Synthesis and biological evaluation of some pyrazole derivatives as anti-inflammatory–antibacterial agents

The present article describes the synthesis of two novel series of thiosemicarbazones 3 and thiazolylhydrazinomethylidenepyrazoles 5. All the newly synthesized target compounds (3a–e and 5a–o) were screened for their in vivo anti-inflammatory (AI) activity using carrageenan-induced rat paw edema assay and in vitro antibacterial activity against two Gram-positive and two Gram-negative bacteria. Eight compounds (3b–d, 5b, 5e, 5f, 5i, and 5o) showed consistently excellent AI activity (≥70% inhibition), at 3?and 4?h after the carrageenan injection, comparable to that of standard drug indomethacin (78%) whereas the remaining twelve compounds have shown significant activity with 57–75% inhibition after 3?h and 56–63% inhibition after 4?h. All the tested compounds showed moderate antibacterial properties.     

Synthesis, biological evaluation, and molecular modeling studies of novel heterocyclic compounds as anti-proliferative agents

Two novel series of heterocyclic compounds have been synthesized. In first series, isatin was allowed to react with substituted aromatic/cyclic carbonyl compounds to get desired mannich bases (2a–e). In second series, 4,5-disubstituted oxazoles (6a–p) were synthesized. Eight compounds (2c, 6a, 6e, 6f, 6i, 6j, 6m, and 6n) were screened for anticancer activity in 60 cell lines. Compound 2c, 1-[(4,7,7-trimethyl-3-oxobicyclo[2.2.1]heptan-2-yl)methyl]indoline-2,3-dione, showed maximum activity and thus, selected for further evaluation at five dose level screening. Furthermore, molecular docking studies of compounds 2c into the colchicine-binding site of tubulin, revealed possible mode of inhibition by the compound.     

Newer thiazolopyrimidine-based sulfonamides clubbed with benzothiazole moiety: synthesis and biological evaluation

A new class of thiazolopyrimidine-based sulfonamides (5a–j) was synthesized from a parent compound 2-methoxy benzoic acid by multistep reaction in order to find new agents to fight against microbial infections. Substituted thiazolopyrimidines (3a–e) were prepared by cyclocondensation of substituted thiazolidinediones (2a–e) with urea in the presence of acid catalyst P₂O₅. Finally, desired compounds (5a–j) were synthesized from intermediates (4a–e) prepared from compounds (3a–e) by chlorosulfonation followed by condensation with corresponding benzothiazole moiety. The synthesized compounds were characterized by IR, ¹H-NMR, ¹³C-NMR spectral data, and elemental analysis, and were evaluated for in vitro antimicrobial activity against certain bacterial and fungal strains using the broth microdilution method as well as antitubercular activity against H₃₇Rv using Lowenstein–Jensen agar method.     

Synthesis and antitumor screening of new series of pyrimido-[4,5-b]quinolines and [1,2,4]triazolo[2′,3′:3,4]pyrimido[6,5-b]quinolines

New series of pyrimido[4,5-b]quinolines and [1,2,4]triazolo[2′,3′:3,4]pyrimido[6,5-b]quinolines have been synthesized. Compounds 4a, 4e, 4f, 4h, 5b, 5d, 6a, 6d, 6e, 8c, 8d, 10c–e, 10h, 11a, 11b, and 12a were tested for in vitro antitumor activity against human breast carcinoma (MCF-7) cell line, where compound 8d was found to be the most active member with IC₅₀ value of 3.62 μM. The DNA-binding affinity for the same compounds showed that compounds 8d and 10d exhibited the highest affinity to DNA. The detailed synthesis, spectroscopic, and biological data are reported.     

Synthesis and evaluation of some semicarbazone- and thiosemicarbazone-based cathepsin B inhibitors

In the present work, we report the synthesis and systematic evaluation of differently substituted semicarbazones and thiosemicarbazones on lysosomal cysteine protease, cathepsin B [3.4.22.1]. Thiosemicarbazones have been found to inhibit cathepsin B activity to a greater extent than semicarbazones. Among the differently functionalized semicarbazones (1a–1j) and thiosemicarbazones (2a–2j), chloro-substituted compounds have been found to inhibit cathepsin B most effectively with the K _i value of 1.16 × 10^?4 and 1.48 × 10^?5 M, respectively. The designed derivatives have been found to be competitive inhibitors to cathepsin B. The results of docking experiments also show a decrease in energy after ligand–enzyme active site interaction supporting the designed compounds as inhibitors to cathepsin B.     

Synthesis and anticonvulsant activity of some new series of pyrrole derivatives

A new series of compounds 3a–f were synthesized from condensation method. Newly synthesized compounds were established by IR, ¹H NMR, ¹³C NMR, mass spectral and elemental analysis. Synthesized compounds 3a–f were screened for anticonvulsant activity. The compound 2,2′-({3-methyl-5-[2-phenylethenyl]-1H-pyrrole-2,4-diyl}dicarbonyl)dihydrazinecarbothioamide 3a showed significant activity compared with other compounds 3b–f against pentamethylene tetrazole-induced seizures.     

Structure–activity relationship study of thiosemicarbazones on an African trypanosome: Trypanosoma brucei brucei

To explore the structure–activity relationships of thiosemicarbazones on African trypanosome: Trypanosoma brucei brucei, a series of thirty-five thiosemicarbazones (1–35) have been synthesized and characterized by their ¹H NMR, ¹³C NMR, and FT-IR spectra. All compounds were tested for trypanocidal activity using the method “Lilit alamar blue”. The comparison of trypanocidal power of thiosemicarbazones was performed considering their structures. This study that was done using acetophenone thiosemicarbazone (1) as basic model, showed that: (a) the presence of lipophilic substituents in para position on benzene ring, (b) substitution of benzene ring and (c) substitution of hydrogen of thioamide function by a phenyl, strongly influence trypanocidal activity. The various modifications to basic structure (1) allowed the synthesis of 1-(4-chlorophenyl) ethylidene-4-phenyl-thiosemicarbazide (34). With a trypanocidal activity of 3.97 μM, this compound is the most active of the series.     

Synthesis, anti-inflammatory, and cytotoxicity evaluation of 9,10-dihydroanthracene-9,10-α,β-succinimide and bis-succinimide derivatives

9,10-Dihydroanthracene-9,10-α,β-succinimide derivatives 4a–e and bis-succinimide derivatives 6a–e have been synthesized by grinding 9,10-dihydroanthracene-9,10-α,β-succinic anhydride 2 with various mono 3a–e and diamines 5a–e in quantitative yields. All the target compounds were fully characterized by spectrometric and spectroscopic means. Compounds 4a–e, 6a–e and recently reported compounds 4f–p were screened for anti-inflammatory and for cytotoxicity against five human cancer cell lines: T47D, NCI H-522, HCT-15, PA1, and HepG-2. Compounds 4e, 4i, 4j, and 4p exhibited good anti-inflammatory activity and compounds with interesting cytotoxic profile were 4c, 6e (T47D); 4e, 4o (NCI H-522); 4n (HCT-15); 4e, 4h, 4o (PA1); and 4a, 4e, 4f, 4i, 4o (HepG-2).     

Synthesis and biological evaluation of novel curcumin analogues as anti-inflammatory, anti-cancer and anti-oxidant agents

A series of novel curcumin analogues 5a–m were synthesized by Claisen-Schmidt condensation of various aromatic and heteroaromatic amides of 3-aminoactophenones 4a–m with 3-bromo-2,4,6-trimethoxybenzaldehyde and characterized by IR, ¹H NMR and mass spectroscopic analysis and were evaluated for anti-inflammatory, anti-cancer and anti-oxidant activity. Out of the 13 synthesized compounds, compounds 5f, 5j and 5m were excellent inhibitors of TNF-α and IL-6. Compounds 5c, 5e, 5b and 5d showed potent COX-2 inhibition, compounds 5d and 5f have shown good trypsin inhibition and compounds 5e, 5g and 5c exhibited excellent β-glucuronidase inhibition. Compounds 5l and 5m showed potent anti-cancer activity against selected five human cancer cell lines. All the compounds exhibited moderate free radical scavenging activity, while compounds 5a and 5m were excellent OH radical scavengers.     

Synthesis and biological evaluation of novel hydroquinone dimethyl ethers as potential anticancer and antimicrobial agents

The synthesis of two novel series of quinol dimethyl ethers linked to either various functionalities or to some biologically active nitrogenous heterocycles is described. Nine of the newly synthesized quinol dimethyl ethers 5a, b, 9b, 10a, d, 12a, b, and 13a, b were selected by the NCI and were tested initially at a single high dose (10 μM) in the full NCI 60 cell panel. Four of the screened quinol dimethyl ethers bearing unsubstituted phenylhydrazone 5a, 4-chlorophenylhydrazone 5b, 4-chlorophenyl-3-sulfanyl-1,2,4-triazole 9b, as well as 4-chloroanilino-1,3,4-oxadiazole 12b moieties satisfied the threshold antitumor screen. 4-Chlorophenylhydrazone 5b showed very promising results and accordingly was chosen for in vivo antitumor screening. Thus, compound 5b of the series could be considered as the potential lead for development of novel anticancer agents. In addition, compounds 5a–c, 6a–c, 9a–c, 10a, b, d, e, g, h, 11a–c, 12a–c, and 13a–c were screened for their in vitro antimicrobial activity. Some of the tested compounds exhibited special high activity comparable to the reference ampicillin against Pseudomonas aeruginosa and Escherichia coli.     

Synthesis, antitumor activity of 2-amino-4H-benzo[h]chromene derivatives, and structure–activity relationships of the 3- and 4-positions

Several 2-amino-4H-benzo[h]chromenes (3a–i) and (5a–h) were obtained by reaction of 4-chloro-1-naphthol (1) with α-cyanocinnamonitrile (2a–i) or ethyl α-cyanocinnamate derivatives (4a–h), respectively. Structures of these compounds were established on the basis of spectral data. The antitumor activity of the synthesized compounds was investigated in comparison with Vinblastine, Colchicine, and Doxorubicin well-known anticancer drugs, using MTT colorimetric assay. Among them, the compounds 5e, 3c, 5f, b, d, 3d, 5c, a were the most active against MCF-7, 5a against HCT-116 and 5a, 3e, a against HepG-2 as compared with the standard drug Vinblastine, while the compounds 5e, 3c, 5f, b, d, 3d, 5c, a, h, 3i, g, a, e were the most active against MCF-7, 5a, c, e, f, b, 3e, c, g, b, 5d, h, 3d, i, 5g against HCT-116, 5a, 3e, a, 5e, 3c, 5d, c, f, 3b, 5g, 3g, 5h against HepG-2 as compared with the standard drug Colchicine. The structure–activity relationships of the 3- and 4-positions were discussed.     

Synthesis and antitumor evaluation of some novel pyrrolizine derivatives

Novel series of pyrrolizines (7, 9a–d, 10a–d, 11a, b, 14a–d, 16, 19, 20a, b, 24, 25a, b), pyrimido[5,4-a]pyrrolizines (12a, b, 13, 15a, b, 18, 21a, b, 22, 23a–d) and pyrido[3,2-a]pyrrolizines (17, 26a, b) were synthesized through different reactions. The chemical structures of all the synthesized pyrrolizine derivatives were determined by spectral and elemental analyses. Antitumor activity evaluation of all the prepared compounds was carried out using NR assay method against breast cancer cell line (MCF-7). The novel pyrrolizine scaffold 7 and all its prepared derivatives showed high antitumor activity comparable to that of doxorubicin.     

Synthesis and pharmacological evaluation of some novel 2-pyrazolines bearing benzenesulfonamide as anti-inflammatory and blood glucose lowering agents

A series of novel pyrazolines (2a–l) bearing benzenesulfonamide moiety were synthesized by condensing appropriate chalcone (1a–l) with 4-hydrazinobenzenesulfonamide hydrochloride. Structure of all novel synthesized compounds was characterized on basis of elemental analysis data and spectral data (IR, ¹HNMR, MS). Compounds (2a–l) were screened for in vivo anti-inflammatory action in carrageenan-induced rat paw edema model and blood glucose lowering action in glucose fed hyperglycemic normal rats. Compounds 2a, 2e, and 2l showed significant anti-inflammatory action (more than 75 %) at 5 h and also showed superior gastrointestinal safety profiles as compared to celecoxib. One compound (2i) was found to exhibit significant blood glucose lowering activity.     

Synthesis, antioxidant, and antibacterial studies of phenolic esters and amides of 2-(1-benzofuran-2-yl) quinoline-4-carboxylic acid

A new series of phenolic esters 2(a–j) and amides 3(a–c) of 2-(1-benzofuran-2-yl) quinoline-4-carboxylic acid were synthesized by the reaction of 2-(1-benzofuran-2-yl)-quinoline-4-carboxylic acid (1) with various substituted phenols and secondary amines using ethyl-(N′,N′-dimethylamino)propyl carbodiimide hydrochloride (EDC.HCl) as a coupling agent. The newly synthesized compounds were evaluated for in vitro antioxidant and antibacterial activity. Among all tested compounds 2a, 2c, 2e, and 2h showed good chelating ability with Fe⁺² ions, whereas compounds 2g and 2j exhibited good scavenging activity with DPPH free radicals. Concerning antibacterial activities compounds 2a, 2b, 2c, and 2h were found to be equipotent to ampicillin against Enterococcus sp and Staphylococcus aureus, while compound 2e is found to be as potent as ampicillin against Pantoea Dispersa and Ochrobactrum sp. amide derivatives 3(a–c) were found to be less potent when compared to standard.     

The synthesis, anti-inflammatory, and anti-microbial activity evaluation of new series of 4-(3-arylureido)phenyl-1,4-dihydropyridine urea derivatives

A new series of 4-(3-arylureido)phenyl-1,4-dihydropyridine urea derivatives were synthesized using simple three component condensation, reduction, and nucleophilic addition sequence in moderate to good yields. All the synthesized compounds 6a–j were evaluated for their anti-inflammatory [against the pro-inflammatory cytokines (tumor necrosis factor-alpha, TNF-α and interleukin-6, IL-6)] and anti-microbial activity (anti-bacterial and anti-fungal). Among all the compound screened, the compound 6b, 6f, and 6j were found to have promising anti-inflammatory activity, 74–83 % TNF-α and 91–96 % IL-6 inhibitory activity, respectively as compared to the standard dexamethasone (71 and 86 % inhibition) but at the MIC of 10 μM/ml. The compounds 6d–e and 6h exhibited relatively lower TNF-α and IL-6 inhibitory activity and found to be moderately potent anti-inflammatory agents. The compounds 6c–e, 6g, and 6i were found to be promising anti-bacterial and anti-fungal agents and remarkably some of the new compounds, viz. 6d and 6i were found be more potent than the standard ciprofloxacin or miconazole. It is to be noted that this is the first report on the anti-inflammatory activity evaluation of novel 1,4-dihydropyridine urea derivatives against the important molecular target, TNF-α, and IL-6.     

1-(7-Chloroquinolin-4-yl)-2-[(1H-pyrrol-2-yl)methylene]hydrazine: a potent compound against cancer

Heteroaromatic derivatives (3a–f) have been synthesized and evaluated for their activity against four cancer cell lines. Among the studied compounds, 1-(7-Chloroquinolin-4-yl)-2-[(1H-pyrrol-2-yl)methylene]hydrazine (3e) exhibited an excellent cytotoxic activity against the referred lines, and especially on melanoma cells (MDAMB-435). In this case, compound 3e is four times more active than the standard substance Doxorubicin. Together with other results from our group, 7-chloro-4-quinolinylhydrazones derived from chloroquine could be considered a relevant finding toward the rational design of new leads for antitumor compounds.     

Synthesis and biological evaluation of novel benzoquinones as potential antimicrobial agents

New series of 2,5-dihydroxyphenyl-1,3-thiazoles 4a–l was synthesized by reacting 2,5-dihydroxyphenacyl bromide with various 4-aryl thiosemicarbazones 3a–l that on oxidation with ferric chloride yielded the corresponding N ¹-substituted benzylidene-N ²-[3-aryl-4-(1,4-benzoquinon-2-yl)-1,3-thiazol-2-ylidene]hydrazines 5a–l. They were evaluated for antibacterial activity against Staphylococcus aureus and Bacillus subtilis as Gram-positive bacteria, Escherichia coli and Pseudomonas aeruginosa as Gram-negative bacteria. They were also evaluated for their in vitro antifungal potential against Candida albicans. Almost all tested compounds were found to possess variable degrees of antimicrobial activity. The obtained data revealed that compounds 4b–h and 5e, 5f and 5l exhibited promising antimicrobial activity against the tested organisms of which compound 4b proved to be the most active.     

Synthesis and pharmacological evaluation of some novel 4-isopropyl thiazole-based sulfonyl derivatives as potent antimicrobial and antitubercular agents

A series of novel sulfonyl derivatives 3-(substituted benzylsulfonyl)-5-(4-isopropylthiazol-2-yl)-4-phenyl-4H-1,2,4-triazoles 4a–4e, isopropyl thiazole-derived schiff bases 8a–8l, and 2-(substituted benzylsulfonyl)-5-(4-isopropylthiazol-2-yl)-1,3,4-oxadiazoles 11a–11e were synthesized and characterized by IR, ¹H NMR, ¹³C NMR, elemental, and mass spectral analysis. All the compounds exhibited moderate to significant antibacterial and antifungal activities. Results of the antitubercular screening against Mycobacterium tuberculosis H37Rv ascertain compounds 4e, 8b, and 8f as excellent antitubercular molecules, when compared with first line drug isoniazid (0.25 μg/mL).     

Synthesis,antimicrobial, and antioxidant activity of benzofuran barbitone and benzofuran thiobarbitone derivatives

The synthesis of novel series of benzofuran derivatives, containing barbitone moiety, 5-[(2/4-substitutedphenyl)(5-substituted-1-benzofuran-2-yl) methylidene]pyrimidin-2,4,6(1H,3H,5H)-trione (4a–i) and thiobarbitone moiety, 5-[(2/4-substitutedphenyl)(5-substituted-1-benzofuran-2-yl)methylidene]-2-thioxodihydropyrimidin-4,6(1H, 5H)-dione (5a–i) have been reported. The target compounds (4a–i) and (5a–i) were synthesized by the Knoevenagel condensation of (5-substituted-1-benzofuran-2-yl)(2/4-substitutedphenyl) methanone (3a–i) with barbituric acid and thiobarbituric acid, respectively, in acid medium. These compounds were screened for the antimicrobial and antioxidant activities. From antimicrobial activity results it was found that compounds 4a, 5a, 4c, and 5c displayed good antibacterial and antifungal activity against all tested strains. Further, the synthesized compounds were studied for docking on the enzyme, Glucosamine-6-phosphate synthase and the compounds 4c and 5c have emerged has an active antimicrobial agent with least binding energy (?5.27 and ?4.85 kJ mol^?1). Compounds 4e, 4f, 5e, and 5f showed promising free radical scavenging activity and compounds 5a and 5b showed good chelating ability with Fe²⁺ ions.     

Synthesis and antitumor activity of certain new thiazolo[2,3-b]quinazoline and thiazolo[3,2-a]pyrimidine analogs

A novel series of thiazolo[2,3-b]quinazoline (16–19, 25–28, and 34–37) and cyclohepta[d]thiazolo[3,2-a]pyrimidine (20–23, 29–32, and 38–41) analogs was designed and synthesized. Structure elucidation of the synthesized compounds was attained by the use of H¹ NMR, C¹³ NMR, and mass spectrometry. The obtained compounds were evaluated for their in vitro antitumor activity using the National Cancer Institute’s 60 cell lines’ panel assay that included nine tumor subpanels, namely, leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancer cells. Most of the investigated compounds showed a remarkable broad-spectrum antitumor activity. Compounds 19, 28, 32, and 34 proved to be 10-, 15-, 2-, and 7-fold more active than 5-FU, with GI₅₀ MG-MID values of 2.4, 1.5, 11.2, and 3.1 μM, respectively.