Synthesis of new heterocyclic hybrids based on pyrazole and thiazolidinone scaffolds as potent inhibitors of tyrosinase.

As a part of ongoing studies in developing new Tyrosinase inhibitors, a class of structurally novel 2-(2,4-dimethoxy phenylamino)-5 methylene-4-thiazolinone derivatives were synthesized by incorporating 2-(2,4-dimethoxy-phenylamino)-thiazol-4-one with various 1-(1-methyl-buta-1,3-dienyl)-3-phenyl-1H-pyrazole-4-carbaldehyde. The results showed that some of the synthesized compounds exhibited significant inhibitory activities. Especially, 5-[3-(2-chloro-phenyl)-1-phenyl-1H-pyrazol-4-ylmethylene]-2-(2,4-dimethoxy-phenylamino)-thiazol-4-one (5h) and 5-[3-(3-chloro-phenyl)-1-phenyl-1H-pyrazol-4-ylmethylene]-2-(2,4-dimethoxy-phenylamino)-thiazol-4-one (5g) possessing 2-chloro-phenyl and 3-chloro-phenyl group exhibited the most potent tyrosinase inhibitory activity with an IC(50) value of 34.12 and 52.62 µM, respectively. The inhibition mechanism analysis of 5h and 5g thiazolidinone derivatives demonstrated that the inhibitory effects of the compounds on tyrosinase were reversible and competitive. Preliminary structure-activity relationships (SAR) analysis suggested that further development of such compounds might be of interest, as it manifests simple reversible slow binding inhibition against monophenolase and diphenolase.

Synthesis of novel 3,5-diaryl pyrazole derivatives using combinatorial chemistry as inhibitors of tyrosinase as well as potent anticancer, anti-inflammatory agents.

In the present article, we have synthesized a combinatorial library of 3,5-diaryl pyrazole derivatives using 8-(2-(hydroxymethyl)-1-methylpyrrolidin-3-yl)-5,7-dimethoxy-2-phenyl-4H-chromen-4-one (1) and hydrazine hydrate in absolute ethyl alcohol under the refluxed conditions. The structures of the compounds were established by IR, (1)H NMR and mass spectral analysis. All the synthesized compounds were evaluated for their anticancer activity against five cell lines (breast cancer cell line, prostate cancer cell line, promyelocytic leukemia cell line, lung cancer cell line, colon cancer cell line) and anti-inflammatory activity against TNF-alpha and IL-6. Out of 15 compounds screened, 2a and 2d exhibited promising anticancer activity (61-73% at 10 microM concentration) against all selected cell lines and IL-6 inhibition (47% and 42% at 10 microM concentration) as in comparison to standard flavopiridol (72-87% inhibition at 0.5 microM) and dexamethasone (85% inhibition at 1 microM concentration), respectively. Cytotoxicity of the compounds checked using CCK-8 cell lines and found to be nontoxic to slightly toxic. Out of 15, four 3,5-diaryl pyrazole derivatives exhibiting potent inhibitory activities against both the monophenolase and diphenolase actions of tyrosinase. The IC(50) values of compounds (2a, 2d, 2h and 2l) for monophenolase inhibition were determined to range between 1.5 and 30 microM. Compounds 2a, 2d, 2h and 2l also inhibited diphenolase significantly with IC(50) values of 29.4, 21.5, 2.84 and 19.6 microM, respectively. All four 3,5-diaryl pyrazole derivatives were active as tyrosinase inhibitors (2a, 2d, 2h and 2l), and belonging to competitive inhibitors. Interestingly, they all manifested simple reversible slow-binding inhibition against diphenolase.

Silica-supported fluoroboric acid (HBF(4)-SiO(2)) catalyzed highly productive synthesis of thiomorpholides as activators of l-asparaginase as well as the antioxidant agent.

An efficient solvent-free procedure for the synthesis of thiomorpholides in the presence of a catalytic amount of solid-supported fluoroboric acid (HBF(4)-SiO(2)) is described. The advantages of this method are high yields, short reaction times, ease of product isolation, low cost, and the catalyst can be recycled for a number of times without significant loss of activity. Three thiomorpholides possessing electron-donating group (4c, 4g, and 4h) were exhibiting excellent stimulatory activities against Erwinia carotovoral-asparaginase. The most potent activator, compound 4h displayed the following kinetic parameters, K(m)=75microM and V(max)=1000micromolmg(-1)min(-1) and K(A)=0.985microM. Furthermore, these compounds (4g, 4h, 4c, 4f, 4a, and 4d) have also shown promising 2,2'-diphenyl-1-picrylhydrazyl (DPPH) reducing antioxidant activity (21-36%) at 1mM concentration as compared to standard butylated hydroxyl anisole (72% at 1mM).

Synthesis and biological screening of a combinatorial library of beta-chlorovinyl chalcones as anticancer, anti-inflammatory and antimicrobial agents.

A combinatorial library of beta-chlorovinyl chalcones (4) were synthesized by Claisen-Schmidt condensation reaction. Catalytic reaction of substituted 3-chloro-3-phenyl-propenal (2) and 1-(2,4-dimethoxy-phenyl)-ethanone or 1-(4-methoxy-phenyl)-ethanone (3) in alkaline conditions furnished the target compound 5-chloro-1-(2,4-dimethoxy-phenyl)-5-phenyl-penta-2,4-dien-1-one (4). The synthesized compounds were screened for their biological activity viz. anticancer, anti-inflammatory and antimicrobial activities. Synthesized compounds 4g and 4h revealed promising anti-inflammatory activity (66-67% TNF-alpha and 95-97% IL-6 inhibitory activity at 10 microM). Cytotoxicity of the compounds checked using CCK-8 cell lines and found to be nontoxic to slightly toxic. Furthermore, the anticancer activity (30-40%) was shown by compounds 4d, 4e, 4h and 4b at 10 microM concentrations against ACHN followed by Calu 1, Panc1, HCT116 and H460 cell lines. Some of the compounds 4d, 4e, 4a, 4i and 4b revealed promising antimicrobial activity at MIC 50-100 microg/mL against selected pathogenic bacteria and fungi.

Synthesis and biological evaluation of simple methoxylated chalcones as anticancer, anti-inflammatory and antioxidant agents.

Chalcones have been identified as interesting compounds with cytotoxicity, anti-inflammatory and antioxidant properties. In the present study, simple methoxychalcones were synthesized by Claisen-Schmidt condensation reaction and evaluated for above biological activities. The structures of the compounds were established by IR, (1)H NMR and mass spectral analysis. The data revealed that compound 3s (99-100% at 10 microM concentration) completely inhibit the selected five human cancer cell lines as compared to standard flavopiridol and gemcitabine (70-90% at 700 nM and 500 nM concentrations, respectively), followed by 3a, 3n,3o,3p,3q,3r. Among the tested compounds 3l, 3m, 3r, and 3s exhibited promising anti-inflammatory activity against TNF-alpha and IL-6 with 90-100% inhibition at 10 microM concentration. DPPH free radical scavenging activity was given by the compounds 3o, 3n, 3l, 3r, 3m, 3a, 3p, 3c and 3s at 1mM concentration. Overall, 3s was obtained as lead compound with promising anticancer, anti-inflammatory and antioxidant activities. Bioavailability of compounds were checked by in vitro cytotoxicity study and confirmed to be nontoxic. The structure activity relationship (SAR) and in silico drug relevant properties (HBDs, HBAs, PSA, cLogP, ionization potential, molecular weight, E(HOMO) and E(LUMO)) further confirmed that the compounds were potential candidates for future drug discovery study.

Synthesis and biological evaluation of a novel series of pyrazole chalcones as anti-inflammatory, antioxidant and antimicrobial agents.

A novel series of 1-(2,4-dimethoxy-phenyl)-3-(1,3-diphenyl-1H-pyrazol-4-yl)-propenone (3) have been prepared by the Claisen-Schmidt condensation of 1-(2,4-dimethoxy-phenyl)-ethanone (1) and substituted 1,3-diphenyl-1H-pyrazole-4-carbaldehydes (2). Substituted 1,3-diphenyl-1H-pyrazole-4-carbaldehydes (2) were prepared by Vilsmeir-Haack reaction on acetophenonephenylhydrazones to offer the target compounds. The structures of the compounds were established by IR, (1)H NMR and mass spectral analysis. All the compounds were evaluated for their anti-inflammatory (TNF-alpha and IL-6 inhibitory assays), antioxidant (DPPH free radical scavenging assay) and antimicrobial activities (agar diffusion method) against some pathogenic bacteria and fungi. Of 10 compounds screened, compounds 3a, 3c and 3g exhibited promising IL-6 inhibitory (35-70% inhibition, 10 microM), free radical scavenging (25-35% DPPH activity) and antimicrobial activities (MIC 100 microg/mL and 250 microg/mL) at varied concentrations. The structure-activity relationship (SAR) and in silico drug relevant properties (HBD, HBA, PSA, cLogP, molecular weight, E(HOMO) and E(LUMO)) further confirmed that the compounds are potential lead compounds for future drug discovery study. Toxicity of the compounds was evaluated theoretically and experimentally and revealed to be nontoxic except 3d and 3j.