chalcone derivatives tested, the sulfonamide chalcone derivative IP-004 was identified as the most potent AMPK activator in human podocytes. Western blot analyses, intracellular calcium measurements and molecular docking simulation indicated that IP-004 activated AMPK by mechanisms involving direct binding at allosteric site of calcium-dependent protein kinase kinase β (CaMKKβ) without affecting intracellular calcium levels. Interestingly, eight weeks of intraperitoneal administration of IP-004 (20 mg/kg/day) significantly decreased fasting blood glucose level, activated AMPK in the livers, muscles and glomeruli, and ameliorated albuminuria in db/db type II diabetic mice. Collectively, this study identifies a novel chalcone derivative capable of activating AMPK in vitro and in vivo and exhibiting efficacy against hyperglycemia and DN in mice. Further development of AMPK activators based on chalcone derivatives may provide an effective treatment of DN.

Finding a Novel Chalcone-Cinnamic Acid Chimeric Compound with Antiproliferative Activity against MCF-7 Cell Line Using a Free-Wilson Type Approach.

In this work, we carried out the design and synthesis of new chimeric compounds from the natural cytotoxic chalcone 2',4'-dihydroxychalcone (2',4'-DHC, A) in combination with cinnamic acids. For this purpose, a descriptive and predictive quantitative structure-activity relationship (QSAR) model was developed to study the chimeric compounds' anti-cancer activities against human breast cancer MCF-7, relying on the presence or absence of structural motifs in the chalcone structure, like in a Free-Wilson approach. For this, we used 207 chalcone derivatives with a great variety of structural modifications over the α and β rings, such as halogens (F, Cl, and Br), heterocyclic rings (piperazine, piperidine, pyridine, etc.), and hydroxyl and methoxy groups. The multilinear equation was obtained by the genetic algorithm technique, using logIC50 as a dependent variable and molecular descriptors (constitutional, topological, functional group count, atom-centered fragments, and molecular properties) as independent variables, with acceptable statistical parameter values (R2 = 86.93, Q2LMO = 82.578, Q2BOOT = 80.436, and Q2EXT = 80.226), which supports the predictive ability of the model. Considering the aromatic and planar nature of the chalcone and cinnamic acid cores, a structural-specific QSAR model was developed by incorporating geometrical descriptors into the previous general QSAR model, again, with acceptable parameters (R2 = 85.554, Q2LMO = 80.534, Q2BOOT = 78.186, and Q2EXT = 79.41). Employing this new QSAR model over the natural parent chalcone 2',4'-DHC (A) and the chimeric compound 2'-hydroxy,4'-cinnamate chalcone (B), the predicted cytotoxic activity was achieved with values of 55.95 and 17.86 µM, respectively. Therefore, to corroborate the predicted cytotoxic activity compounds A and B were synthesized by two- and three-step reactions. The structures were confirmed by 1H and 13C NMR and ESI+MS analysis and further evaluated in vitro against HepG2, Hep3B (liver), A-549 (lung), MCF-7 (breast), and CasKi (cervical) human cancer cell lines. The results showed IC50 values of 11.89, 10.27, 56.75, 14.86, and 29.72 µM, respectively, for the chimeric cinnamate chalcone B. Finally, we employed B as a molecular scaffold for the generation of cinnamate candidates (C-K), which incorporated structural motifs that enhance the cytotoxic activity (pyridine ring, halogens, and methoxy groups) according to our QSAR model. ADME/tox in silico analysis showed that the synthesized compounds A and B, as well as the proposed chalcones C and G, are the best candidates with adequate drug-likeness properties. From all these results, we propose B (as a molecular scaffold) and our two QSAR models as reliable tools for the generation of anti-cancer compounds over the MCF-7 cell line.

Ethoxyphathalimide linked some 2, 4, 8-Triphenyl-4H-9-thia-1, 4a, 5, 7-tetraaza-fluoren-6-ylamine derivatives: Synthesis and Pharmacological Evaluation from Chalcone

Synthesis of benzalacetophenones (1a-c) has been achieved by the aldol condensation of substituted acetophenone with benzaldehyde. These were treated with thiourea by utilizing HCl to give substituted dihydropyrimidine-thiones (2a-c). Cyclization of these compounds with DMF and chloroacetic acid yielded pyrimidothiazolidinone moieties (3a-c). Reaction of benzaldehyde with 3a-c produced corresponding chalcone derivatives (4a-c). These chalcone derivatives when treated with guanidine nitrate in presence of a base gave (5a-c). Condensation of 5a-c with bromoethoxyphthalimide afforded titled compounds (6a-c). Structures of prepared scaffolds were established by the spectral studies, elemental analysis and chemical tests. Subsequently, heterocyclic hybrids (5a-c, 6a-c) were assayed to their in vitro anti-microbial activity against a variety of infectious strains of bacteria and fungi.

Therapeutic aspects of biologically potent vanillin derivatives: A critical review

4-hydroxy 3-methoxy benzaldehyde (Vanillin) is an aromatic phenolic aldehyde with unique chemical properties and pharmacological impact. Because of its potent nature, it acts as a lead for drug discovery and development techniques. Heterocyclic compounds with vanillin moiety were efficacious and thrive against many emerging infectious diseases, which can also lead to develop numerous fused heterocyclic vanillin derivatives and various heterocyclic compounds such as pyrimidines, quinoxalines, imidazoles or thiazoles. Greener-mediated synthesis is a sustained chemical reaction used to synthesize hazardless vanillin derivatives with a high yield of product in desired time. Due to its several reasonable modifications with high bioactivity, vanillin moiety can be used to develop various potent derivatives like vanillin-based ferrocenyl chalcone derivatives, vanillin-hydrazone derivatives, Schiff base and Mannich base-based derivatives, pyrazoline vanillin-based derivatives, triazole-based vanillin derivatives and vanillin hybrids plays a crucial role in the coordination chemistry. These derivatives exhibited plenty of biological applications, which include anticancer, antioxidant, antibacterial, antitubercular, antimalarial, antiviral, anti-inflammatory, anti-Alzheimer and anti-diabetic effects. Hence, this review focuses on the significance of vanillin derivatives responsible for biological activity.
 Keywords: Vanillin; 4-hydroxy 3-methoxy benzaldehyde; Vanillin derivatives; Antimicrobial; Anticancer; Biological applications