Two Novel Regioisomeric Series of Bis-pyrazolines: Synthesis, In Silico Study, DFT Calculations, and Comparative Antibacterial Potency Profile against Drug-Resistant Bacteria; MSSA, MRSA, and VRSA.

Aims: Design and synthesis of antimicrobial prototypes that are capable of eradicating bacterial biofilm formation that is responsible for many health challenges particularly with antibiotic-resistant bacterial species. Materials and Methods: The utility of 1,3-diarylenones, aka chalcones, 3a-i and 8a-j as building blocks to construct the corresponding bis-pyrazoline derivatives 5aa-bh and 9ad-bj. Screening the antibacterial behavior of the novel bis-pyrazoline derivatives against methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), and vancomycin-resistant S. aureus (VRSA) bacterial strains was investigated. Results: Chalcones were used as building scaffolds to construct two series of di- and trisubstituted bis-pyrazoline derivatives. Numerous novel bis-compounds displayed decent bacterial biofilm suppression. Conclusions: Two regioisomeric series of bis-chalcones were designed and constructed, and their structural diversity was manipulated to access the intrinsically bioactive, pyrazoline ring. The newly synthesized bis-pyrazoline derivatives presented decent antibacterial behavior against multiple drug-resistant bacterial strands (MSSA, MRSA, and VRSA).

Novel xylenyl-spaced bis-thiazoles/thiazines: synthesis, biological profile as herpes simplex virus type 1 inhibitors and in silico simulations.

Aims: Development of some potent bis-thiazole and bis-thiazine derivatives that could be used as antiviral prototypes. Materials & methods: Xylenyl-spaced bis-carbazone scaffold 3 was used as a versatile building block for bis-thiazole derivatives 6a-e and 9a-d and bis-thiazine derivatives 12a-f. These bis-heterocycles were screened as herpes simplex virus type 1 (HSV-1) inhibitors. Results: The new bis-heterocyclic compounds showed remarkable antiviral activity (e.g., compound 6d cytotoxicity concentration CC50 >500 µg/ml). The antiviral capacity of the synthesized bis-compounds was supported by a molecular docking study against the glycoprotein D receptor of HSV-1. Compounds 6b, 9b, and 12c displayed the best binding coefficients. Conclusion: A new series of xylenyl-spaced bis-carbazone scaffolds were used as a building scaffold to construct a host of bis-thiazole/thiazine derivatives that could be used as antiviral prototypes.

Three series of potent antiviral prototypes were successfully designed. The building blocks of these prototypes are readily accessible from commercially available starting materials. These prototypes were tagged with thiazole moieties due to their diverse biological activities. These analogues were screened as herpes simplex virus type 1 (HSV-1) inhibitors to examine their antiviral potential. In vitro screening revealed that several prototypes possess good antiviral activities against an HSV-1 receptor compared with acyclovir. Compound 6d showed remarkable antiviral activity with a cytotoxicity concentration CC₅₀ >500 µg/ml. The antiviral capability of the newly synthesized materials was supported by computational calculations against the surface glycoprotein D receptor of the HSV-1. Compounds 6b, 9b and 12c had the best binding affinity toward the target protein receptor, with binding energies of -9.5, -9.8 and -9.6 kcal/mol, respectively. These results were in great accord with the recorded in vitro screening data.

Antimicrobial Potency and E. coli ß-Carbonic Anhydrase Inhibition Efficacy of Phenazone-Based Molecules.

In this investigation, 4-antipyrinecarboxaldhyde was reacted with methyl hydrazinecarbodithioate to afford the carbodithioate derivative 3. The as-prepared carbodithioate derivative 3 is considered to be a key molecule for the preparation of new antipyrine-1,3,4-thiadiazole-based molecules (4-9) through its reaction with the appropriate hydrazonoyl halides. Furthermore, a typical Biginelli three-component cyclocondensation reaction involving ethyl acetoacetate, 4-antipyrinecarboxaldhyde, and thiourea under the standard conditions is carried out in the presence of sulfuric acid to afford the corresponding antipyrine-pyrimidine hybrid molecule (10). The latter was submitted to react with hydrazine monohydrate to provide the corresponding hydrazide derivative (11) which, under reaction with ethyl acetoacetate in refluxing ethanol containing catalytic amount of acetic acid, afforded the corresponding derivative (12). The structure of the newly synthesized compounds was affirmed by their spectral and microanalytical data. We also screened for their antimicrobial potential (ZOI and MIC) and conducted a kinetic study. Additionally, the mechanism of biological action was assessed by a membrane leakage assay and SEM imaging technique. Moreover, the biological activities and the binding modes of these compounds were further supplemented by an in silico docking study against E. coli ß-carbonic anhydrase. The amount of cellular protein released by E. coli is directly correlated to the concentration of compound 9, which was found to be 177.99 µg/mL following treatment with 1.0 mg/mL of compound 9. This finding supports compound 9's antibacterial properties and explains how the formation of holes in the E. coli cell membrane results in the release of proteins from the cytoplasm. The newly synthesized compounds represent acceptable antimicrobial activities with potential action against E. coli ß-carbonic anhydrase. The docking studies and antimicrobial activity test proved that compound (9) declared a greater activity than the other synthesized compounds.

Novel 3-phenylquinazolin-2,4(1H,3H)-diones as dual VEGFR-2/c-Met-TK inhibitors: design, synthesis, and biological evaluation.

Multitarget anticancer drugs are more superior than single target drugs regarding patient compliance, drug adverse effects, drug-drug interactions, drug resistance as well as pharmaceutical industry economics. Dysregulation of both VEGFR-2 and c-Met tyrosine kinases (TKs) could result in development and progression of different human cancers. Herein, we reported a novel series of 3-phenylquinazolin-2,4(1H,3H)-diones with thiourea moiety as dual VEGFR-2/c-Met TKs. Compared to sorafenib, cabozantinib went behind VEGFR-2 inhibition to target c-Met TK. The dual VEGFR-2/c-Met inhibitory activity of cabozantinib is due to a longer HB domain than that of sorafenib. Based on pharmacophore of cabozantinib analogues, we designed new dual VEGFR-2/c-Met TKs. We synthesized the target compounds via a new single pot three-component reaction. The cytotoxic activity of synthesized compounds was conducted against HCT-116 colorectal cancer cell line. Compounds 3c and 3e exhibited the highest cytotoxic activity against HCT-116 cell line (IC50 1.184 and 3.403 µM, respectively). The in vitro enzyme inhibitory activity was carried out against both VEGFR-2 and c-Met TKs. Compound 3e has the highest inhibitory activity against both VEGFR-2/c-Met (IC50 = 83 and 48 nM, respectively). Docking studies showed that α-oxo moiety in quinazoline ring formed hydrogen bond HB with Met1160 residue in the adenine region of c-Met TK.

Synthesis and Molecular Docking Study of Some New Thiazole-coumarin Molecular Hybrids as Antibacterial Agents.

BACKGROUND: The emergence of drug-resistant bacteria and multidrug-resistant diseases, both of which are associated with high mortality, has posed a serious global health issue. Thiazoles and coumarins were reported as antimicrobial agents. OBJECTIVE: This research paper aims to describe the synthesis of some novel thiazole derivatives bear-ing a coumarin residue as antibacterial agents Methods: The thiazole - coumarin hybrids were synthesized starting from the condensation of 3-acetyl coumarin (1) hydrazine carbothioamide (2) or thisemicarbazide then reacting the resulting products with different p-substituted phenacyl bromides (4a-e), hydrazonoyl chlorides (8a-e), and (11). In vitro antibacterial activity was studied in this work. In addition, molecular docking studies for the new compounds have also been carried out to investigate the binding mode of actions against the target DNA gyrase B. RESULTS: Some of the newly synthesized compounds such as compounds 10b, 7, and 6b showed pronounced activities against Gram (+ve) and Gram (-ve) bacteria compared to a reference antibacterial agent. Compounds 10b, 7, and 6b exhibited the best binding affinity against the target. CONCLUSION: We could obtain a series of precious hitherto unknown thiazole derivatives with varied antibacterial activities from cheap laboratory-available starting material following rather simple environmentally friendly techniques avoiding the use of hazardous or heavy metal-containing catalysts.

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.

Design and biological evaluation of 3-substituted quinazoline-2,4(1H,3H)-dione derivatives as dual c-Met/VEGFR-2-TK inhibitors.

The dual c-Met/vascular endothelial growth factor receptor 2 (VEGFR-2) TK inhibition is a good strategy to overcome therapeutic resistance to small molecules VEGFR-2 inhibitors. In this study, we designed 3-substituted quinazoline-2,4(1H,3H)-dione derivatives as dual c-Met/VEGFR-2 TK inhibitors. We introduced new synthetic methods for reported derivatives of 3-substituted quinazoline-2,4(1H,3H)-dione 2a-g, in addition to the preparation of some new derivatives namely, 3 and 4a-j. Three compounds namely, 2c, 4b, and 4e showed substantial amount of inhibition for both c-Met and VEGFR-2 TK (IC50 range 0.052-0.084 µM). Both compounds 4b, 4e showed HB with highly conserved residue Asp1222 in the HB region of c-Met TK. For VEGFR-2 TK, compound 4b showed HB with a highly conserved residue Asp1046 in the HB region. Compound 4e showed HB with Glu885 and Asp1046. Moreover, in silico prediction of pharmacokinetic and physicochemical parameters of target compounds was carried out using SwissADME website. The quinazoline-2,4(1H,3H)-dione derivatives are promising antiproliferative candidates that require further optimisation.HighlightsNew 3-substituted quinazoline-2,4(1H,3H)-dione derivatives were synthesised and characterised.Compounds 4b and 4e showed higher cytotoxic activity than cabozantinib against HCT-116 colorectal cell lines.Both compounds 4b and 4e showed less toxicity to WI38 normal cell line compared to HCT 116 colon cancer cell line.Compound 4b was superior to cabozantinib in VEGFR-2 inhibition while compound 2c was equipotent to cabozantinib.Compounds 4b and 4e showed remarkable c-Met inhibitory activity.Compounds 4b and 4e arrested cell cycle and induced significant levels of apoptosis.In silico ADME prediction revealed high oral bioavailability and enhanced water solubility of target compounds as compared to cabozantinib.Target compounds interacted with both c-Met and VEGFR-2 active site in similar way to cabozantinib.

Design, synthesis and molecular docking of novel substituted azepines as inhibitors of PI3K/Akt/TSC2/mTOR signaling pathway in colorectal carcinoma.

A series of novel substituted azepines (2-7) was synthesized using both traditional and ultrasonic techniques. The efficiency of the reaction rate and yield was improved by sonication technique. We identified the newly synthesized compounds based on their melting points, elemental analyses, and spectral data. Human cancers are regulated mainly by the phosphatidylinositol 3-kinase/protein kinases B (PI3K/Akt) pathway, and its abnormal activation is linked to carcinogenesis, and angiogenesis. Using in-silico studies, we evaluated the ability of all the novel substituted diazepines and oxazepines to prevent cancer growth and metastasis by targeting the PI3K/Akt signaling pathway. Based on our findings, compounds 4a and 7a were chosen for in-vitro testing as they ranked via molecular docking the highest binding energies of -10.9, -10.3, -10.6, and -10.4 kcal/mol respectively. Compounds 4a and 7a displayed significant cytotoxicity on Caco-2 colorectal cancer cells with IC50 values of 8.445 ± 2.26 and 33.04 ± 2.06 µM, respectively. Additionally, they considerably suppressed the PI3K/Akt proteins and generated reactive oxygen species (ROS), which increased p53 and Bax, decreased Bcl-2 levels, and arrested the cell cycle at sub-G0/G1 phase. We also observed a remarkable overexpression of the Tuberous Sclerosis Complex 2 (TSC2) gene, an inhibitor of the mammalian target of rapamycin (mTOR). These results showed that compounds 4a and 7a obeyed Lipinski's rule of five and might be potential cancer treatment scaffolds by preventing metastasis and proliferation via blocking the PI3K/Akt/TSC2/m-TOR signaling pathway. This supports our hypothesis that diazepine 4a and oxazepine 7a are promising drug candidates for colorectal cancer.

Newly Synthesized Pyrazolinone Chalcones as Anticancer Agents via Inhibiting the PI3K/Akt/ERK1/2 Signaling Pathway.

A series of novel pyrazolinone chalcones 3-9 have been synthesized through the condensation of azo pyrazolinone derivatives with various aromatic aldehydes. Spectroscopic techniques and elemental analysis have both corroborated this. Furthermore, all compounds were screened in silico for their ability to inhibit cancer proliferation and metastasis by targeting the PI3K/Akt signaling pathway. This inhibitory pathway might be an efficient approach for the death of cancer cells, angiogenesis, and metastasis prevention. Our results indicated that only compound 6b was the top-ranked. It demonstrated the highest binding energies of -11.1 and -10.7 kcal/mol against the target proteins PI3K and Akt, respectively; thus, it was chosen for in vitro studies. Compound 6b exhibited the most effective cytotoxic impact against the Caco cell line with IC50 of 23.34 ± 0.14 µM. Furthermore, it showed significant inhibition of PI3K/Akt proteins and oxidative stress, leading to elevated Bax and p53 expression, reduced Bcl-2 expression, and triggered cell cycle arrest at the sub-G0/G1 phase. Additionally, it showed significant downregulation of the Raf-1 gene, leading to ERK1/2 protein inhibition. These findings demonstrate that compound 6b obeyed Lipinski's rule of five and might be used as a favored scaffold for cancer treatment by inhibiting proliferation and metastasis via inhibition of the PI3K/Akt and Raf-1/ERK1/2 signaling pathways.

In silico study to identify novel potential thiadiazole-based molecules as anti-Covid-19 candidates by hierarchical virtual screening and molecular dynamics simulations.

In the present study, a new category of 1,3,4-thiadiazoles was developed by submitting methyl 2-(4-hydroxy-3-methoxybenzylidene) hydrazine-1-carbodithioate to react with the appropriate hydrazonoyl halides in presence of few drops of diisopropyl ethyl amine. The chemical structures of the newly synthesized derivatives were inferred by means of their micro-analytical and spectral data. Utilizing combined molecular docking and molecular dynamics techniques, the binding affinities and features of the synthesized compounds were evaluated against four SARS-CoV-2 target enzymes, namely, main protease (Mpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), and receptor-binding domain (RBD) of the spike protein. Compound 7 demonstrated promising binding affinities with the target enzymes Mpro, PLpro, RdRp, and RBD with docking scores of -11.4, -9.4, -8.2, and -6.8 kcal/mol, respectively. In addition, compound 7 exhibited MM-GBSA//100 ns MD docking score of -35.9 kcal/mol against Mpro. Structural and energetic analyses revealed the stability of the 7-Mpro complex over 100 ns MD simulations. In addition, compound 7 obeyed Lipinski's rule of five, as it has acceptable absorption, distribution, and oral bioavailability inside the body. Therefore, compound 7 is considered as a promising starting point for designing potential therapeutic agents against Covid-19. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-01985-1.

Synthesis, characterization, in silico molecular docking, and antibacterial activities of some new nitrogen-heterocyclic analogues based on a p-phenolic unit.

Nitrogen-containing heterocycles have shown pharmacological properties against various diseases. Herein, in our study, flavoHB enzyme is a highly promising well-validated target for identification of antibacterial inhibitors using in silico and in vitro techniques. To identify a new class of antimicrobial agents, N-(4-hydroxyphenyl)-3-oxobutanamide was utilized as a precursor in the synthesis of several nitrogen-based heterocycles (pyridine, pyrimidine, and pyrazole) attached to p-phenolic substrates 2-8. Treatment of 3-oxobutanimide 1 with malononitrile and/or ethyl cyanoacetate in ethanolic piperidine afforded the pyridinone analogues 2a,b. On the other hand, treatment of 1 with arylidene cyanothioacetamide furnished the pyridinthione derivative 3. The reaction of starting material 1 with salicylaldehyde and/or dimethyl formamide dimethyl acetal (DMF-DMA) yielded the pyridinones 4 and 5, respectively. Reaction of 1 with terephthalaldehyde and urea or thiourea gave bis structures 6a,b. The reaction of compound 1 with ethyl isothiocyanate and hydrazine hydrate afforded pyrimidine and pyrazole derivatives 7 and 8, respectively. The structures of newly prepared compounds 2-8 were elucidated using elemental data and spectral analyses such as IR, 1H NMR, 13C NMR, and MS. In addition, an in-house nitrogen-containing heterocycle analogues library 2-8 was examined and screened in vitro for their antibacterial effects against Gram-negative bacteria, Escherichia coli and Gram-positive bacteria, Staphylococcus haemolyticus, Kocuria kristinae, Enterococcus casseliflavus, and Bacillus cereus. Compounds 6a and 6b have also shown the highest antibacterial activity against all types of bacteria strains tested except Kocuria kristinae. Further, the molecular docking study of the newly prepared compounds with the target enzyme flavohemoglobin (flavoHB) was undertaken to explore their potential inhibitory activities. The results of the docking study indicated that compounds 6a and 6b have exerted the highest docking scores against the active site of flavoHB. As a result, the in vitro and molecular docking study findings suggested that the compounds 6a and 6b (with pyrimidine moiety, amide linkage, and phenolic substrate) might be potent bacterial flavohemoglobin (flavoHB) inhibitors and they could set a promising starting point for future design of antibacterial agents.

Design, synthetic approach, in silico molecular docking and antibacterial activity of quinazolin-2,4-dione hybrids bearing bioactive scaffolds.

Antimicrobial resistance (AMR) is one of ten global public health threats facing humanity. This created the need to identify and develop effective inhibitors as antimicrobial agents. In this respect, quinazolin-2,4-dione hybrids bearing N-heterocyclic cores such as pyrrolidine-2,5-dione, pyrazole and oxadiazole and/or bioactive scaffolds such as hydrazone, amide, sulfonamide, azomethine, and thiourea linkage are described for design, synthesis, antibacterial investigation, and in silico studies. The characterization of the target compounds was accomplished by elemental analysis and various spectroscopic data like FT-IR, 1H-NMR, 13C-NMR and MS. The antibacterial evaluation was achieved for the newly synthesized compounds using two G -ve bacteria (Escherichia coli ATCC 25955 and Pseudomonas aeruginosa ATCC 10145), and two G +ve bacteria (Bacillus subtilis ATCC 6633 and Staphylococcus aureus NRRL B-767). Synthesized compounds exhibited various activities against the tested pathogens, the results revealed that compound 3c exhibited a characteristic antimicrobial efficacy against all the tested pathogenic strains at a concentration lower than the tested standard drug ranging from 2.5 to 10 µg ml-1. Moreover, the molecular docking study against the target S. aureus tyrosyl-tRNA synthetase (PDB ID: 1JIJ) was carried out to investigate the mechanism of action of the prepared compounds, which is in line with an in vitro study. Most new compounds exhibited zero violation of Lipinski's rule (Ro5). These candidate molecules have shown promising antibacterial activity. Among these molecules, compound 3c with di-hydroxyl groups on two phenyl rings at position-4 exhibited a promising potent antibacterial inhibitory effect. Further SAR analysis reveals that a greater number of hydroxyl groups in an organic compound might be crucial for antibacterial efficacy. These findings demonstrate the potential activity of compound 3c as an antibacterial agent.

Synthesis, Identification, Computer-Aided Docking Studies, and ADMET Prediction of Novel Benzimidazo-1,2,3-triazole Based Molecules as Potential Antimicrobial Agents.

2-azido-1H-benzo[d]imidazole derivatives 1a,b were reacted with a ß-ketoester such as acetylacetone in the presence of sodium ethoxide to obtain the desired molecules 2a,b. The latter acted as a key molecule for the synthesis of new carbazone derivatives 4a,b that were submitted to react with 2-oxo-N-phenyl-2-(phenylamino)acetohydrazonoyl chloride to obtain the target thiadiazole derivatives 6a,b. The structures of the newly synthesized compounds were inferred from correct spectral and microanalytical data. Moreover, the newly prepared compounds were subjected to molecular docking studies with DNA gyrase B and exhibited binding energy that extended from -9.8 to -6.4 kcal/mol, which confirmed their excellent potency. The compounds 6a,b were found to be with the minimum binding energy (-9.7 and -9.8 kcal/mol) as compared to the standard drug ciprofloxacin (-7.4 kcal/mol) against the target enzyme DNA gyrase B. In addition, the newly synthesized compounds were also examined and screened for their in vitro antimicrobial activity against pathogenic microorganisms Staphylococcus aureus, E. coli, Pseudomonas aeruginosa, Aspergillus niger, and Candida albicans. Among the newly synthesized molecules, significant antimicrobial activity against all the tested microorganisms was obtained for the compounds 6a,b. The in silico and in vitro findings showed that compounds 6a,b were the most active against bacterial strains, and could serve as potential antimicrobial agents.

New Amino Acid Schiff Bases as Anticancer Agents via Potential Mitochondrial Complex I-Associated Hexokinase Inhibition and Targeting AMP-Protein Kinases/mTOR Signaling Pathway.

Two series of novel amino acid Schiff base ligands containing heterocyclic moieties, such as quinazolinone 3-11 and indole 12-20 were successfully synthesized and confirmed by spectroscopic techniques and elemental analysis. Furthermore, all compounds were investigated in silico for their ability to inhibit mitochondrial NADH: ubiquinone oxidoreductase (complex I) by targeting the AMPK/mTOR signaling pathway and inhibiting hexokinase, a key glycolytic enzyme to prevent the Warburg effect in cancer cells. This inhibitory pathway may be an effective strategy to cause cancer cell death due to an insufficient amount of ATP. Our results revealed that, out of 18 compounds, two (11 and 20) were top-ranked as they exhibited the highest binding energies of -8.8, -13.0, -7.9, and -10.0 kcal/mol in the docking analysis, so they were then selected for in vitro assessment. Compound 11 promoted the best cytotoxic effect on MCF-7 with IC50 = 64.05 ± 0.14 µg/mL (0.135 mM) while compound 20 exhibited the best cytotoxic effect on MDA-231 with IC50 = 46.29 ± 0.09 µg/mL (0.166 mM) Compounds 11 and 20 showed significant activation of AMPK protein and oxidative stress, which led to elevated expression of p53 and Bax, reduced Bcl-2 expression, and caused cell cycle arrest at the sub-G0/G1 phase. Moreover, compounds 11 and 20 showed significant inhibition of the mTOR protein, which led to the activation of aerobic glycolysis for survival. This alternative pathway was also blocked as compounds 11 and 20 showed significant inhibitory effects on the hexokinase enzyme. These findings demonstrate that compounds 11 and 20 obeyed Lipinski's rule of five and could be used as privileged scaffolds for cancer therapy via their potential inhibition of mitochondrial complex I-associated hexokinase.

Eco-Friendly Synthesis, Biological Evaluation, and In Silico Molecular Docking Approach of Some New Quinoline Derivatives as Potential Antioxidant and Antibacterial Agents.

A new series of quinoline derivatives 5-12 were efficiently synthesized via one-pot multicomponent reaction (MCR) of resorcinol, aromatic aldehydes, ß-ketoesters, and aliphatic/aromatic amines under solvent-free conditions. All products were obtained in excellent yields, pure at low-cost processing, and short time. The structures of all compounds were characterized by means of spectral and elemental analyses. In addition, all the synthesized compounds 5-12 were in vitro screened for their antioxidant and antibacterial activity. Moreover, in silico molecular docking studies of the new quinoline derivatives with the target enzymes, human NAD (P)H dehydrogenase (quinone 1) and DNA gyrase, were achieved to endorse their binding affinities and to understand ligand-enzyme possible intermolecular interactions. Compound 9 displayed promising antioxidant and antibacterial activity, as well as it was found to have the highest negative binding energy of -9.1 and -9.3 kcal/mol for human NAD (P)H dehydrogenase (quinone 1) and DNA gyrase, respectively. Further, it complied with the Lipinski's rule of five, Veber, and Ghose. Therefore, the quinoline analogue 9 could be promising chemical scaffold for the development of future drug candidates as antioxidant and antibacterial agents.

Synthesis, Molecular Docking Studies and In Silico ADMET Screening of New Heterocycles Linked Thiazole Conjugates as Potent Anti-Hepatic Cancer Agents.

Thiazoles are important scaffolds in organic chemistry. Biosynthesis of thiazoles is considered to be an excellent target for the design of novel classes of therapeutic agents. In this study, a new series of 2-ethylidenehydrazono-5-arylazothiazoles 5a-d and 2-ethylidenehydrazono-5-arylazo- thiazolones 8a-d were synthesized via the cyclocondensation reaction of the appropriate hydrazonyl halides 4a-d and 7a-d with ethylidene thiosemicarbazide 3, respectively. Furthermore, the thiosemicarbazide derivative 3 was reacted with different bromoacetyl compounds 10-12 to afford the respective thiazole derivatives 13-15. Chemical composition of the novel derivatives was established on bases of their spectral data (FTIR, 1H-NMR, 13C-NMR and mass spectrometry) and microanalytical data. The newly synthesized derivatives were screened for their in vitro anti-hepatic cancer potency using an MTT assay. Moreover, an in silico technique was used to assess the interaction modes of the compounds with the active site of Rho6 protein. The docking studies of the target Rho6 with the newly synthesized fourteen compounds showed good docking scores with acceptable binding interactions. The presented results revealed that the newly synthesized compounds exhibited promising inhibition activity against hepatic cancer cell lines (HepG2).

Thiazole-Based Thiosemicarbazones: Synthesis, Cytotoxicity Evaluation and Molecular Docking Study.

INTRODUCTION: Hybrid drug design has developed as a prime method for the development of novel anticancer therapies that can theoretically solve much of the pharmacokinetic disadvantages of traditional anticancer drugs. Thus a number of studies have indicated that thiazole-thiophene hybrids and their bis derivatives have important anticancer activity. Mammalian Rab7b protein is a member of the Rab GTPase protein family that controls the trafficking from endosomes to the TGN. Alteration in the Rab7b expression is implicated in differentiation of malignant cells, causing cancer. METHODS: 1-(4-Methyl-2-(2-(1-(thiophen-2-yl) ethylidene) hydrazinyl) thiazol-5-yl) ethanone was used as building block for synthesis of novel series of 5-(1-(2-(thiazol-2-yl) hydrazono) ethyl) thiazole derivatives. The bioactivities of the synthesized compounds were evaluated with respect to their antitumor activities against MCF-7 tumor cells using MTT assay. Computer-aided docking protocol was performed to study the possible molecular interactions between the newly synthetic thiazole compounds and the active binding site of the target protein Rab7b. Moreover, the in silico prediction of adsorption, distribution, metabolism, excretion (ADME) and toxicity (T) properties of synthesized compounds were carried out using admetSAR tool. RESULTS: The results obtained showed that derivatives 9 and 11b have promising activity (IC50 = 14.6 ± 0.8 and 28.3 ± 1.5 µM, respectively) compared to Cisplatin (IC50 = 13.6 ± 0.9 µM). The molecular docking analysis reveals that the synthesized compounds are predicted to be fit into the binding site of the target Rab7b. In summary, the synthetic thiazole compounds 1-17 could be used as potent inhibitors as anticancer drugs. CONCLUSION: Promising anticancer activity of compounds 9 and 11 compared with cisplatin reference drug suggests that these ligands may contribute as lead compounds in search of new anticancer agents to combat chemo-resistance.

Synthesis, Molecular Docking Analysis and in Vitro Biological Evaluation of Some New Heterocyclic Scaffolds-Based Indole Moiety as Possible Antimicrobial Agents.

In the present study, a general approach for the synthesis of 1-(1H-indol-3-yl)-3,3-dimercaptoprop-2-en-1-one (1) and 5-(1H-indol-3-yl)-3H-1,2-dithiole-3-thione (2) was performed. They are currently used as efficient precursors for the synthesis of some new compounds bearing five- and/or six-membered heterocyclic moieties, e.g., chromenol (3, 4), 3,4-dihydroquinoline (7, 8) and thiopyran (10, 12)-based indole core. In addition, molecular docking studies were achieved, which showed that all the newly synthesized compounds are interacting with the active site region of the target enzymes, the targets UDP-N-acetylmuramatel-alanine ligase (MurC), and human lanosterol14α-demethylase, through hydrogen bonds and pi-stacked interactions. Among these docked ligand molecules, the compound (9) was found to have the minimum binding energy (-11.5 and -8.5 Kcal/mol) as compared to the standard drug ampicillin (-8.0 and -8.1 Kcal/mol) against the target enzymes UDP-N-acetylmuramatel-alanine ligase (MurC), and Human lanosterol14α-demethylase, respectively. Subsequently, all new synthesized analogues were screened for their antibacterial activities against Gram-positive (Bacillus subtilis), and Gram-negative bacteria (Escherichia coli), as well as for antifungal activities against Candida albicans and Aspergillus flavus. The obtained data suggest that the compounds exhibited good to excellent activity against bacterial and fungi strains. The compound (E)-2-(6-(1H-indole-3-carbonyl)-5-thioxotetrahydrothieno [3,2-b]furan-2(3H)-ylidene)-3-(1H-indol-3-yl)-3-oxopropanedithioic acid (9) showed a high binding affinity as well as an excellent biological activity. Therefore, it could serve as the lead for further optimization and to arrive at potential antimicrobial agent.

Synthesis, Molecular Docking Screening and Anti-Proliferative Potency Evaluation of Some New Imidazo[2,1-b]Thiazole Linked Thiadiazole Conjugates.

BACKGROUND: Imidazo[2,1-b]thiazole scaffolds were reported to possess various pharmaceutical activities. RESULTS: The novel compound named methyl-2-(1-(3-methyl-6-(p-tolyl)imidazo[2,1-b]thiazol-2-yl)ethylidene)hydrazine-1-carbodithioate 3 acted as a predecessor molecule for the synthesis of new thiadiazole derivatives incorporating imidazo[2,1-b]thiazole moiety. The reaction of 3 with the appropriate hydrazonoyl halide derivatives 4a-j and 7-9 had produced the respective 1,3,4-thiadiazole derivatives 6a-j and 10-12. The chemical composition of all the newly synthesized derivatives were confirmed by their microanalytical and spectral data (FT-IR, mass spectrometry, 1H-NMR and 13C-NMR). All the produced novel compounds were screened for their anti-proliferative efficacy on hepatic cancer cell lines (HepG2). In addition, a computational molecular docking study was carried out to determine the ability of the synthesized thiadiazole molecules to interact with active site of the target Glypican-3 protein (GPC-3). Moreover, the physiochemical properties of the synthesized compounds were derived to determine the viability of the compounds as drug candidates for hepatic cancer. CONCLUSION: All the tested compounds had exhibited good anti-proliferative efficacy against hepatic cancer cell lines. In addition, the molecular docking results showed strong binding interactions of the synthesized compounds with the target GPC-3 protein with lower energy scores. Thus, such novel compounds may act as promising candidates as drugs against hepatocellular carcinoma.

Synthesis, In Silico and In Vitro Assessment of New Quinazolinones as Anticancer Agents via Potential AKT Inhibition.

A series of novel quinazolinone derivatives (2-13) was synthesized and examined for their cytotoxicity to HepG2, MCF-7, and Caco-2 in an MTT assay. Among these derivatives, compounds 4 and 9 exhibited significant cytotoxic activity against Caco-2, HepG2, and MCF-7 cancer cells. Compound 4 had more significant inhibitory effects than compound 9 on Caco-2, HepG2, and MCF-7 cell lines, with IC50 values of 23.31 ± 0.09, 53.29 ± 0.25, and 72.22 ± 0.14µM, respectively. The AKT pathway is one of human cancer's most often deregulated signals. AKT is also overexpressed in human cancers such as glioma, lung, breast, ovarian, gastric, and pancreas. A molecular docking study was performed to analyze the inhibitory action of newly synthetic quinazolinone derivatives against Homo sapiens AKT1 protein. Molecular docking simulations were found to be in accordance with in vitro studies, and hence supported the biological activity. The results suggested that compounds 4 and 9 could be used as drug candidates for cancer therapy via its potential inhibition of AKT1 as described by docking study.