Synthesis,biological and computational studies of flavonoid acetamide derivatives

This study reports the synthesis and characterization of a novel class of flavonoid acetamide derivatives (FA) of quercetin, apigenin, fisetin, kaempferol, and luteolin. Flavonoids display numerous biological properties but are limited by aqueous insolubility, enzymatic degradation, instability, and low bioavailability. FAs were synthesized, with 80–82% yields, through the sequential modification of the flavonoid hydroxyl groups into the acetamide moieties. Bioavailability, antioxidant, and ADMET are structure–activity-dependent properties that vary across different classes of flavonoids and dictate the prevalent biological applications of the flavonoids. Thus, the FAs were evaluated for their bioavailability, antioxidant, and ADMET toxicity properties versus the unmodified flavonoids (UFs). In vitro bioavailability analysis shows that the UFs have bio-availabilities in the range of 10.78–19.29% against that of the FAs in the range of 20.70–34.87%. The antioxidant capacity was measured using the 2,2-diphenyl-1-picrylhydrazyl (DPPH·) assay with recorded IC₅₀ values of 2.19–13.03 μM for the UFs. Conversely, the FAs had high DPPH IC₅₀ values ranging from 33.83 to 67.10 μM and corresponding to lower antioxidant activity. The FAs showed favorable ADMET properties. The modification of flavonoids into FAs significantly improves the bioavailability and the ADMET toxicity properties, albeit with decreased antioxidant activity. This work highlights the effect of the global modification of the flavonoids with the acetamide groups on the bioavailability, antioxidant, and ADMET toxicity properties which are critical determinants in the biological applications of the flavonoids.

This study reports the synthesis and characterization of a novel class of flavonoid acetamide derivatives (FA) of quercetin, apigenin, fisetin, kaempferol, and luteolin.     

Synthesis,characterization, and theoretical studies of the photovoltaic properties of novel reactive azonitrobenzaldehyde derivatives

All dyes conduct but at different degrees of absorption; it is interesting to study the degree of conductivity and absorptivity of novel reactive azo-dyes in respect to dye-sensitized solar cells (DSSCs) to ascertain their viability for such applications. In this study, four novel reactive azo-dyes were experimentally synthesized from p-aminobenzaldehyde, 4-amino-3-nitrobenzaldehyde, and aniline through series of condensation and coupling reactions. The various functional groups, molecular connectivities, and molecular weight of the various fragments of the synthesized dyes were elucidated using the GC-MS, FT-IR, UV-vis, and NMR respectively. The experimentally determined structures were modeled and investigated using density functional theory (DFT) and time-dependent density functional theory (TD-DFT) approaches to computationally compute the electronic structure properties, reactivity, absorption and solvatochromism in four different phases: gas, ethanol, acetone, and water, and the photovoltaic properties for possible applications in dye-sensitized solar cells (DSSCs). By comparing the HOMO (E_H) and the LUMO (E_L) energies from the results obtained demonstrates that dye D has the highest E_L energy value of −2.48 eV with a relatively lowest E_H energy value of −5.63 eV such that it lies underneath the conduction band edge of TiO₂ which is necessary to enable charge regeneration. Pi-electron delocalization was observed from the natural bond orbital (NBO) calculations between the different aromatic rings with dye B and A having the relatively highest and least second-order stabilization energies between σ* → σ* and LP* → LP interacting orbitals respectively. It is also observed in all the solvents that the Gibbs free energy of injection (ΔG_inject) is greater than 0.2 eV and hence, all the studied azo structures in the four phases provided efficient electron injection and light harvesting efficiency (LHE), however, the value of ΔG_inject for dyes B and D is greatest in all the four phases and thus, provided the highest electron injection of all the dyes. From the fact-findings of quantum theory of atoms-in-molecules (QTAIM), dyes A and C have extra-stability due to their relatively high numbers of intramolecular H-bond interactions along with some additional intra-atomic bonding between atoms within the studied compounds. Hence, all the four dyes are good for DSSCs applications.

Four novel reactive azo-dyes were experimentally synthesized from p-aminobenzaldehyde, 4-amino-3-nitrobenzaldehyde, and aniline through series of condensation and coupling reactions, and their properties were assessed for possible application in dye-sensitized solar cells.     

Synthesis of an unusual quinazoline alkaloid: theoretical and experimental investigations of its structural,electronic, molecular and biological properties

An unusual quinazoline alkaloid (1) was obtained when 2-aminobenzaldehyde was refluxed with pyrrolidine in ethanol for 12 h. The synthesized compound was characterized using spectral data analysis augmented with X-ray and literature precedent. Single crystal analysis depicted four conformations differing slightly in bond angles and bond lengths. Compound 1 crystallizes in a triclinic crystal system with a P$\bar{1}$ space group having two molecules within the unit cell. The experimentally obtained parameters were compared to those obtained theoretically, which depicted a good agreement. Using the DFT/B3LYP/6-31G (d,p) level of theory, HOMO–LUMO energy gap, molecular electrostatic potential (MEP), vibrational (IR) and NMR analyses were carried out. The HOMO–LUMO energy gap allowed the calculation of chemical hardness, chemical inertness, electronegativity and the electrophilicity index of the molecule, which depicted its potential kinetic stability and reactivity. Prediction of activity spectra of the target compound revealed that compound 1 possesses notable antineoplastic activity with P_a = 0.884. The molecule was therefore evaluated against various cancerous cell lines in an in vitro SRB assay which depicted that compound 1 possesses the highest growth inhibition activity against THP-1 cell lines with an IC₅₀ of 7 μM.

A comparative overview of theoretical and experimental studies concerning the electronic, structural and biological domains of the synthesized unusual quinazoline alkaloid is presented.     

Unorthodox synthesis,biological activity and DFT studies of novel and multifunctionalized naphthoxocine derivatives

A new promising protocol has been developed for the synthesis of scarce oxocine derivatives 3a–e and 6 through addition of amine-based nucleophiles such as hydroxylamine hydrochloride, primary amine and hydrazide to chromonylidene benzothiazol-2-ylacetonitrile 2 in refluxing dioxane under metal free reaction conditions in moderate to good yields. Other nitrogen nucleophiles such as piperidine, hydrazine and thiosemicarbazide failed to afford the corresponding oxocinols, and instead pyridine derivatives 7, 8 and 10 were obtained exclusively. Predictive study for the biological activities using PASS (prediction of activity spectra for biologically active substances) online software showed optimistic activities for oxocinols 3a–e in the treatment of cancer, influenza A and microbial infections. Additionally, DFT studies of oxocine derivatives 3a–e and 6 indicated the presence of required thermodynamics parameters for the application in dye-sensitized solar cells (DSSCs).

A new promising protocol has been developed for the synthesis of scarce oxocine derivatives through addition of amine-based nucleophiles to chromonylidene benzothiazol-2-ylacetonitrile under metal free reaction conditions in moderate to good yields.     

Synthesis and biological evaluation of indazole derivatives as anti-cancer agents

Several FDA approved small molecule anti-cancer drugs contain indazole scaffolds. Here, we report the design, synthesis and biological evaluation of a series of indazole derivatives. In vitro antiproliferative activity screening showed that compound 2f had potent growth inhibitory activity against several cancer cell lines (IC₅₀ = 0.23–1.15 μM). Treatment of the breast cancer cell line 4T1 with 2f inhibited cell proliferation and colony formation. 2f dose-dependently promoted the apoptosis of 4T1 cells, which was connected with the upregulation of cleaved caspase-3 and Bax, and downregulation of Bcl-2. 2f also decreased the mitochondrial membrane potential and increased the levels of reactive oxygen species (ROS) in 4T1 cells. Additionally, treatment with 2f disrupted 4T1 cells migration and invasion, and the reduction of matrix metalloproteinase metalloproteinase-9 (MMP9) and increase of tissue inhibitor matrix metalloproteinase 2 (TIMP2) were also observed. Moreover, 2f could suppress the growth of the 4T1 tumor model without obvious side effects in vivo. Taken together, these results identified 2f as a potential small molecule anti-cancer agent.

One of the synthesized indazole derivatives, 2f, displayed inhibitory activities against proliferation, migration and invasion of breast cancer cell line 4T1, with the potential of inducing cell apoptosis, and suppressing tumor growth in vivo.     

Investigation of some benzoquinazoline and quinazoline derivatives as novel inhibitors of HCV-NS3/4A protease: biological,molecular docking and QSAR studies

Morbidity and mortality due to hepatitis C virus (HCV) is a globe health concern. Hence, there is a persistent demand to design and optimize current HCV therapy and develop novel agents. HCV NS3/A4 protease plays an essential role in HCV life cycle and replication. Thus, HCV NS3/A4 protease inhibitors are one of the best therapeutic targets for the identification of novel candidate drugs. Recent studies have shown some benzoquinazolines as potent antiviral agents and promising HAV-3C protease inhibitors. In the present study, a series of benzo[g]quinazolines (1–13) and their quinazoline analogues (14–17) were evaluated for their HCV-NS3/4A inhibitory activities using in vitro assay. Our results revealed that the target compounds inhibited the activity of the NS3/4A enzyme, (IC₅₀ = 6.41 ± 0.12 to 78.80 ± 1.70 μM) in comparison to telaprevir (IC₅₀ = 1.72 ± 0.03 μM) as a reference drug. Compounds 1, 2, 3, 9, 10 and 13 showed the highest activity (IC₅₀ = 11.02 ± 0.25, 6.41 ± 0.12, 9.35 ± 0.19, 9.08 ± 0.20, 16.03 ± 0.34 and 7.21 ± 0.15 μM, respectively). Molecular docking was performed to study the binding modes of the docked-chosen benzo[g]quinazolines, hydrogen bonding, and amino acid residues at the catalytic triad of the NS3/4A enzyme of HCV. The QSAR was determined to explore the relationships between the molecular structures of the targets and their biological activities by developing prediction models among the known HCV NS3/A4 inhibitors and then to predict the inhibitory activity of the target molecules synthesized.

HCV NS3/A4 protease inhibitors are one of the best therapeutic targets for the identification of novel candidate drugs. A series of benzo[g]quinazolines and their quinazoline analogues were evaluated for their HCV-NS3/4A inhibitory activities.     

Novel quercetin and apigenin-acetamide derivatives: design,synthesis, characterization,biological evaluation and molecular docking studies

Flavonoids exhibit essential but limited biological properties which can be enhanced through chemical modifications. In this study, we designed, synthesized, and characterized two novel flavonoid derivatives, quercetin penta-acetamide (1S3) and apigenin tri-acetamide (2S3). These compounds were confirmed using (¹H, ¹³C) NMR, UV-Vis, and FT-IR characterizations. Their interaction with fish sperm DNA (FS-DNA) at physiological pH was investigated by UV-Vis and fluorescence spectrophotometry. The binding constant (K_b) for the UV-Vis experiment was found to be 1.43 ± 0.3 × 10⁴ M⁻¹ for 1S3 and 2.08 ± 0.2 × 10⁴ M⁻¹ for 2S3. The binding constants (K_SV) for the fluorescence quenching experiment were 1.83 × 10⁴ M⁻¹ and 1.96 × 10⁴ M⁻¹ for 1S3 and 2S3, respectively. Based on molecular modeling and docking studies, the binding affinities were found to be −7.9 and −9.1 kcal mol⁻¹, for 1S3 and 2S3, respectively. The compound–DNA docked model correlated with our experimental results, and they are groove binders. Furthermore, mutagenicity potential was examined. 1S3 and its metabolites showed no mutagenic activity for both TA98 and TA100 strains. 2S3 did not show any mutagenic activity for the strain TA 98, while its metabolites were only active at high doses. Both 2S3 and its metabolites showed mutagenic activity in the TA100 strain.

The interaction of new molecules obtained by the design and synthesis of flavonoid derivatives by molecular docking with DNA.     

Synthesis and properties of porous polymers synthesized by Michael addition reactions of multi-functional acrylate,diamine, and dithiol compounds

Porous polymers have been synthesized by Michael addition reactions of multi-functional acrylate and diamine or dithiol compounds. Aza-Michael addition reaction of multi-functional acrylate, trimethylolpropane propoxylate triacrylate (TPT) and hexamethylene diamine (HDA) in dimethyl sulfoxide (DMSO) successfully yielded the porous polymer. The porous structure was characterized by connected globules or co-continuous structure, and could be controlled by the reaction conditions. Mechanical properties of the porous polymers were investigated by compression test. The porous polymers with co-continuous structure showed higher Young''s modulus than those with connected globules. The porous polymer absorbed some organic solvents, especially CHCl₃. The porous polymer as prepared in DMSO state showed coloring induced by Christiansen filter effect depending on the reaction time and observation temperature. The thio-Michael addition reaction of TPT and 1,6-hexanedithiol (HDT) in DMSO using different base catalysts also yielded the porous polymer. The porous structure could be controlled by the catalysts amount when the reaction was initiated by a photo-base generator as the base catalyst. The present reaction systems make it possible to synthesize the porous polymers with simple process without phase separator.

Porous polymers have been synthesized by Michael addition reactions of multi-functional acrylate and diamine or dithiol compounds.     

Synthesis and biological activity,and molecular modelling studies of potent cytotoxic podophyllotoxin-naphthoquinone compounds

A new approach for the synthesis of podophyllotoxin-naphthoquinone compounds using microwave-assisted three-component reactions is reported in this study. Novel podophyllotoxin-naphthoquinone derivatives with modification on ring E were synthesized. All the synthetic compounds were assessed in terms of their cytotoxicity profile against four cancer cell lines (KB, HepG2, A549, and MCF7), and noncancerous Hek-293 cell lines. Notably, treatment of SK-LU-1 cells with compounds 5a and 5b resulted in G2/M phase arrest of the cell cycle, caspase-3/7 activation, and apoptosis. Additionally, molecular docking studies were performed and showed important interaction of two compounds against residues in the colchicine-binding-site of tubulin as well. Taken together, compounds 5a and 5b were identified as potent anticancer agents.

A new approach for the synthesis of podophyllotoxin-naphthoquinone compounds using microwave-assisted three-component reactions is reported in this study.     

Synthesis of histidine kinase inhibitors and their biological properties

Infections caused by multidrug-resistant bacteria represent a significant and ever-increasing cause of morbidity and mortality. There is thus an urgent need to develop efficient and well-tolerated antibacterials targeting unique cellular processes. Numerous studies have led to the identification of new biological targets to fight bacterial resistance. Two-component signal transduction systems are widely employed by bacteria to translate external and cellular signals into a cellular response. They are ubiquitous in bacteria, absent in the animal kingdom and are integrated into various virulence pathways. Several chemical series, including isothiazolidones, imidazolium salts, benzoxazines, salicylanilides, thiophenes, thiazolidiones, benzimidazoles, and other derivatives deduced by different approaches have been reported in the literature to have histidine kinase (HK) inhibitory activity. In this review, we report on the design and the synthesis of these HKs inhibitors and their potential to serve as antibacterial agents.     

New carvacrol and thymol derivatives as potential insecticides: synthesis,biological activity,computational studies and nanoencapsulation

New compounds with potential insecticide activity were synthesized by structural modifications performed in the monoterpenoid phenolic moieties of carvacrol and thymol, resulting in a set of derivatives with the ether function containing the propyl, chloropropyl or hydroxypropyl chains, as well as a bicyclic ether with an unsaturated chain containing a carboxylic acid terminal. In addition, an analogue of carvacrol and thymol isomers bearing methoxyl, 1-hydroxyethyl and (3-chlorobenzoyl)oxy, instead of the three original methyl groups, was also synthesized. Several structural changes that resulted in diminished insecticide activity have been identified, but two significantly active molecules have been synthesized, one of them being less toxic to human cells than the naturally-derived starting materials. Structure-based inverted virtual screening and molecular dynamics simulations demonstrate that these active molecules likely target the insect odorant binding proteins and/or acetylcholinesterase and are able to form stable complexes. For the most promising compounds, nanoencapsulation assays were carried out in liposomes of egg phosphatidylcholine/cholesterol (7 : 3) prepared by both thin film hydration and ethanolic injection methods. The compound-loaded liposomes were generally monodisperse and with sizes smaller than or around 200 nm. The thin film hydration method allowed high encapsulation efficiencies (above 85%) for both compounds and a delayed release, while for the systems prepared by ethanolic injection the encapsulation efficiency is lower than 50%, but the release is almost complete in two days.

Thymol and carvacrol derivatives were synthesised. Two of them proved to be mildly active against Sf9 insect cell line and one has presented selectivity by proving to be less toxic to human cells than the naturally derived starting materials.     

Synthesis and biological activities of 4"-deoxy-4"-sulfonamido-oleandomycin derivatives

Chemical modification of the macrolide antibiotic oleandomycin (C-1) is described. Reductive amination of 11-acetyl-4"-deoxy-4"-oxo-oleandomycin (C-6) with ammonium acetate provides amino-oleandomycin derivative C-7 in which the 4"-amine is oriented in the axial configuration. The structure-activity relationship of a series of 4"-sulfonamide analogs prepared from amino-oleandomycin derivative C-7 is discussed. Noteworthy is the significant in vitro potency enhancement of the para-chlorobenzenesulfonamide analog C-12 over that of the parent oleandomycin. The absolute configuration of the 4"-amino-oleandomycin derivative C-7 was established through X-ray analysis of the para-iodobenzenesulfonamide analog C-14.     

Synthetic- and DFT modelling studies on regioselective modified Mannich reactions of hydroxy-KYNA derivatives

The syntheses of hydroxy-substituted kynurenic acid (KYNA) derivatives have been achieved by an optimised Conrad–Limpach procedure. The derivatives were then reacted with morpholine and paraformaldehyde, as a representative amine and aldehyde, in a modified Mannich reaction. The newly introduced substituents altered the preferred reaction centre of the KYNA skeleton. A systematic investigation of substitutions was carried out, using different reaction conditions, resulting in mono- or disubstituted derivatives. Product selectivity and regioselectivity were rationalised by DFT calculations disclosing HOMO distribution and NBO charges on the potential nucleophilic centres in the anion of the appropriate KYNA ester assumed to be active components towards the iminium ion intermediate.

New side of KYNA in modified Mannich reaction – systematic investigation of the reactivity of hydroxylated derivatives rationalised with comparative DFT calculations.     

Synthesis and biological evaluation of 2,2-dimethylbenzopyran derivatives as potent neuroprotection agents

The development of novel neuroprotection agents is of great significance for the treatment of ischemic stroke. In this study, a series of compounds comprising 2,2-dimethylbenzopyran groups and cinnamic acid groups have been synthesized. Preferential combination principles and bioisostere that improved the neuroprotective effect of the compounds were identified for this series via biological activity assay in vitro. Meanwhile, a functional reversal group of the acrylamide amide resulted in the most active compounds. Among them, BN-07 significantly improved the morphology of neurons and obviously increased cell survival rate of primary neurons induced by oxygen glucose deprivation (OGD), superior to clinically used anti-ischemic stroke drug edaravone (Eda). Overall, our findings may provide an alternative strategy for the design of novel anti-ischemic stroke agents with more potency than Eda.

Novel compounds comprising 2,2-dimethylbenzopyran and cinnamic acid were synthesized. BN-07 significantly increased survival rate of primary neurons, superior to edaravone.     

Synthesis and biological activities of novel trifluoromethylpyridine amide derivatives containing sulfur moieties

A series of trifluoromethylpyridine amide derivatives containing sulfur moieties (thioether, sulfone and sulfoxide) was designed and synthesized. Their antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo), Ralstonia solanacearum (R. solanacearum) and insecticidal activities against P. xylostella were evaluated. Notably, the half-maximal effective concentration (EC₅₀) value of sulfone-containing compound F10 is 83 mg L⁻¹ against Xoo, which is better than that of commercial thiodiazole copper (97 mg L⁻¹) and bismerthiazol (112 mg L⁻¹). Thioether-containing compounds E1, E3, E5, E6, E10, E11 and E13 showed much higher activities against R. solanacearum with the EC₅₀ value from 40 to 78 mg L⁻¹, which are much lower than that of thiodiazole copper (87 mg L⁻¹) and bismerthiazol (124 mg L⁻¹). Generally, most of the sulfone-containing compounds and sulfoxide-containing compounds showed higher activities against Xoo than that of the corresponding thioether-containing compound, but most of the thioether-containing compounds contributed higher antibacterial activities against R. solanacearum. Furthermore, title compounds E3, E11, E24 and G2 showed good insecticidal activities of 75%, 70%, 70% and 75%, respectively.

Novel trifluoromethylpyridine amide derivatives containing sulfur moieties were synthesized, which exhibited good antibacterial and insecticidal activities for potential crop protection agents.     

Synthesis and biological evaluation of novel sinomenine derivatives as anti-inflammatory and analgesic agent

Sinomenine (SIN) has long been known as an anti-inflammatory drug, while poor efficiency and large-dose treatment had limited its further application. A series of novel SIN derivatives 1–26 were designed and synthesized to improve its anti-inflammatory activity. The anti-inflammatory activity evaluation showed most of the derivatives exhibited enhanced anti-inflammatory activity in vitro compared to SIN. Compound 17 significantly inhibited LPS-induced secretion of pro-inflammatory factors NO (IC₅₀ = 30.28 ± 1.70 μM), and suppressed the expression of iNOS, IL-6 and TNF-α in RAW264.7 cells. Moreover, compound 17 showed excellent anti-inflammatory in mouse paw edema. Immunohistochemistry results revealed that compound 17 exerted anti-inflammatory activity by inhibiting the pro-inflammatory cytokine TNF-α. Furthermore, compound 17 exhibited an analgesic effect in vivo. The results attained in this study indicated that compound 17 had the potential to be developed into an anti-inflammation and analgesic agent.

A series of novel sinomenine derivatives were designed and synthesized. Among them, compound 17 showed strong anti-inflammatory and analgesic activities.