Synthesis,characterization, anticancer activity,and molecular docking of some new sugar hydrazone and arylidene derivatives

New sugar hydrazone moieties, their oxadiazoline derivatives, and arylidene analogues were prepared and chemically elucidated using spectroscopic analysis, such as nuclear magnetic resonance, for hydrogen ¹HNMR, carbon ¹³CNMR, elemental analysis, and Infrared (IR). The prepared compounds were purified and tested against breast cancer cells (MCF-7). Compounds 4c, 4d, 6b, and 6d exhibited moderate to very high anti-breast cancer activity, with a percentage of inhibition of 96.19%, 93.08%, 74.33%, and 86.05% respectively; the reference 5-fluorouracil had an inhibitory percentage of 96.02%.     

Design,synthesis, and biological evaluation of diarylpyrazole derivatives as antitumor agents targeting microtubules

A new series of novel diarylpyrazole derivatives as microtubule destabilizers were synthesized and evaluated for the anti-proliferative activities. Anti-proliferative assays were performed on the human cervix adenocarcinoma cell line (HeLa) and human gastric adenocarcinoma cell line (SGC-7901), and the compound 9s containing indole ring showed great anti-proliferative activity against HeLa cells with IC₅₀ value of 1.9 ± 0.11 μM. Further biological studies showed that 9s was able to inhibit tubulin polymerization, disrupt the cytoskeleton, block the cell cycle in the G2/M phase, and induce cell apoptosis in a concentration-dependent manner. In addition, the results of molecular docking studies showed that compound 9s could bind tightly to the colchicine binding site of tubulin through hydrogen bonding interaction. These preliminary results recommend that compound 9s is likely to be a microtubule destabilizer that deserves further investigation.     

Design,synthesis and anti-diabetic activity of chromen-2-one derivatives

DPP-IV inhibitors have been immersed as promising pathway to treat Type 2 diabetes. Here we have reported designing of coumarin derivatives as DPP-IV inhibitors. Designed compounds have been studied for their binding with DPP-IV enzyme through molecular docking followed by synthesis. All synthesized compounds have been fully characterized and screened for DPP-IV inhibition activity. Two compounds showed very good inhibition at 10 μM concentration.     

Design,synthesis, antitubercular and antibacterial activities of pyrrolo[3,2-b]pyridine-3-carboxamide linked 2-methoxypyridine derivatives and in silico docking studies

Abstract

A novel series pyrrolo[3,2-b]pyridine-3-carboxamide linked 2-methoxypyridine derivatives have been designed, synthesized and confirmed by FT-IR, ¹H NMR, ¹³C NMR, ¹⁹F NMR, MS, and elemental analysis. The synthesized compounds were screened for their antitubercular activity using microplate alamar blue assay method and antibacterial activity. Among the tested compounds, 4- fluorophenyl (8m), 4- chlorophenyl (8n) and 4-methoxyphenyl (8i) showed potent anti-TB activity (3.12?µg/mL) in comparison with reference drug, Pyrazinamide ((3.12?µg/mL). In addition, all compounds were docked into DprE1 (PDB code: 4KW5) to explore their binding interactions at the active site. The compounds exhibited essential key interactions as that of reported DprE1 inhibitors and hence, the synthesized compounds may be considered as molecular scaffolds for antitubercular activity. Compounds, 4-chlorophenyl (8n) and 4-flurophenyl (8m) showed significant antibacterial activity against Escherichia coli and Staphylococcus aureus strains. In silico prediction of toxicities, druglikeness and drug score profiles of the tested compounds are promising.     

New triazole derivatives containing substituted 1, 2, 3-triazole side chains: Design,synthesis and antifungal activity

In order to discover new generation of triazole antifungal agents,a series of novel antifungal triazoles were designed and synthesized by structural simplification of our previously identified triazole-piperdine-heterocycle lead compounds.Several target compounds showed good antifungal activity with a broad spectrum.In particular,compound 7l was highly active against Candida albicans and Candida glabrata.Moreover,compound 7l showed potent in vivo antifungal efficacy in the Caenorhabditis elegans-C.albicans infection model.     

Design,synthesis and in silico study of pyridine based 1,3,4-oxadiazole embedded hydrazinecarbothioamide derivatives as potent anti-tubercular agent

Development of novel, safe and effective drug candidates combating the emerging drug resistance has remained a major focus in the mainstream of anti-tuberculosis research. Here, we inspired to design and synthesize series of new pyridin-4-yl-1,3,4-oxadiazol-2-yl-thio-ethylidene-hydrazinecarbothioamide derivatives as potential anti-tubercular agents. The anti-tubercular bioactive assay demonstrated that the synthesized compounds exhibit potent anti-tubercular activity (MIC = 3.9–7.81 μg/mL) in comparison with reference drugs Rifampicin and Isoniazid.We employed pharmacophore probing approach for the identification of CYP51 as a possible drug target for the synthesized compounds. To understand the preferable binding mode, the synthesized molecules were docked onto the active site of Sterol 14 α-demethylases (CYP51) target. From the binding free energy of the docking results it was revealed that the compounds were effective CYP51 inhibitors and acts as antitubercular agent.     

The design of fluoroquinolone-based cholinesterase inhibitors: Synthesis,biological evaluation and in silico docking studies

An enhanced acetylcholinesterase (AChE) activity is a hallmark in early stages of Alzheimer's ailment that results in decreased acetylcholine (ACh) levels, which in turn leads to cholinergic dysfunction and neurodegeneration. Consequently, inhibition of both AChE and butyrylcholinesterase (BChE) is important to prolong ACh activity in synapses for the enhanced cholinergic neurotransmission. In this study, a series of new fluoroquinolone derivatives (7a-m) have synthesized and evaluated for AChE and BChE inhibitory activities. The screening results suggested that 7 g bearing ortho fluorophenyl was the most active inhibitor against both AChE and BChE, exhibiting IC₅₀ values of 0.70 ± 0.10 µM and 2.20 ± 0.10 µM, respectively. The structure–activity relationship (SAR) revealed that compounds containing electronegative functions (F, Cl, OMe, N and O) at the ortho position of the phenyl group exhibited higher activities as compared to their meta- and/or para substituted counterparts. Molecular docking studies of synthesized compounds 7a, 7g, 7j and 7l docked into the active site of AChE and 7a-f docked into the active site of BChE revealed that these compounds exhibited conventional H-bonding along with π-π interaction with the active residues of AChE through their electronegative functions and phenyl ring, respectively. All the synthesized compounds are characterized by spectroscopic methods including FT-IR, ¹H- and ¹³C NMR as well as elemental analysis. This is the first example of fluoroquinolone-based cholinesterase inhibitors.     

1,2,3-Triazole tethered acetophenones: Synthesis,bioevaluation and molecular docking study

A small focused library of eighteen new 1,2,3-triazole tethered acetophenones has been efficiently prepared via click chemistry approach and evaluated for their antifungal and antioxidant activity. The antifungal activity was evaluated against five human pathogenic fungal strains: Candida albicans, Fusarium oxysporum, Aspergillus flavus, Aspergillus niger, and Cryptococcus neoformans. Among the synthesized compounds, 9c, 9i, and 9p found to be more potent antifungal agents that the reference standard. These 1,2,3-triazole based derivatives were also evaluated for antioxidant activity, and compound 9h was found to be the most potent antioxidant as compared to the standard drug. Furthermore, molecular docking study of the newly synthesized compounds was performed and results showed good binding mode in the active site of fungal C. albicans enzyme P450 cytochrome lanosterol 14a-demethylase. Moreover, the synthesized compounds were also analyzed for ADME properties and showed potential as good oral drug candidates.     

Design,cytotoxic effects on breast cancer cell line (MDA-MB 231), and molecular docking of some maleimide-benzenesulfonamide derivatives

A group of novel maleimide-benzenesulfonamide derivatives 3a-d was designed and synthesized for their evaluation as a potential anti-breast cancer agent. The structures of these derivatives were confirmed by their ¹H, ¹³C NMR, Mass, FT-IR spectral data, and melting points. The cytotoxic activity (in vitro) of the selected molecules against MDA-MB231 ​cell line was evaluated by MTT method. Among them, compounds 3a and 3d exhibited a significant cytotoxicity with the IC₅₀ value of 1.61 and 1.26 ​μM, respectively, whereas compounds 3b and 3c showed a moderate cytotoxicity with IC₅₀ values of 0.45 and 1.12 ​μM, respectively against MDA-MB231 ​cells. Docking modeling of the synthesized compounds 3a-d into binding sites of human aromatase protein (PDB ID: 4GL7) was performed to investigate if these derivatives possess analogous binding mode to breast cancer proteins. Docking results showed these compounds have efficient interactions such as hydrogen bonding, Van der Waals interactions, and hydrophobic interactions with the active site residues of the aromatase protein (PDB ID: 4GL7). The low binding energies and a number of hydrogen bonding indicated that the maleimide-benzenesulfonamide derivatives might be considered as a promising anti-breast cancer agent with further developments in drug discovery.     

Influence of the particle size on the antibacterial activity of green synthesized zinc oxide nanoparticles using Dysphania ambrosioides extract,supported by molecular docking analysis

Bacteria-associated infections have increased in recent years due to treatment resistance developed by these microorganisms. Due to the high antibacterial capacity associated with their nanometric size, nanoparticles, such as zinc oxide (ZnO), have proven to be an alternative for general medical procedures. One of the methodologies to synthesize them is green synthesis, where the most commonly used resources are plant species. Using Dysphania ambrosioides extract at various synthesis temperatures (200, 400, 600, and 800 °C), zinc oxide nanoparticles (ZnO-NPs) with average sizes ranging from 7 to 130 nm, quasi-spherical shapes, and hexagonal prism shapes were synthesized. Larger sizes were obtained by increasing the synthesis temperature. The ZnO crystalline phase was confirmed by X-ray diffraction and transmission electron microscopy. The sizes and shapes were observed by field emission scanning electron microscopy. The Zn-O bond vibration was identified by Fourier transform infrared spectroscopy. Thermogravimetry showed the stability of ZnO-NPs. The antibacterial evaluations, disk diffusion test, and minimum bactericidal concentration, demonstrated the influence of particle size. The smaller the nanoparticle size, the higher the inhibition for all pathogenic strains: Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, and dental pathogens: Streptococcus mutans, Streptococcus sanguinis, Porphyromonas gingivalis, and Prevotella intermedia. The molecular docking study showed a favorable interaction between ZnO-NPs and some proteins in Gram-positive and Gram-negative bacteria, such as TagF in Staphylococcus epidermidis and AcrAB-TolC in Escherichia coli, which led to proposing them as possible targets of nanoparticles.     

Novel family of fused tricyclic [1,4]diazepines: Design,synthesis, crystal structures and molecular docking studies

An efficient one-pot strategy for the synthesis of a new family of imidazo[1,4]diazepines has been developed and its mechanism has been proposed, which follows a seven-membered ring closure reaction. The condensation of 2- and 4-imidazolecarboxaldehyde with pyrazole amines provides six compounds 1–6, which are based on two types of fused tricyclic scaffolds. All presented compounds were fully spectroscopically characterized and their structure was unambiguously determined by single crystal X-ray crystallography. Molecular docking studies reveal a high similarity between binding modes of diazepines 1, 6 and eticlopride in the dopamine D₃ receptor, as well as between enantiomers 2S, 6S and nortriptyline in dopamine transporter DAT.     

Novel imidazole derivatives as antifungal agents: Synthesis,biological evaluation,ADME prediction and molecular docking studies

Abstract

A series of 2-(substituteddithiocarbamoyl)-N-[4-((1H-imidazol-1-yl)methyl)phenyl]acetamide derivatives was designed and synthesized to combat the increasing incidence of drug-resistant fungal infections. All synthesized compounds were characterized by IR, ¹H-NMR, ¹³C-NMR, and HRMS spectra and elemental analyses. Antifungal activity tests were performed against four different fungal strains. Molecular docking studies were performed to investigate the mode of action towards the fungal lanosterol 14α-demethylase, a cytochrome P450-dependent enzyme. ADME studies were carried out and a connection between activities and physicochemical properties of the target compounds was determined. Most of the final compounds exhibited significant activity against Candida albicans and Candida krusei with MIC₅₀ value 12.5?μg/mL. The results of in vitro anti-Candida activity, a docking study and ADME prediction revealed that the newly synthesized compounds have potential anti-Candida activity and evidenced the most active derivative, 5b (2-Pyrrolidinthiocarbonylthio-N-[4-((1H-imidazol-1-yl)methyl)phenyl]acetamide), which can be further optimized as a lead compound.     

The novel 4-hydroxyphenylpyruvate dioxygenase inhibitors in vivo and in silico approach: 3D-QSAR analysis,molecular docking,bioassay and molecular dynamics

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is not only an important target enzyme for the treatment of type I tyrosinemia, but also a new target for design bleaching herbicides, and it plays key role in the biosynthesis of tocopherol and plastoquinone. Thirty-six known active pyridine derivatives were collected, and comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models based on common skeleton were constructed to obtain novel HPPD herbicides with higher activity. Two new HPPD inhibitors were rationally designed and synthesized according to the CoMFA and CoMSIA models and verified by enzyme activity, biological assays, and molecular docking. The promising compound W1 ((E)-5-(3-(4-bromophenyl)acryloyl)-6-hydroxy-2,3-dihydropyridin-4(1H)-one) showed better AtHPPD inhibitory activity, and the bioassay results revealed that some weeds showed bleaching symptoms. The good binding stability of W1 and protein was confirmed by molecular dynamics simulation in 100 ns. These results would be highly useful in the progress of new HPPD inhibitors discovery.     

1,2,3-triazole derivative: Synthesis,characterization, DFT,molecular docking study and antibacterial-antileishmanial activities

In this study, 4-((1-(4-chlorobenzyl)-1H-1,2,3-triazole-4-yl)methoxy)-3-methoxybenzaldehyde (I) was synthesized and molecular structure of compound I was confirmed by FTIR and NMR (¹H and ¹³C NMR) spectroscopic methods. The geometric structure of compound I was optimized by DFT/B3LYP method using 6–311++G(d, p) basis set. The molecular docking study was carried out against six different proteins. The antibacterial and antileishmanial activities of compound I were tested by microdilution broth with Alamar blue method and minimum inhibitor concentrations (MIC) were determined. According to the test results, it was found to be effective against eleven types of bacteria at different concentrations (MIC: 312–5000 ​μg/mL). In addition, compound I was not effective against leishmania species at the concentrations that were examined.     

Development of nanoformulation for hyperpigmentation disorders: Experimental evaluations,in vitro efficacy and in silico molecular docking studies

Hyperpigmentation is a crucial dermatological disorder. This study aims to formulate a nanoemulsion formulation containing chlorogenic acid (CA) for hyperpigmentation treatment, to carry out characterization studies, and to investigate its efficacy and safety in vitro and in silico analysis.In line with this purpose, CA nanoemulsions (CA-NEs) were developed using the ultrasonic homogenization method. Accelerated stability tests were performed to examine the kinetic and thermodynamic stability of the CA-NEs to ascertain the presence of any stability issues. After the heating–cooling test, appropriate CA-NEs were stored for 60 days in three different stability environments to examine the physicochemical stability and determine the finalized formulation. The toxicity of the finalized CA-NE formulation was evaluated by genotoxicity/mutagenicity and cytotoxicity tests. The tyrosinase and melanogenesis activities of the finalized CA-NE formulation were determined on the Melanoma B16F0 cell line. Finally, the molecular docking method was used to reveal interactions of CA that play an essential role in tyrosinase inhibition. Additionally, the mushroom and human tyrosinase enzymes were used to determine the activity of CA. In addition, the comparison study with the molecular docking method was carried out using kojic acid as a reference molecule.In conclusion, the molecular docking study, pharmacokinetic analyses, and in vitro studies showed that F4P1 coded CA-NE formulation might hold promise as an innovative formulation in cosmetic applications such as skin-lightening effects with its high efficacy and safety profile.     

Bioactive Fluorenes. Part II. Unprecedented biologically active thiazole derivatives based-2,7-dichlorofluorene as competent DHFR inhibitors: Design,synthesis, and molecular docking approaches

In this study, a new series of (4-(2,7-dichloro-9H-fluoren-4-yl)thiazol-yl)acetamide derivatives was synthesized, and the new heterocycles were completely characterized, evaluated for their antimicrobial activity, and screened for cytotoxic activity against human lung carcinoma (A-549) and human breast carcinoma (MCF-7) cell lines. A molecular docking study was undertaken to identify the possible mode of action of the synthesized compounds, which suggested binding interactions with the dihydrofolate reductase (DHFR) active sites.Most of the synthesized compounds displayed meaningful activity against A-549 and MCF-7 cell lines when compared to 5-fluorouracil (5-FU), which was used as a reference drug. Furthermore, some of the prepared compounds exhibited potent antibacterial and antifungal activities. The highly pronounced biological activities of the compounds under investigation offer such species as promising future drug prospects which may find applications in the fields of biological and medicinal sciences.     

Synthesis and antimicrobial bioassays of 1,3,4-thiadiazole sulfone derivatives containing amide moiety: A study based on molecular dynamics (MD) simulations,MM/GBSA,and molecular docking

The backbone structure (1,3,4-thiadiazole sulfone derivatives containing amide moiety) of target compounds was determined by modification and optimization of the theoretical design based on commercial chemical carboxin, including molecular docking, scaffold hopping, ligand expansion, etc.In this paper, 23 target compounds were synthesized by the combination of theoretical design and chemical synthesis, and characterized by ¹H NMR, ¹³C NMR and HR MS. Addtionally, the antibacterical bioassay showed that most target compounds performed excellent inhibition on Xanthomonas axonopodis pv. citri (Xac) and Xanthomonas oryzae pv. oryzae (Xoo) in vitro. Meanwhile, molecular docking, molecular dynamics (MD) simulations, and studies on ligand/protein (carboxin/2FBW and 4n/2FBW) complex systems were displayed, and the interaction patterns of ligand/protein complex system were predicted by molecular docking. Besides, the ligand/protein complex system was subject to MD simulation. The analysis of molecular dynamics such as RMSD values suggested that compound/2FBW complexes were stable. MM/GBSA (Molecular mechanics generalized born surface area) dynamic binding affinity results revealed that the active residues (TYR58, HIS26, ARG43, SER39, etc.) played an essential part in the binding of the compound(s) to form a stable low-energy ligand/protein complex, while the MD trajectories demonstrated that the interactions of drugs with 2FBW affected the tertiary structure and increased the stability of protein. Besides, compound 4n also showed control efficacies (curative and protective) on Xoo in vivo, where the curative efficacy was 35.91% and the protective efficacy was 18.97%. In a word, this study showed that 1,3,4-thiadiazole sulfone derivatives containing amide moiety designed based on the structure of carboxin were promising agricultural antibacterial agents, featuring certain stability of binding affinity to proteins and carboxin.     

Microwave assisted synthesis of 2-amino-4-chloro-pyrimidine derivatives: Anticancer and computational study on potential inhibitory action against COVID-19

We report microwave synthesis of seven unique pyrimidine anchored derivatives (1–7) incorporating multifunctional amino derivatives along with their in vitro anticancer activity and their activity against COVID-19 in silico. 1–7 were characterized by different analytical and spectroscopic techniques. Cytotoxic activity of 1–7 was tested against HCT116 and MCF7 cell lines, whereby 6 exhibited highest anticancer activity on HCT116 and MCF7 with EC₅₀ values of 89.24 ± 1.36 µM and 89.37 ± 1.17 µM, respectively.Molecular docking was performed for derivatives (1–7) on main protease for SARS-CoV-2 (PDB ID: 6LU7). Results revealed that most of the derivatives had superior or equivalent affinity for the 3CLpro, as determined by docking and binding energy scores. 6 topped the rest with highest binding energy score of ?8.12 kcal/mol with inhibition constant reported as 1.11 µM. ADME, drug-likeness, and pharmacokinetics properties of 1–7 were tested using Swiss ADME tool. Toxicity analysis was done with pkCSM online server.All derivatives showed high GI absorption. Except 1 and 3, all derivatives showed blood brain barrier permeability. Most derivatives showed negative logKp values suggesting derivatives are less skin permeable and bioavailability score of all derivatives was 0.55. The toxicity analysis demonstrated that all derivatives have no skin sensitization properties. 6 and 7 showed maximum tolerated dose (Human) values of ?0.03 and ?0.018, respectively and absence of AMES toxicity.