Inhibitory effects of triarylpyrazole derivatives on LPS-induced nitric oxide and PGE2 productions in murine RAW 264.7 macrophages.

In this article, a series of 22 triarylpyrazole derivatives were evaluated for in vitro antiinflammatory activity as inhibitors of nitric oxide (NO) and prostaglandin E2 (PGE2) release induced by lipopolysaccharide (LPS) in murine RAW 264.7 macrophages. The synthesized compounds 1a-h, 2a-f and 3a-h were first examined for their cytotoxicity for determination of the non-toxic concentration for antiinflammatory screening, so that the inhibitory effects against NO and PGE2 production were not caused by non-specific cytotoxicity. Compounds 1h and 2f were the most active PGE2 inhibitors with IC50 values of 2.94 µM and 4.21 µM, respectively. Western blotting and cell-free COX-2 screening revealed that their effects were due to inhibition of COX-2 protein expression. Moreover, compound 1h exerted strong inhibitory effect on the expression of COX-2 mRNA in LPS-induced murine RAW 264.7 macrophages.

Synthesis of New Triarylpyrazole Derivatives Possessing Terminal Sulfonamide Moiety and Their Inhibitory Effects on PGE2 and Nitric Oxide Productions in Lipopolysaccharide-Induced RAW 264.7 Macrophages.

This article describes the design, synthesis, and in vitro anti-inflammatory screening of new triarylpyrazole derivatives. A total of 34 new compounds were synthesized containing a terminal arylsulfonamide moiety and a different linker between the sulfonamide and pyridine ring at position 4 of the pyrazole ring. All the target compounds were tested for both cytotoxicity and nitric oxide (NO) production inhibition in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Compounds 1b, 1d, 1g, 2a, and 2c showed the highest NO inhibition percentages and the lowest cytotoxic effect. The most potent derivatives were tested for their ability to inhibit prostaglandin E2 (PGE2) in LPS-induced RAW 264.7 macrophages. The IC50 for nitric oxide inhibition, PGE2 inhibition, and cell viability were determined. In addition, 1b, 1d, 1g, 2a, and 2c were tested for their inhibitory effect on LPS-induced inducible nitric oxide synthase (iNOS) and Cyclooxygenase 2 (COX-2) protein expression as well as iNOS enzymatic activity.

Design, synthesis, and in vitro antiproliferative and kinase inhibitory effects of pyrimidinylpyrazole derivatives terminating with arylsulfonamido or cyclic sulfamide substituents.

A novel series of substituted pyrimidine compounds bearing N-phenylpyrazole and terminating with aryl and cyclic sulfonamido moiety were designed, synthesized, and evaluated in vitro as antiproliferative agents against a panel of 53 cell lines of different tissues at the NCI. Among them, compound 1d with p-chlorobenzenesulfonamido terminal moiety, ethylene spacer, and 4-chloro-3-methoxyphenyl ring at position 3 of the pyrazole nucleus showed the highest mean percentage inhibition value over the whole cancer cell line panel at 10 µM concentration. It showed broad-spectrum antiproliferative activity over many cell lines of different cancer types. For instance, compound 1d inhibited the growth of HL-60 (TB), SR leukemia, and T-47D and MCF-7 breast cancer cell line by 135.92%, 119.44%, 95.32%, and 82.03% at 10 µM, respectively. And it inhibited the growth of COLO 205 colon, HT29 colon, BT-549 breast, and ACHN renal cancer cell lines by more than 80% at the same test concentration. However, testing compound 1d upon determining its IC50 against the most sensitive cell lines showed to good extent selectivity against HT29 colon cancer cell line than HL-60 leukemia and MRC-5 lung fibroblasts (normal cells). Compound 1d was further tested against 12 kinases of different kinase families, and the highest inhibitory effect was exerted against RAF1, V600E-B-RAF, and V600K-B-RAF kinases.

Synthesis of New Tricyclic and Tetracyclic Fused Coumarin Sulfonate Derivatives and Their Inhibitory Effects on LPS-Induced Nitric Oxide and PGE2 Productions in RAW 264.7 Macrophages: Part 2.

The synthesis of a new series of 21 fused coumarin derivatives is described, and the biological evaluation of their in vitro antiinflammatory effects as inhibitors of lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E2 (PGE2 ) production in RAW 264.7 macrophages. The target compounds 1a-u were first tested for cytotoxicity to determine a non-toxic concentration for antiinflammatory screening, so that the inhibitory effects against NO and PGE2 production would not be caused by cytotoxicity. Compounds 1f and 1p were the most active PGE2 inhibitors with IC50 values of 0.89 and 0.95 µM, respectively. Western blot and cell-free COX-2 screening showed that their effects were due to inhibition of both COX-2 protein expression and COX-2 enzyme activity. Their IC50 values against the COX-2 enzyme were 0.67 and 0.85 µM, respectively, which is more potent than etoricoxib. The selectivity indexes of compounds 1f and 1p against COX-2 compared to COX-1 were 41.1 and 42.5, respectively. Compound 1f showed strong inhibitory effects at 5 µM concentration on COX-2 mRNA expression in LPS-induced RAW 264.7 macrophages. Moreover, the tricyclic compounds 1l and 1n as well as the tetracyclic analog 1u were the most potent NO inhibitors, with one-digit micromolar IC50 values. They showed dose-dependent inhibition of inducible nitric oxide synthase (iNOS) protein expression. The tetracyclic derivative 1u was the most potent inhibitor of NO production. It also exhibited a strong inhibitory effect on iNOS mRNA expression in LPS-induced RAW 264.7 macrophages.

Cell-based biological evaluation of a new bisamide FMS kinase inhibitor possessing pyrrolo[3,2-c]pyridine scaffold.

A bisamide compound 1 possessing the pyrrolo[3,2-c]pyridine nucleus was synthesized and biologically evaluated. It was tested for kinase inhibitory activity over a panel of 47 kinases, and its selectivity toward the FMS kinase was accidentally discovered. Compound 1 was tested over a panel of seven ovarian, two prostate, and six breast cancer cell lines at a single dose concentration of 10 µM and showed high activity. It was further tested in a 5-dose mode to determine its IC50 and total growth inhibition (TGI) values over the 15 cell lines. Compound 1 showed high potency on the submicromolar scale and good efficacy. The cytotoxic effect of compound 1 over peritoneal macrophages was also investigated. Compound 1 demonstrated higher selectivity against different cancer cell lines compared with HS-27 fibroblasts.

Synthesis of pyrrolo[2,3-d]pyrimidine derivatives and their antiproliferative activity against melanoma cell line.

Synthesis of a new series of diarylureas and amides having pyrrolo[2,3-d]pyrimidine scaffold is described. Their in vitro antiproliferative activities against A375 human melanoma cell line and HS 27 fibroblast cell line were tested and the effect of substituents on pyrrolo[2,3-d]pyrimidine was investigated. The newly synthesized compounds, except N-acetyl derivatives (Id, Ie, and Im), generally showed superior or similar activity against A375 to Sorafenib. Among all of these derivatives, compounds Iq and Ir having imidazole and morpholine moieties, respectively, showed the most potent antiproliferative activity against A375.

Novel lbeta-methylcarbapenems having cyclic sulfonamide moieties: synthesis and evaluation of in vitro antibacterial activity.

The synthesis of a new series of 1beta-methylcarbapenems having cyclic sulfonamide moieties is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituent on the pyrrolidine ring was investigated. A particular compound (IIIi) having 2-methyl-[1,2,6]thiadiazinan-1,1-dioxide moiety showed the most potent antibacterial activity.

Synthesis and antibacterial activity of 1beta-methyl-2-(5-substituted thiazolo pyrrolidin-3-ylthio)carbapenem derivatives.

The synthesis of a new series of 1beta-methylcarbapenems having the substituted thiazolopyrrolidine moiety is described. Their in vitro antibacterial activities against both Gram-positive including MRSA and Gram-negative bacteria were tested and the effect of substituent on the thiazole ring was investigated. A particular compound (28c) having 4'-amide substituted thiazole moiety showed the most potent antibacterial activity.

Antiproliferative diarylpyrazole derivatives as dual inhibitors of the ERK pathway and COX-2.

A series of 3,4-diarylpyrazole-1-carboxamide derivatives was designed and synthesized. A selected group of the target compounds was tested for in vitro antiproliferative activities over a panel of 60 cancer cell lines at the National Cancer Institute (NCI, Bethesda, MD, USA) at a single-dose concentration of 10 µm, and the four most active compounds 9a, 9l, 9n, and 10o were further tested in a five-dose testing mode to determine their IC50 values over the 60 cell lines. In addition, a selected group of target compounds were tested for inhibitory effect over cyclooxygenase isozymes. Compounds 9a, 9l, 9n, and 10o were also tested for MEK and ERK kinase inhibitory activity using Western blot assay. Compound 10o was selective toward melanoma cell line subpanel, and its antiproliferative activity may be attributed to selective cyclooxygenase-2 inhibition and ERK pathway inhibition.

New diarylureas and diarylamides containing 1,3,4-triarylpyrazole scaffold: Synthesis, antiproliferative evaluation against melanoma cell lines, ERK kinase inhibition, and molecular docking studies.

Synthesis of a new series of diarylureas and diarylamides possessing 1,3,4-triarylpyrazole scaffold is described. Their in vitro antiproliferative activities against 9 human melanoma cell lines were tested. Compounds 12, 13, 15, and 21-23 showed the highest potency against A375P melanoma cell line. In addition, compounds 10-15 and 19-24 showed high potency over the NCI 8 tested melanoma cell-lines panel. The IC(50) values for compound 23 were 0.36 µM and 0.84 µM over LOX IMVI and M14 cell lines, respectively. Compounds 21 and 23 showed high, dose-dependent inhibition of ERK kinase. Virtual screening was carried out through docking of compound 21 into the domain of V600E-B-RAF and the binding mode was studied.

Synthesis and antibacterial activity of 1beta-methyl-2-[5-(1,2-disubstituted ethyl)pyrrolidin-3-ylthio]carbapenem derivatives.

The synthesis of a new series of 1beta-methylcarbapenems having a 5-(1,2-disubstituted ethyl) pyrrolidine moiety is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of the substituent on the pyrrolidine ring was investigated. A particular compound IIIf having a 1-methoxyimino-2-carbamoylethyl substituted moiety showed the most potent antibacterial activity.

Synthesis and antibacterial activity of 1beta-methylcarbapenems having a 2, 2-disubstituted-1, 3-diazabicyclo[3.3.0]octan-4-one moiety and related compounds. Part III.

The synthesis of new series of 1beta-methylcarbapenems having a 2, 2-disubstituted-1, 3-diazabicyclo[3.3.0]octan- and -[4.3.0]nonan-4-one moiety is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of the substituent of the bicyclic ring was investigated. A particular compound (16 f) bearing a hydroxymethyl group showed the most potent antibacterial activity and the compound (17 a) with a 1, 3-diazabicyclo[4.3.0]nonane moiety exhibited excellent stability against renal dehydropeptidase-I (DHP-I) to Meropenem.