Synthesis and biological evaluation of novel triazole substituted pyrazolyl-methylenehydrazinyl-5-arylidene thiazolidinone derivatives as antibacterial and cytotoxic agents

Novel triazole substituted pyrazolyl-methylenehydrazinyl-5-arylidene thiazolidinone derivatives 6a–n and 7a–l were synthesized and characterized by Fourier transform infrared, ¹H and ¹³C nuclear magnetic resonance, mass spectrometry and elemental (CHN) analysis. The in vitro antibacterial (6a–n and 7a–l) and cytotoxic (6a–n) activities were evaluated for these compounds. The results revealed that the compounds 6b, 6i, 6k, 7b, 7h displayed good antibacterial activity. The compounds 6c (IC₅₀ = 5.4 μM), 6l (IC₅₀ = 6.3 μM) and 6f (IC₅₀ = 9.85 μM) were effective for inhibition of human breast cancer cell line MCF-7. Similarly, the compounds 6b (IC₅₀ = 8.7 μM) and 6c (IC₅₀ = 9.06 μM) were shown to have effective inhibition on human cervical cancer cell line Hela.     

Synthesis,evaluation and docking studies of some 4-thiazolone derivatives as effective lipoxygenase inhibitors

Some promising 4-thiazolone derivatives as lipoxygenase inhibitors were designed, synthesized, characterized and evaluated for anti-inflammatory activity and respective ulcerogenic liabilities. Compounds (1b, 1e, 3b, and 3e) exhibited considerable in vivo anti-inflammatory activity (57.61, 79.35, 75.00, and 79.35%) against carrageenan-induced rat paw edema model, whereas compounds (1e, 3b, and 3e) were found active against the arachidonic acid-induced paw edema model (55.38, 55.38, and 58.46%). The most potent compound (3e) exhibited lesser ulcerogenic liability compared to the standard diclofenac and zileuton. Further, the promising compounds (1e and 3e) were evaluated for in vitro lipoxygenase (LOX; IC₅₀?=?12.98 µM and IC₅₀?=?12.67 µM) and cyclooxygenase (COX) inhibition assay (COX-1; IC₅₀?>?50 µM and, COX-2; IC₅₀?>?50 µM). The enzyme kinetics of compound 3e was evaluated against LOX enzyme and supported by in silico molecular docking and molecular dynamics simulations studies. Overall, the results substantiated that 5-benzylidene-2-phenyl-4-thiazolones are promising pharmacophore for anti-inflammatory activity.     

Synthesis,antifungal and insecticidal activity of novel [1,2,4]triazolo[4,3-<Emphasis Type="Italic">a</Emphasis>]pyridine derivatives containing a sulfide substructure

A series of [1,2,4]triazolo[4,3-a]pyridine derivatives bearing a sulfide substructure was designed, synthesized and characterized via ¹H·NMR, ¹³C·NMR, IR and elemental analyses. Bioassay Results indicated some of the derivatives displayed good fungicidal activity on Rhizoctonia cerealis, moderated insecticidal activity against Plutella xylostella and good insecticidal activity on Helicoverpa armigera. The inhibitory effects of compounds 4g and 4u against Rhizotonia cerealis were 70.9% at 50 μg mL^?1; the IC₅₀ values of compounds 4d and 4s against Plutella xylostella were 43.87 and 50.75 μg mL^?1, respectively. And the IC₅₀ values of compounds 4d, 4q, and 4s on Helicoverpa armigera were 58.3, 77.14 and 65.31 μg mL^?1, respectively, which were better than that of commercial chlorpyrifos (103.77 μg mL^?1).     

Synthesis and dynamics studies of barbituric acid derivatives as urease inhibitors

Background

Discovery of potent inhibitors of urease (jack bean) enzyme is the first step in the development of drugs against diseases caused by ureolytic enzyme.

Results

Thirty-two derivatives of barbituric acid as zwitterionic adducts of diethyl ammonium salts were synthesized. All synthesized compounds (4a–z and 5a–s) were screened for their in vitro inhibition potential against urease enzyme (jack bean urease). The compounds 4i (IC₅₀ = 17.6 ± 0.23 µM) and 5l (IC₅₀ = 17.2 ± 0.44 µM) were found to be the most active members of the series, and showed several fold more urease inhibition activity than the standard compound thiourea (IC₅₀ = 21.2 ± 1.3 µM). Whereas, compounds 4a–b, 4d–e, 4g–h, 4j–4r, 4x, 4z, 5b, 5e, 5k, 5n–5q having IC₅₀ values in the range of 22.7 ± 0.20 µM–43.8 ± 0.33 µM, were also found as potent urease inhibitors. Furthermore, Molecular Dynamics simulation and molecular docking studies were carried out to analyze the binding mode of barbituric acid derivatives using MOE. During MD simulation enol form is found to be more stable over its keto form due to their coordination with catalytic Nickel ion of Urease. Additionally, structural–activity relationship using automated docking method was applied where the compounds with high biological activity are deeply buried within the binding pocket of urease. As multiple hydrophilic crucial interactions with Ala169, KCX219, Asp362 and Ala366 stabilize the compound within the binding site, thus contributing greater activity.

Conclusions

This research study is useful for the discovery of economically, efficient viable new drug against infectious diseases.

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Graphical abstract: STD. Thiourea (IC₅₀ = 21.2 ± 1.3 µM)

     

Design,synthesis, activity evaluation and QSAR studies of novel antimalarial 1,2,3-triazolo-β-lactam derivatives

This paper describes the synthesis of some new β-lactam derivatives containing the 1,2,3-triazole moiety. All the compounds were evaluated for their in vitro antimicrobial and antimalarial activities. Moderate to excellent antimalarial activities were encountered. The results showed that compounds 5a, 5c, 5f, 5i exhibited the most potent antimalarial activity with IC₅₀ values of 0.85, < 0.97, < 0.97, 1.81 µM against chloroquine-resistant P. falciparum K1 strain. A QSAR study highlights the structure–activity relationships that correlate the observed antimalarial activities with changes in the compounds’ structural features.     

Synthesis and properties of novel stilbene-twelve alkyl quaternary ammonium salts as antibacterial optical whitening agents

Four novel stilbene-twelve alkyl quaternary ammonium salts 5a–d were synthesized. All synthesized compounds were characterized by FT-IR, ¹H-NMR and elemental analysis. Compounds 5a–d showed efficient whitening effect on cotton fiber and high fastness. Furthermore, compound 5c showed better stability to light than C186 in aqueous solution. The preliminary biological experiment demonstrated compounds 5a–d possessed significant antibacterial activities. Among them, compound 5d turned out to be the most active compound against Candida albicans with MIC₅₀ 4 μg/mL as well as E. coli with MIC₅₀ 16 μg/mL.     

2-Morpholinoethyl-substituted <Emphasis Type="Italic">N</Emphasis>-heterocyclic carbene (NHC) precursors and their silver(I)NHC complexes: synthesis,crystal structure and in vitro anticancer properties

In this study, a series of unsymmetrically 2-morpholinoethyl-substituted benzimidazolium salts and their Ag(I)NHC complexes were synthesized. The 1,3-dialkylbenzimidazolium salts (1a–d) were synthesized in dimethylformamide at 80 °C temperature from the N-(2-morpholinoethyl)benzimidazole and alkyl halides. The Ag(I)NHC complexes (2a–d) were synthesized in dichloromethane at room temperature from the benzimidazolium salts and Ag₂O. All compounds were characterized by spectroscopic techniques (NMR and FT-IR) and elemental analyses. Also, the salt 1c and complex 2c were characterized by single-crystal X-ray crystallography. Anticancer activities of 2-morpholinoethyl-substituted benzimidazolium salts and Ag(I)NHC complexes were investigated against the MCF-7 breast cancer cell line, and the IC₃₀ and IC₅₀ values of these compounds were found to be in the range of 241–490 and 6–14 µM, respectively.     

Synthesis and in vitro anticancer,antibacterial, and antioxidant studies of unsymmetrical Schiff base derivatives of 4-[(1<Emphasis Type="Italic">E</Emphasis>)-<Emphasis Type="Italic">N</Emphasis>-(2-aminoethyl)ethanimidoyl]benzene-1,3-diol

Schiff bases such as 2-hydroxy-1-(4-hydroxyphenyl)ethanone (DHAP) and its derivatives have attracted attention because they are useful in design and development of novel organic compounds for potential pharmaceutical applications. In this work, a series of 4-[(1E)-N-(2-aminoethyl)ethanimidoyl]benzene-1,3-diol (4a–h) Schiff bases were synthesized by reaction of ethylenediamine, DHAP, and appropriate aldehyde moieties. The compositions of the prepared compounds were established using elemental analysis and Fourier-transform infrared (FTIR) and ultraviolet–visible (UV–Vis) spectroscopies. The compounds were screened against three Gram-positive and three Gram-negative bacteria, and the results compared with standard drugs ciprofloxacin and amoxicillin. Compounds 4g, 4h were found to have higher activity against Staphylococcus aureus with minimum inhibitory concentration (MIC) value of 2.5 mg/mL, while compounds 4f and 4h inhibited Escherichia coli with MIC values of 2.5 and 5 mg/mL, respectively. The IC₅₀ values of compounds 4a–h for scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical ranged from 2.63 ± 0.79 to 3.85 ± 0.83 µM with good correlation coefficient of R ² = 0.957–0.994. In vitro anticancer screening of the compounds showed that compounds 4f, 4h, and parthenolide efficiently affected cell viability of cancer cell line MCF-7 with IC₅₀ values of 4.10 ± 1.32, 4.01 ± 2.26, and 0.44 ± 2.02 µM, respectively.     

Design,synthesis, biological evaluation and molecular docking of novel substituted 1-ethyl-1<Emphasis Type="Italic">H</Emphasis>-benzimidazole fluorinated derivatives as thrombin inhibitors

Six novel substituted 1-ethyl-1H-benzimidazole fluorinated derivatives were designed and synthesised based on computer-aided simulation. The structures of the target compounds were characterised by ¹H NMR, ¹³C NMR, ¹⁹F NMR and FT-ICR-MS. The preliminary screening inhibition rate data of synthesised compounds were more than 80 %. Compounds 12a and 12f were evaluated for their anti-thrombin activity in vitro (IC₅₀). The tested data indicated that the compounds showed better thrombin inhibitory activity than reference drug argatroban (9.88 ± 2.26 nM). Especially, compound 12f was the most potent derivative with an IC₅₀ of 3.21 ± 0.57 nM and could act as a candidate compound for further exploration of thrombin inhibitor.     

Synthesis and biological evaluation of analogs of altohyrtin C (spongistatin 2)

Several structural analogs that contain only part of the altohyrtin structure have been prepared and compared with synthetic altohyrtin C (2) for in vitro cytotoxicity against human colon (HCT116) and ovarian (A2780) cell lines. Whereas altohyrtin C was found to be exceedingly potent against these lines (IC₅₀=0.0003 μM), analogs 3-5 were >27,000-fold less potent (IC₅₀>8 μM). Analogs 6 and 7 also demonstrated weak cytotoxicity with IC₅₀ values for the HCT116 and A2780 cells of 4.8 μM and 2.4 μM, respectively, for 6.     

Design and synthesis of some new tri-substituted pyrazole derivatives as anticancer agents

A new series of tri-substituted pyrazole derivatives were designed as anti-cancer agents and synthesized, starting with the formylation of semicarbazone via the Vilsmeier–Haack reaction to give 3-(4-bromophenyl)-1H-pyrazole-4-carbaldehyde I which was the precursor of compounds 1–9. The new chemical entities were screened for their anti-cancer activity on various human cancer cell lines, namely: hepatocellular carcinoma HepG2, breast cancer MCF-7, lung carcinoma A549 and prostatic cancer PC3. Most of the synthesized compounds showed remarkable activity on the tested cell lines, while compound 2 had the highest potency against the HepG2 cell line with an IC₅₀ of 9.13 µM compared with doxorubicin (IC₅₀ = 34.24 µM), the reference standard used in this study, and compound 7 was the most active on the rest of the three cell lines; MCF-7, A549 and PC3 (IC₅₀ = 16.52, 6.52 and 9.13 µM, respectively) relative to IC₅₀ = 20.85, 5.93 and 38.02 µM of the standard. Thus, some of the synthesized tri-substituted pyrazole derivatives, specially 2 and 7, have the potential to be developed into potent anticancer agents.     

New benzothiazole/benzoxazole-pyrazole hybrids with potential as COX inhibitors: design,synthesis and anticancer activity evaluation

Ten new hybrids were designed and synthesized, their chemical structures were confirmed through spectral and elemental analysis. The new hybrids were screened against lung, breast and liver cancer cell lines (A549, MCF7 and Hep3B), in addition to normal fibroblast cells. Compound 13a was the most active and selective one on the lung cancer cell line (A549), its IC₅₀ and S.I. values were 2.4 µM and 83.2, respectively. Compound 14b was active on MCF7 with the best selectivity towards this cell line. The new derivatives were screened for their inhibitory activity against COX enzymes, the obtained results revealed that compound 13a and 14b were more active inhibitors for COX-2 than celecoxib. This finding encourages us to consider COX-2 inhibitory activity as a proposed mechanism for their anticancer activity.     

Mono-, Di- and Tetranuclear Complexes and Clusters With Bromine-Functionalized Bis(diphenylphosphino)amine Ligands

We report the preparation of bromo-aryl functionalized bis(diphenylphosphino)amine ligands of the type Ph₂PNArPPh₂ (1, Ar = p-BrC₆H₄; 2, Ar = p-BrC₆H₄–C₆H₄) and their coordination properties. Mono- and dinuclear complexes were formed with Cu(I), Au(I), Pd(II), Pt(II) and tetranuclear cobalt carbonyl clusters were obtained. The crystal structures of [PdCl₂(1)] (3), [PdCl₂(2)] (4), [(AuCl)(μ-1)] (6), [Co₄(CO)₅(μ-CO)₃(μ-dppa)(μ-1)] (dppa = Ph₂PNHPPh₂) (8) and [Co₄(CO)₅(μ-CO)₃(μ-dppm)(μ-1)] (dppm = Ph₂PCH₂PPh₂) (9) have been determined by X-ray diffraction. Whereas the diphosphine ligands chelate the metal center in 3 and 4, and in the Pt(II) complex 5 which is analogous to 3, ligand 1 acts as a bridge in 6 where the separation between the two Au(I) centers is 3.0402(5) Å. In the tetranuclear clusters 8 and 9, and in the cluster 10 analogous to 9 with 2 as bridging ligand, two orthogonal Co–Co edges are bridged by a diphosphine ligand and each cobalt center is thus coordinated by one P donor. Complex 3 was shown to react with the Pd(0) complex [Pd(dba)₂] (dba = dibenzylideneacetone) to afford a tetranuclear complex resulting from both the insertion of Pd(0) into the ligand C–Br bond and Pd(II)/Pd(0) comproportionation to form a doubly ligand-bridged Pd(I)–Pd(I) core.     

Synthesis,characterization, biological evaluation and molecular docking studies of 2-(1H-benzo[d]imidazol-2-ylthio)-<Emphasis Type="Italic">N</Emphasis>-(substituted 4-oxothiazolidin-3-yl) acetamides

Background

A series of 2-(1H-benzo[d]imidazol-2-ylthio)-N-(substituted 4-oxothiazolidin-3-yl) acetamides was synthesized and characterized by physicochemical and spectral means. The synthesized compounds were evaluated for their in vitro antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Candida albicans and Aspergillus niger by tube dilution method. The in vitro cytotoxicity study of the compounds was carried out against human colorectal (HCT116) cell line. The most promising anticancer derivatives (5l, 5k, 5i and 5p) were further docked to study their binding efficacy to the active site of the cyclin-dependent kinase-8.

Results

All the compounds possessed significant antimicrobial activity with MIC in the range of 0.007 and 0.061 µM/ml. The cytotoxicity study revealed that almost all the derivatives were potent in inhibiting the growth of HCT116 cell line in comparison to the standard drug 5-fluorouracil. Compounds 5l and 5k (IC₅₀ = 0.00005 and 0.00012 µM/ml, respectively) were highly cytotoxic towards HCT116 cell line in comparison to 5-fluorouracil (IC₅₀ = 0.00615 µM/ml) taken as standard drug.

Conclusion

The molecular docking studies of potent anticancer compounds 5l, 5k, 5i and 5p showed their putative binding mode and significant interactions with cyclin-dependent kinase-8 as prospective agents for treating colon cancer.

     

Synthesis and in vitro cytotoxic evaluation of some novel hexahydroquinoline derivatives containing benzofuran moiety

A series of new ethyl 4-(2-(benzofuran-2-yl)-4-substituted-1,4,5,6,7,8-hexahydroquinolin-1-yl)-benzoate 3a–c was synthesized by Michael condensation of benzofuran chalcones 1a–c and cyclohexanone to give 2-(2-benzofuranyl)-4-substituted-5,6,7,8-tetrahydro-4-H -chromene 2a–c, followed by reaction of the latter with ethyl 4-aminobenzoate. Condensation of 3a–c with different amines afforded the corresponding amides 4a–e. On the other hand, upon treatment compounds 3a–c with hydrazine hydrate gave the benzohydrazide derivatives 5a–c. The reaction of compounds 5a–c with different thio/isocyanate gave the corresponding thiosemicarbazide and semicarbazide derivatives 6a–c. Meanwhile compounds 5a–c were reacted with ethyl cyanoacetate and different β-dicarbonyl compounds such as acetyl acetone, ethyl acetoacetate, and diethyl malonate to afford pyrazolyl derivatives 7a, b; 8a, b; 9a, b; and 10a–c, respectively. Moreover, 5a–c were reacted with carbon disulfide to synthesize the corresponding oxadiazolyl derivatives 11a–c, while their condensation with different aromatic aldehydes gave the corresponding Schiff bases 12a–d. Cytotoxic evaluation of some of the newly synthesized compounds against human hepatocellular carcinoma cell lines (HepG-2) revealed that the tested compounds produce promising inhibitory effect against the growth of HepG-2 cells with IC₅₀ values ranged from 11.9 to 19.3 µg/mL.     

Regioselective Friedel–Crafts deacylations of polycyclic aromatic ketones in the pyrene series

1,3,6,8-tetrabenzoylpyrene (1,3,6,8-Bz ₄ PY) and 1,3,6-tribenzoylpyrene (1,3,6-Bz ₃ PY) were synthesized and their crystal structures were determined. The Friedel–Crafts deacylations in PPA of 1,3,6,8-Bz ₄ PY (at 120–200 °C) and of 1,3,6-Bz ₃ PY (at 80–160 °C) have been studied. The mono-deacylation of 1,3,6-Bz ₃ PY was regioselective and led to three dibenzoylpyrenes in the following order of relative amounts: 1,8-Bz ₂ PY > 1,6-Bz ₂ PY > 1,3-Bz ₂ PY. 1,3,6,8-Bz ₄ PY was resistant to deacylation at 120–160 °C. The deacylations of 1,3,6,8-Bz ₄ PY at 200 °C gave the polycyclic aromatic ketone (PAK) 8H-dibenzo[def,qr]chrysen-8-one (DBCO) via an intramolecular Scholl reaction. Two plausible pathways of the Friedel–Crafts deacylation of 1,3,6,8-Bz ₄ PY to give DBCO are proposed. A density functional theory (DFT) B3LYP/6-311(d,p) computational study of the conformational spaces of 1,3,6-Bz ₃ PY and 1,3,6,8-Bz ₄ PY was performed. The estimated energy barriers of formation of dibenzoylpyrenes by deacylation of 1,3,6-Bz ₃ PY increase in the following order: 1,8-Bz ₂ PY < 1,3-Bz ₂ PY < 1,6-Bz ₂ PY. A mechanism of the Friedel–Crafts deacylation of 1,3,6-Bz ₃ PY in PPA via the respective O-protonated ketone and σ-complexes is presented.     

Synthesis and antitumor activity of novel phenylhydrazonopyrazolone derivatives and molecular dynamics simulations

SHP2 is a new promising target for anti-cancer drug discovery. A series of novel phenylhydrazonopyrazolone derivatives was synthesized by a more convenient method, and their chemical structures were characterized by various spectroscopic methods. The inhibitory effects of these compounds on SHP2 enzyme and SHP2-dependent cancer cell H1975 were evaluated. The compound 11f with IC₅₀ value of 3.38 μmol/L exhibited more potent antitumor activity against H1975 cell than GS-493 (IC₅₀?=?20.92 μmol/L). Molecular dynamics simulation of compound 11f displayed a possible mode of interaction between this compound and SHP2 enzyme.     

Synthesis and characterization of half-sandwich ruthenium(II) complexes with N-alkyl pyridyl-imine ligands and their application in transfer hydrogenation of ketones

A series of new arene ruthenium(II) complexes were prepared by reaction of ruthenium(II) precursors of the general formula [(η⁶-arene)Ru(μ-Cl)Cl]₂ with N,N′-bidentate pyridyl-imine ligands to form complexes of the type [(η⁶-arene)RuCl(C₅H₄N-2-CH=N-R)]PF₆, with arene = C₆H₆, R = iso-propyl (1a), tert-butyl (1b), cyclohexyl (1c), cyclopentyl (1d) and n-butyl (1e); arene = p-cymene, R = iso-propyl (2a), tert-butyl (2b). The complexes were fully characterized by ¹H NMR and ¹³C NMR, UV–Vis and IR spectroscopies, elemental analyses, and the single-crystal X-ray structures of 2a and 2b have been determined. The single-crystal molecular structure revealed both compounds with a pseudo-octahedral geometry around the Ru(II) center, normally referred to as a piano stool conformation, with the pyridyl-imine as a bidentate N,N ligand. The activity of all complexes in the transfer hydrogenation of cyclohexanone in the presence of NaOH and iso-propanol is reported, the compounds showing turnover numbers of close to 1990 and high conversions. Complex 2b was also shown to be very effective for a range of aliphatic and cyclic ketones, giving conversions of up to 100 %.     

The role of substituents in a bidentate <Emphasis Type="Italic">N</Emphasis>,<Emphasis Type="Italic">N</Emphasis>-chelating ligand on the substitution of aqua ligands from mononuclear Pt(II) complexes

The rate of substitution of aqua ligands from three mononuclear platinum(II) complexes, namely [Pt{2-(pyrazol-1-ylmethyl)pyridine}(H₂O)₂](ClO₄)₂, [Pt(H ₂ Py)]; [Pt{2-(3,5-dimethylpyrazol-1-ylmethyl)pyridine}(H₂O)₂](ClO₄)₂, [Pt(dCH ₃ Py)] and [Pt{2-[(3,5-bis(trifluoromethyl)pyrazoly-1-ylmethyl]pyridine}(H₂O)₂](ClO₄)₂, [Pt(dCF ₃ Py)] by thiourea, N,N-dimethylthiourea and N,N,N′,N′-tetramethylthiourea, was studied in aqueous perchloric acid medium of constant ionic strength. The substitution reactions were investigated under pseudo-first-order conditions as a function of nucleophile concentration and temperature using UV/Visible and stopped-flow spectrophotometries. The observed pseudo-first-order rate constants, \( k_{{{\text{obs }}\left( {1/2} \right)}} \), for the stepwise substitution of the first and second aqua ligands obeyed the rate law: \( k_{{{\text{obs}}\left( {1/2} \right)}} = k_{{2 \left( { 1 {\text{st/2nd}}} \right)}} \left[ {\text{Nu}} \right] \). The first substitution reaction takes place trans to the pyrazole ligand, while the second entering nucleophile is stabilised at the reaction site trans to the pyridine ligand. The rate of substitution of the first aqua ligand from the complexes followed the order: Pt(dCF ₃ Py) > Pt(H ₂ Py) > Pt(dCH ₃ Py), while that of the second was Pt(H ₂ Py) ≈ Pt(dCF ₃ Py) > Pt(dCH ₃ Py). Lower pK _a values were found for the deprotonation of the aqua ligand cis to the pyrazole ring. Density functional theory calculations were performed to support the interpretation of the experimental results.