Compounds 4g Research Articles

Synthesis and biological evaluation of new 2-Amino-7-hydroxy-8-methyl-4-aryl-4H-chromene-3-carbonitrile derivatives

A series of new 2-amino-7-hydroxy-8-methyl-4-aryl-4H-chromene-3-carbonitrile derivatives (4a-4g) have been synthesized by a one-pot multicomponent reaction of 2-methylresorcinol (1) and malononitrile (2) with various aldehydes (3). All the synthesised compounds (4a-4g) have been characterised using FT-IR, 1H NMR, 13C NMR, HR-MS and evaluated for swarming behaviour, biofilm formation, biofilm disruption and urease activity against P. mirabilis (MTCC-425). Among all the synthesized compounds, compounds 4a, 4b and 4g showed slightly inhibited swarming behaviour and compounds 4f and 4g inhibited biofilm formation with increasing concentration. SEM (Scanning Electron Microscope) imaging shows that compound 4e effectively disrupts the preformed biofilm. Also, compounds 4d and 4e showed 40% reduction in urease activity. The SAR studies of synthesized compounds are elaborated in detail to provide key structural features. Furthermore, molecular docking studies against urease could provide a mechanistic basis for the inhibition. The per-residue interaction analysis suggested the involvement of non-bonded and bonded interactions with the active site of urease. Hence, the aim of the below study was to synthesize new chromene derivatives and study their biological activities.

Synthesis of novel vicinal diaryl triazoles with sulfur and hydrazine linkers as highly potent anticancer and antioxidant agents

Heading the list of the critical health-related issues worldwide, cancer continues to be one of the most serious life-threatening diseases. Moreover, development of new antioxidants is a field of growing interest because some synthetic antioxidants such as BHA and BHT are now suspected to be potentially harmful to human health. Accordingly, two series of 1,2,4-triazole–ring-containing combretastatin analogs; 8a-j with sulfur linker and 9a-j with hydrazine linker were synthesized. All twenty compounds were tested in vitro for their anticancer activity on three different cancer cell lines including A549, MCF7, and HepG2. A superior cytotoxic activity of all compounds with sulfur linker (8) as compared to doxorubicin, on A549, MCF7 cancer cells, was observed. Furthermore, the best results against HepG2 were obtained for 8e, 8c, 8f and 8g. In addition, compound 8g has also exhibited strong binding affinity against estrogen receptor alpha through in silico molecular docking simulations. Moreover, the antioxidant activity of all derivatives was evaluated using FRAP assay and DPPH test. The compounds 8e, bearing 3,4,5‑methoxy phenyl moiety, and 9g, carrying fluorophenyl group, were the most potent radical scavengers in the DPPH method and also had the superior capacity in the FRAP assay.

Highly Efficient Bimetallic Catalyst for the Synthesis of N-substituted Decahydroacridine-1,8-diones and Xanthene-1,8-diones: Evaluation of their Biological Activity

Background: Bimetallic catalysis plays a major role in boosting the catalytic performance of monometallic counterparts due to the synergetic effect. Method and Materials: In the present study, we have exploited ZrCl4:Mg(ClO4)2 as an efficient bimetallic catalyst for the synthesis of a few biologically relevant N-substituted decahydroacridine-1,8-diones and xanthene-1,8-diones under solvent-free conditions. The complete characterization data (XRD, SEM, BET, pH, TGA, and IR) of the bimetallic catalyst, ZrCl4: Mg(ClO4)2, are provided in the supporting information. Results: Among the compounds screened for anti-oxidant and anti-microbial activities, the acridine derivatives with chloro and fluoro substitutions (compounds 4b, 4c, 4d, and 4j) have exhibited potent activities when compared to other compounds. Among the xanthene derivatives screened for anti-oxidant activity, compounds 5c, 5i, and 5j with chloro and nitro derivatives exhibited potent antioxidant activity, and the rest all showed moderately potent activity. Conclusion: Among the compounds screened for antibacterial activity, compound 5j with chloro substitution showed potent activity, followed by compounds 5c, 5d, 5h, and 5i against Gram +ve bacteria, and compounds 5h, 5f, and 5g with N,N-dimethyl, methoxy and hydroxy substitutions have shown potent activity against Gram -ve bacteria.

Design and Synthesis of Potent Anticancer Agents Using Coumarin‐Quinazolinone Based Scaffolds: Exploration of ADME Properties and Molecular Docking Studies

AbstractCancer remains a complex global threat causing widespread deaths. Developing effective anticancer agents despite advancements still remained challenging. In this work it is designed and synthesised therapeutically active anticancer agents based on coumarin‐quinazolinone 5(a–j) through nucleophilic substitution reaction of 4‐bromomethyl coumarin derivatives with 6,7‐bis(2‐methoxyethoxy)quinazolin‐4(3H)‐one and characterised by using FTIR, 1HNMR, 13C NMR and LCMS analysis. The compounds 5(a–j) were screened for in vitro anticancer activity against A‐549 lung cancer cell lines and MDA‐MB‐231 cell lines. Compound 5i emerged as the most promising antiproliferative candidate demonstrating an IC50 value of 7.11 μM against A‐549 cell lines. Meanwhile compound 5g found as a hit candidate in the case of MDA‐MB‐231, exhibiting an IC50 of 5.12 μM, surpassing the potency of the standard drug doxorubicin (IC50 5.89 μM). Further, the safety profile of coumarin‐quinazolinone scafolds (5a–j) were examined for their cytotoxicity towards human embryonic kidney cell lines (HEK293). It was found that the most active compounds exhibited good safety profile towards human embryonic cell lines. Additionally, molecular docking investigations confirmed that compounds 5(a–j) exhibited elevated docking scores and demonstrated favourable interactions with the HER2 (PDB:3PP0) and VEGFR2 (PDB:4ASE). Furthermore, we investigated the ADME properties using the SwissADME tool.

Synthesis and molecular docking studies of new aryl imeglimin derivatives as a potent antidiabetic agent in a diabetic zebrafish model

Diabetes mellitus (DM) is a persistent, progressive, and multifaceted disease characterized by elevated blood glucose levels. Type 2 diabetes mellitus is associated with a relative deficit in insulin mainly due to beta cell dysfunction and peripheral insulin resistance. Metformin has been widely prescribed as a primary treatment option to address this condition. On the other hand, an emerging glucose-reducing agent known as imeglimin has garnered attention due to its similarity to metformin in terms of chemical structure. In this study, an innovative series of imeglimin derivatives, labeled 3(a–j), were synthesized through a one-step reaction involving an aldehyde and metformin. The chemical structures of these derivatives were thoroughly characterized using ESI–MS, 1H, and 13C NMR spectroscopy. In vivo tests on a zebrafish diabetic model were used to evaluate the efficacy of the synthesized compounds. All compounds 3(a–j) showed significant antidiabetic effects. It is worth mentioning that compounds 3b (FBS = 72.3 ± 7.2 mg/dL) and 3g (FBS = 72.7 ± 4.3 mg/dL) have antidiabetic effects comparable to those of the standard drugs metformin (FBS = 74.0 ± 5.1 mg/dL) and imeglimin (82.3 ± 5.2 mg/dL). In addition, a docking study was performed to predict the possible interactions between the synthesized compounds and both SIRT1 and GSK-3β targets. The docking results were in good agreement with the experimental assay results.

Synthesis and anti-breast cancer evaluation of fused imidazole-imidazo[1,2-c][1,2,3]triazoles: PEG-400 mediated one-pot reaction under ultrasonic irradiation

Synthetic chemists have organized easy and effective ways for perfect synthesis in response to the requirement for scaffolds that are crucial for medical applications. To investigate the synthesis of fused 1,2,3-triazoles in the presence of ultrasound, the [3 + 2] cycloaddition followed by CN bond formation reaction between 2-chloro-N-(1-methyl-1H-imidazol-2-yl)acetamide and substituted aryl iodoalkynes was carried out ourpreviously reported condition. The cancer activity of the synthesized compounds were then tested in vitro against two breast cancer cell lines MCF-7 and MDA-MB231 and some of the compounds 5g and 5j showed more potent activity against MCF-7 compared to standard erlotinib (IC50 = 4.70 ± 0.11 μM) with IC50 values 4.02 ± 0.74 and 4.23 ± 0.65 μM. Later, in vitro EGFR results revealed that compound 5g (IC50 = 0.38 ± 0.02 μM) have shown more effective than the conventional medicine erlotinib (IC50 = 0.42 ± 0.04 μM). Compounds 5j (IC50 = 0.42 ± 0.05 μM) have shown equipotent, 5i (IC50 = 0.53 ± 0.02 μM) and 5k (IC50 = 0.58 ± 0.02 μM) were shown good activity compared to the standard erlotinib. In silico investigations of more potent compounds (5g, 5i, 5j, 5k, and 5q) and erlotinib on the EGFR protein indicated that all five compounds had comparable binding energies and inhibition constants than the erlotinib.

Design, synthesis, molecular docking, and molecular dynamic studies of novel quinazoline derivatives as phosphodiesterase 7 inhibitors.

Introduction: Phosphodiesterase 7 (PDE7) is a high-affinity cyclic AMP (cAMP)-specific PDE that is expressed in immune and proinflammatory cells. In this work, we explore the possibility that selective small molecule inhibitors of this enzyme family could provide a novel approach to alleviate the inflammation that is associated with many inflammatory diseases. Methods: A series of novel substituted 4-hydrazinoquinazoline derivatives and fused triazoloquinazolines were designed, synthesized, and evaluated in vitro for their PDE7A inhibition activities, in comparison with Theophylline, a non-selective PDE inhibitor, and BRL50481, a selective PDE7A inhibitor. This series of novel quinazoline derivatives were synthesized via multi-step reactions. The reaction sequence began with selective monohydrazinolysis of compounds 2a,b to give 3a,b. Schiff bases 4a-h were synthesized by the reaction of the quinazolylhydrazines 3a,b with various substituted aromatic aldehydes. The reaction of 4a-h with bromine in acetic acid, in turn, gave fused triazoloquinazolines 5a-h. These compounds were characterized by satisfied spectrum analyses mainly including 1HNMR, 13CNMR, and MS together with elemental analyses. Results and discussion: The results of in vitro PDE7A inhibition activity clearly indicated that compounds 4b, 4g, 5c, and 5f exhibited good potency. Molecular docking and molecular dynamic simulation studies further supported our findings and provided the basis of interaction in terms of conventional hydrogen bonds and π-π stacking patterns. The present results lay the groundwork for developing lead compounds with improved phosphodiesterase seven inhibitory activities.

Multi Targeted Ligands for Potential Inhibition of Dipeptidyl Peptidase 4, Acetylcholinesterase and Cyclooxygenase 2

Two series of novel compounds were designed by combining indomethacin and ibuprofen with sixteen sulfa drugs. These compounds were systematically evaluated through target fishing using the Pharm Mapper, leading to the identification of DPP-4, AChE, and COX-2 as potential targets. Molecular docking was performed to evaluate the binding affinity of designed compounds against the identified three target proteins. The results revealed that the designed compounds exhibited binding affinities ranging from ~8 to -12kcal/mol, 12 to 13 kcal/mol and 8 to 11kcal/mol for DPP-4, AChE and COX-2 respectively. The binding affinities were found to be comparable or higher than binding affinity of co-crystallized ligand, which was found to be ~10, 12 and 9 kcal/mol respectively. Further investigation into the binding modes of these compounds was carried out. Notably, for DPP-4 complexes, interactions with Arg125, Glu205, and Glu206 were observed which are essential for substrate and inhibitor binding. For AChE complexes, interactions involved crucial His447 residues, essential for acetylcholine hydrolysis. In the case of COX-2, hydrogen bond interaction was noted with Arg120 located at the entrance of the hydrophobic channel. Despite favorable binding potentials, ADME profiling highlighted five compounds (1A, 1F, 1G, 1H, and 1O) with drug-like characteristics but lacking blood-brain barrier permeation ability. Out of five compounds, 1H stood out, demonstrating superior binding affinity and interactions vital residues necessary for catalytic activity of three enzymes. Thus, 1H emerges as a promising candidate for Multi-Targeted Drug-Like (MTDL) development aimed at addressing diabetes mellitus related dementia.

Statine-based peptidomimetic compounds as inhibitors for SARS-CoV-2 main protease (SARS-CoV‑2 Mpro)

COVID-19 is a multisystemic disease caused by the SARS-CoV-2 airborne virus, a member of the Coronaviridae family. It has a positive sense single-stranded RNA genome and encodes two non-structural proteins through viral cysteine-proteases processing. Blocking this step is crucial to control virus replication. In this work, we reported the synthesis of 23 statine-based peptidomimetics to determine their ability to inhibit the main protease (Mpro) activity of SARS-CoV-2. Among the 23 peptidomimetics, 15 compounds effectively inhibited Mpro activity by 50% or more, while three compounds (7d, 8e, and 9g) exhibited maximum inhibition above 70% and IC50 < 1 µM. Compounds 7d, 8e, and 9g inhibited roughly 80% of SARS-CoV-2 replication and proved no cytotoxicity. Molecular docking simulations show putative hydrogen bond and hydrophobic interactions between specific amino acids and these inhibitors. Molecular dynamics simulations further confirmed the stability and persisting interactions in Mpro's subsites, exhibiting favorable free energy binding (ΔGbind) values. These findings suggest the statine-based peptidomimetics as potential therapeutic agents against SARS-CoV-2 by targeting Mpro.

Synthesis, bioactivity evaluation and theoretical study of nicotinamide derivatives containing diphenyl ether fragments as potential succinate dehydrogenase inhibitors

To obtain nicotinamide fungicides with higher inhibitory activity against Rhizoctonia solani, 24 nicotinamide derivatives were designed and synthesized by introducing the diphenyl ether fragments into the structure of boscalid. Biological assays revealed that the obtained compounds exhibited varying degrees of antifungal activity. Among them, compound 2-chloro-N-(2-(2,4-dichlorophenoxy)phenyl)nicotinamide (7g) exhibited prominent biological activity against R. solani (EC50 = 0.034 mg/L), surpassing the inhibitory effect of boscalid. Experimentally, compound 7g was a promising fungicide with low toxicity that targeted succinate dehydrogenase, as confirmed by the tests of cytotoxicity, inhibition of enzyme activity, mitochondrial membrane potential, and mycelial respiration. This study highlighted the potential of nicotinamide derivatives containing diphenyl ether fragments designed based on theoretical calculations as succinate dehydrogenase inhibitor (SDHI) fungicides.

Design, Synthesis, and Evaluation of [18F]BIBD-300 as a Positron Emission Tomography Tracer for Poly(ADP-Ribose) Polymerase-1.

Compounds 8a-j were designed to adjust the mode of interaction and lipophilicity of FTT by scaffold hopping and changing the length of the alkoxy groups. Compounds 8a, 8d, 8g, and BIBD-300 were screened for high-affinity PARP-1 through enzyme inhibition assays and are worthy of further evaluation. PET imaging of MCF-7 subcutaneous tumors with moderate expression of PARP-1 showed that compared to [18F]FTT, [18F]8a, [18F]8d, and [18F]8g exhibited greater nonspecific uptake, a lower target-to-nontarget ratio, and severe defluorination, while [18F]BIBD-300 exhibited lower nonspecific uptake and a greater target-to-nontarget ratio. PET imaging of 22Rv1 subcutaneous tumors, which highly express PARP-1, confirmed that the uptake of [18F]BIBD-300 in normal organs, such as the liver, muscle, and bone, was lower than that of [18F]FTT, and the ratio of tumor-to-muscle and tumor-to-liver [18F]BIBD-300 was greater than that of [18F]FTT. The biodistribution results in mice with MCF-7 and 22Rv1 subcutaneous tumors further validated the results of PET imaging. Unlike [18F]FTT, which mainly relies on hepatobiliary clearance, [18F]BIBD-300, which has lower lipophilicity, undergoes a partial shift from hepatobiliary to renal clearance, providing the possibility for [18F]BIBD-300 to indicate liver cancer. The difference in the PET imaging results for [18F]FTT, [18F]BIBD-300, and [18F]8j in 22Rv1 mice and the corresponding molecular docking results further confirmed that subtle structural modifications in lipophilicity greatly optimize the properties of the tracer. Cell uptake experiments also demonstrated that [18F]BIBD-300 has a high affinity for PARP-1. Metabolized and unmetabolized [18F]FTT and [18F]BIBD-300 were detected in the brain, indicating that they could not accurately quantify the amount of PARP-1 in the brain. However, PET imaging of glioma showed that both [18F]FTT and [18F]BIBD-300 could accurately localize both in situ to C6 and U87MG tumors. Based on its potential advantages in the diagnosis of breast cancer, prostate cancer, and glioma, as well as liver cancer, [18F]BIBD-300 is a new option for an excellent PARP-1 tracer.

Microwave accelerated green access to functionalized pyrazolo[5,1-b]quinazoline-3-carboxylate scaffold and their pharmacological screening

Herein, we explored an environmentally benign synthesis of pyrazolo[5,1-b]quinazoline-3-carboxylate derivatives 4(a-u) as potential antimicrobial, antitubercular as well as antimalarial agents. Our approach employed microwave-assisted PEG-400 as a biodegradable reaction medium to expedite the one-pot fusion of 1,3-dicarbonyl compounds 1(a-c), substituted aldehydes 2(a-g), and ethyl-3-aminopyrazole-4-carboxylate (3a). The current protocol offers the advantages of a low E-factor, high atom economy, mild reaction condition, reusability of PEG-400 and produce water as a byproduct with a favorable yield (up to 96 % yield) in a short reaction time. Compared to the MIC values of standard antibiotics against their respective strains, compound 4g exhibited superior activity against Bacillus subtilis while compound 4r demonstrated a more favorable MIC against Pseudomonas aeruginosa. Against Candida albicans, compounds 4c, 4f, 4i, 4o, 4r, and 4u showed excellent antifungal activity as compared standard medications griseofulvin and fluconazole. Compounds 4d and 4p showed significant antitubercular activity against Mycobacterium tuberculosis H37Rv whereas compounds 4d, 4e, 4p and 4q showed good antimalarial activity against Plasmodium falciparum in contrast to standard drug ciprofloxacin and quinine respectively. In vitro cytotoxicity assay against S. pombe cells indicated that the majority of tested compounds exhibit more than 80 % cell viability, suggesting their non-toxic nature. A molecular docking study was conducted to elucidate the potential interactions between compound 4u and the active site of DNA gyrase. Based on the noteworthy findings from the investigation of drug-like properties and ADMET predictions, these derivatives depict an efficient multifunctional action and offer prospective access for future discoveries of antimicrobial, antitubercular, as well as antimalarial studies.

Synthesis, biological activity, X-ray crystallographic, DFT calculations and molecular dynamics simulation studies of 2-phenylthiazole-1,3,5-triazine derivatives as potential cholinesterase inhibitors

Seven 2-phenylthiazole-1,3,5-triazine derivatives were synthesized and estimated for cholinesterase inhibitory activity. All target compounds were characterized by 1H NMR, 13C NMR, FT-IR, and HRMS, and their purity was tested by HPLC to be above 99%. The in vitro enzyme inhibitory activity assays determined that the majority of compounds exhibited moderate to good inhibitory effects on acetylcholinesterase or butyrylcholinesterase and compound 6g displayed the best acetylcholinesterase (IC50 = 0.26 μM) and butyrylcholinesterase inhibitory activity (IC50 = 0.78 μM). The structures of compounds 6a and 6g was further investigated by single-crystal X-ray diffraction, and the Hirshfeld surfaces, crystal voids, and molecular energy framework analysis were further discussed to study the molecular conformations, crystal packing modes, intermolecular interactions, and their energies. What's more, the density functional theory calculations including frontier molecular orbitals, global reactivity descriptors, and molecular electrostatic potential were carried out to reveal the chemical reactivity and stability of 6a and 6g molecules. Molecular docking study indicated that compound 6g could not only interact with acetylcholinesterase but also with butyrylcholinesterase. Molecular dynamics simulations study showed that compound 6g could bind to acetylcholinesterase stably. In addition, ADMET properties prediction implied the drug-like properties and safety of seven compounds. Considering these results, several of the target compounds could work as novel cholinesterase inhibitors, and compound 6g may possess the potential to become a lead compound to develop novel anti-Alzheimer drugs.

A new class of pyrrolo[2,3-b]quinoxalines: synthesis, anticancer and antimicrobial activities

Abstract A series of 3-chloro-1-aryl-4-dihydro-2H-pyrrolo[2,3-b]quinoxalin-2-ones and 3-chloro-1-aryl-6,7-dimethyl-1,4-dihydro-2H-pyrrolo[2,3-b]quinoxalin-2-ones was prepared by the condensation of o-phenylenediamine or 4,5-dimethyl-1,2-aminobenzene with N-aryl-3,4-dichloro-maleimides. All the prepared quinoxalines were tested for their antitumor activity against three human cancer cell lines (prostate cells PC3, colorectal cells Caco-2, and cervical cells HeLa), and a mammalian cell line (Vero cells). The compounds were also tested for their antibacterial properties against three different bacterial cells Escherichia coli, Bacillus spizizenii, and Pseudomonas aeruginosa. The compounds 3c, 3d, 3g, 3h, 3i and 4a, 4b, 4h showed anti-proliferative activity against the tested cell lines. Regarding their antibacterial activity, compounds 3a, 3g, 4a, and 4h showed inhibitory activity against E. coli, and B. spizizenii only.

Synthesis of new 4-aminobenzoic acid (PABA) hydrazide-hydrazone/sulfonate hybrids and antimicrobial evaluation with ascorbic acid/salicylic acid/N-acetyl cysteine combinations

One of the most serious threats to human health is the increasing prevalence of drug-resistant pathogens. The development of new antibiotics capable of combating drug resistance is critical. In various bacteria and plant species, 4-aminobenzoic acid (PABA) is produced and used as a substrate for folate generation. In this study, a new series of PABA analogs were synthesized and evaluated for their antimicrobial activity. Thirteen novel compounds were prepared by linking PABA hydrazide to sulfonate esters via a hydrazone bridge (4a–m). The structures of these compounds were characterized by 1H and 13C NMR and FT-IR spectroscopy as well as by LC-MS. Following structural characterization, all compounds were tested for their antimicrobial activity against Staphylococcus aureus (ATCC 29213), Enterococcus faecium (ATCC 19434), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), and Candida albicans (ATCC 10231) strains. Four compounds were found to have moderate antimicrobial activity against the P. aeruginosa strain. These compounds, including 4e, 4f, 4g, and 4m, containing a hydrazide-hydrazone sulfonate functionality, showed the best MIC value of 64 μg/mL. In addition, synergistic effects of ascorbic acid, salicylic acid, and N-acetyl cysteine (NAC) with synthesized compounds were also investigated. It was observed that the combination of compounds 4f and 4g with NAC showed antipseudomonal activity with MIC values of 32 μg/mL and 16 μg/mL, respectively, against the P. aeuriginosa strain. The antimicrobial activity of 4f and 4g was enhanced by two folds in combination with NAC. Our findings in this study can be crucial for the development of new potent antimicrobial agents.

Design, synthesis and characterization of ethyl 3-benzoyl-7-morpholinoindolizine-1-carboxylate as anti-tubercular agents: In silico screening for possible target identification.

A thorough search for the development of innovative drugs to treat tuberculosis, especially considering the urgent need to address developing drug resistance, we report here a synthetic series of ethyl 3-benzoyl-7-morpholinoindolizine-1-carboxylate analogues (5a-o) as potent anti-tubercular agents. These morpholino-indolizines were synthesized by reacting 4-morpholino pyridinium salts, with various electron-deficient acetylenes to afford the ethyl 3-benzoyl-7-morpholinoindolizine-1-carboxylate analogues (5a-o). All synthesized intermediate and final compounds are characterized by spectroscopic methods such as 1H NMR, 13C NMR and HRMS and further examined for their anti-tubercular activity against the M. tuberculosis H37Rv strain (ATCC 27294-American type cell culture). All the compounds screened for anti-tubercular activity in the range of 6.25-50 μM against the H37Rv strain of Mycobacterium tuberculosis. Compound 5g showed prominent activity with MIC99 2.55 μg/mL whereas compounds 5d and 5j showed activity with MIC99 18.91 μg/mL and 25.07 μg/mL, respectively. In silico analysis of these compounds revealed drug-likeness. Additionally, the molecular target identification for Malate synthase (PDB 5CBB) is attained by computational approach. The compound 5g with a MIC99 value of 2.55 μg/mL against M. tuberculosis H37Rv emerged as the most promising anti-TB drug and in silico investigations suggest Malate synthase (5CBB) might be the compound's possible target.

Benzohydrazide as a good precursor for the synthesis of novel bioactive and anti-oxidant 2-phenyl-1,3,4-oxadiazol-aminoacid derivatives: Structural determination, biological and anti-oxidant activity

The synthesis and biological assessment of 2,5-disubstituted-1,3,4-oxadiazole derivatives from benzo hydrazide and amino acids as novel potential antioxidant and antibacterial agents have been reported. The structures of the new compounds were characterized by physicochemical properties and spectral methods. The synthesized compounds were screened for their in vitro antibacterial activity against three Gram-positive bacterial strains, namely Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 14579, Listeria innocua ATCC 33090, and two Gram-negative bacterial strains, namely Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, and antifungal activity against Candida albicans ATCC 10231 in comparison with Amoxicillin, Tetracycline, Gentamicin and Oxacillin as standards. Most of the compounds have excellent efficacy, and some of them, such as 5i, 5g, 5d, 5c, and 5j can inhibit their activity better or very close to that of Amoxicillin, Tetracycline, Gentamicin, Oxacillin used as standards. Compounds 5b and 5i provided good results against L. innocua with inhibition values of IZ = 14 mm and IZ = 22 mm, respectively, while the rest of the compounds and antibiotics were unable to inhibit it. Compounds 5c, 5d, 5g and 5j showed excellent activity against C. albicans with values between 31 mm and 34 mm. These results were better than all the standards used. The MIC value (25 µg/ml) for derivatives 5(c-e), 5g and 5(i-j) against B. cereus represent the best activity of the tested compounds. All the target compounds were also screened for radical scavenging antioxidant activities by DPPH, FRAP, and TAC assays and found to be excellent antioxidant agents. According to the results, it was observed that most derivatives synthesized showed excellent activity with a concentration of 250 µg/ml as an antioxidant agent (76 % < RSA < 95.5 %) which gave an inhibition percentage that was better or very close to that of ascorbic acid and better than BHT.

New benzothiazole and benzoxazole picolinamide conjugates as potential anti-cancer agents: Design, synthesis, molecular docking and anticancer studies

An efficient synthesis was developed for the synthesis of N-(benzo[d]thiazol/oxazole-2-yl)-6-methyl-5-phenylpicolinamide derivatives(5a-5 h;8 compounds) with good yields by condensation reactions using benzo[d]thiazol/oxazole-2-amines with 5‑bromo-6‑methoxy picolinic acids in the presence of Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (HATU)/ 4-Dimethylaminopyridine (DMAP) in Dimethylformamide (DMF) followed by coupling with phenylboronic acid in the presence of 1,1 -Bis(diphenylphosphino)ferrocene dichloropalladium(II):(Pd(dppf)Cl2·CH2Cl2), Cs2CO3 in Dioxane/H2O medium. Further, the anticancer potential of these derivatives was evaluated against DU-145(prostrate) and SKOV-3 (ovarian) cell lines. Results indicated moderate to good activity, with compound 5f exhibiting the best cytotoxicity with IC50 values of 8.3 and 8.9 µM for SKOV-3 and DU145 cells respectively as compared to standard Doxorubicin values 0.53 ± 0.08 and 0.68 ± 0.05 for same cell lines.. Additionally, molecular binding studies showed that compounds 5f and 5e had strong binding to human epidermal growth factor receptor, with binding energies of -8.5 and -8.2 Kcal/mol indicates conformational change in the structure of the receptor, leading to activation of signaling pathways promoting proliferation. So, the presence of electron rich OCH3 group on phenyl ring as well as thiazole ring in the designed molecule 5f makes it more potent to show strong cytotoxicity which was also revealed by its binding studies towards the human epidermal growth factor receptor. However, fluorine makes the compounds 5 g and 5 h to show moderate activity against these cancer cell lines.

New pyridine-based chalcones and pyrazolines with anticancer, antibacterial, and antiplasmodial activities.

New pyridine-based chalcones 4a-h and pyrazolines 5a-h (N-acetyl), 6a-h (N-phenyl), and 7a-h (N-4-chlorophenyl) were synthesized and evaluated by the National Cancer Institute (NCI) against 60 different human cancer cell lines. Pyrazolines 6a, 6c-h, and 7a-h satisfied the pre-determined threshold inhibition criteria, obtaining that compounds 6c and 6f exhibited high antiproliferative activity, reaching submicromolar GI50 values from 0.38 to 0.45 μM, respectively. Moreover, compound 7g (4-CH3) exhibited the highest cytostatic activity of these series against different cancer cell lines from leukemia, nonsmall cell lung, colon, ovarian, renal, and prostate cancer, with LC50 values ranging from 5.41 to 8.35 μM, showing better cytotoxic activity than doxorubicin. Furthermore, the compounds were tested for antibacterial and antiplasmodial activities. Chalcone 4c was the most active with minimal inhibitory concentration (MIC) = 2 μg/mL against methicillin-resistant Staphylococcus aureus (MRSA), while the pyrazoline 6h showed a MIC = 8 μg/mL against Neisseria gonorrhoeae. For anti-Plasmodium falciparum activity, the chalcones display higher activity with EC50 values ranging from 10.26 to 10.94 μg/mL. Docking studies were conducted against relevant proteins from P. falciparum, exhibiting the minimum binding energy with plasmepsin II. In vivo toxicity assay in Galleria mellonella suggests that most compounds are low or nontoxic.

Efficient synthesis, crystallographic study, antimicrobial activity and in silico studies of novel bioactive α-aminophosphonates based on pyridine moiety

This study articulates the synthesis, spectroscopic characterization, antimicrobial evaluation, theoretical calculations, and molecular docking analysis of a novel α-aminophosphonates derived from aminopyridine as potential antibacterial pharmacophore. The structures of all compounds was established using FTIR, 1H, 13C, 31P NMR spectroscopy. A single crystal of the studied compound 3g was selected for X-ray diffraction analysis, it crystallizes in the monoclinic crystal system with P 21/n space group. Theoretical studies based on density functional theory (DFT) at the B3LYP /6-31G (d, p) level of theory was utilized to investigate the stability and electronic properties electronic of the studied α-aminophosphonates. The ADME/toxicity analyzes carried out by Swiss ADME and OSIRIS software show that all synthesized molecules exhibited good pharmacokinetics, bioavailability and had no toxicity profile.