Novel benzenesulfonamide-bearing pyrazoles and 1,2,4-thiadiazoles as selective carbonic anhydrase inhibitors

Two series comprising 20 novel benzenesulfonamides bearing thioureido-linked pyrazole 8 and amino-1,2,4-thiadiazole 10 were synthesized and assayed as human carbonic anhydrase (hCA) inhibitors against isoforms I and II as well as the tumor-associated isoforms IX and XII. Molecular modeling studies of some potent derivatives ( 8a , 8c , 10a , and 10c ) were also performed against isoforms hCA I, II, and XII. Both the promising series of compounds were synthesized by using commercially available mtethyl ketones and sulfanilamide as the starting materials. Interestingly, this paper also reports a novel methodology for the synthesis of amino-1,2,4-thiadiazoles 10 using 3-amino isoxazoles and 4-isothiocyanatobenzenesulfonamide as reactants. The activity profile of all the newly synthesized compounds reveals that amino-linked 1,2,4-thiadiazoles 10 were better inhibitors of the cytosolic isoform, hCA I, as compared to thioureido-linked pyrazoles 8 . Further, hCA II was strongly inhibited by nearly all the newly synthesized sulfonamides, while all the compounds were less effective as hCA IX and XII inhibitors compared to the standard drug acetazolamide. However, in terms of selectivity, compound 8e was found to be the most selective inhibitor of hCA II, which is the isoform associated with glaucoma, edema, altitude sickness, and epilepsy.     

New library of pyrazole–imidazo[1,2‐α]pyridine molecular conjugates: Synthesis,antibacterial activity and molecular docking studies

A library of novel pyrazole–imidazo[1,2‐α]pyridine scaffolds was designed and synthesized through a one‐pot three‐component tandem reaction. The structures of synthesized conjugates were confirmed by spectroscopic techniques (NMR, IR and HRMS). In vitro antibacterial evaluation of the twelve synthesized molecules ( 7a , 8a–k ) against methicillin‐resistant Staphylococcus aureus and normal strains of Escherichia coli, Salmonella typhimurium, Klebsiella pneumonia and Pseudomonas aeruginosa established 8b , 8d , 8e , 8h and 8i as potent antibacterial agents with superior minimum bactericidal concentration, compared with standard drug ciprofloxacin. Molecular docking studies of all active compounds into the binding site of glucosamine‐6‐phosphate synthase were further performed in order to have a comprehensive understanding of putative binding modes within the active sites of the receptor.     

In vitro evaluation of dichloro-bis(pyrazole)palladium(II) and dichloro-bis(pyrazole)platinum(II) complexes as anticancer agents

Introduction  Cisplatin (cis-diamminedichloroplatinum) was first identified for its anti-bacterial activity, and was later also shown to be an efficient anticancer agent. However, the therapeutic use of this anticancer drug is somewhat limited by its toxic side effects, which include nephrotoxicity, nausea, and vomiting. Furthermore the development of drug-resistant tumours is commonly observed following therapy with cisplatin. Hence there is a need for improved platinum derived drugs to overcome these limitations. Aims  Apoptosis contributes significantly to the cytotoxic effects of anticancer agents such as cisplatin; therefore in this study the potential anticancer properties of a series of pyrazole palladium(II) and platinum(II) complexes, [(3,5-R₂pz)₂PdCl₂] {R = H (1), R = Me (2)} and [(3,5-R₂pz)₂PtCl₂] {R = H (3), R = Me (4)}, were evaluated by assessment of their pro-apoptotic activity. Methods  The induction of apoptosis was measured in CHO cells by the detection of phosphatidylserine (PS) exposure using the annexin V and APOPercentage™ assays; DNA fragmentation using the Terminal deoxynucleotide transferase dUTP Nick End Labelling (TUNEL) assay; and the detection of activated caspase-3. Results  The platinum complexes were shown to be considerably more active than the palladium complexes, with complex 3 demonstrating the highest level of cytotoxic and pro-apoptotic activity. The LD₅₀ values for complex 3 and cisplatin were 20 and 70 μM, respectively, demonstrating that the cytotoxic activity for complex 3 was three times higher than for cisplatin. Various human cancer cell lines, including CaSki, HeLa, as well as the p53 mutant Jurkat T cell line were also shown to be susceptible to complex 3. Conclusions  Collectively, this in vitro study provides insights into action of palladium and platinum complexes and demonstrates the potential use of these compounds, and in particular complex 3, in the development of new anticancer agents.     

Pyrazole exacerbates handling-induced convulsions in mice

Severity of handling-induced convulsions was reduced in mice in comparison to the scores on an initial test administered 4 days earlier. Daily injections of pyrazole, an inhibitor of alcohol dehydrogenase, prevented the reduction of convulsions in handled mice and exacerbated convulsions in mice tested for the first time after injection. The effects of pyrazole were dose-related.     

Synthesis and cytotoxicity of bis-1,3,4-oxadiazoles and bis-pyrazoles derived from 1,4-bis[5-thio-4-substituted-1,2,4-triazol-3-yl]-butane and their DNA binding studies

A new series of 1,4-bis[5-(5-mercapto-1,3,4-oxadiazol-2-yl-methyl)-thio-4-substituted-1,2,4-triazol-3-yl]-butane 7-12 and 1,4-bis[5-(1-oxo-1-(3,5 dimethyl pyrazol-1-yl)-methyl)-thio-4-substitued-1,2,4-triazol-3-yl]-butane 13-18 were prepared from 1,4-bis(5[hydrazinocarbonylmethylthio]-4-substituted-1,2,4-triazol-3-yl) butane based derivativess were synthesized 1-6. All the synthesized compounds were characterized by IR, NMR and Mass spectral studies. The synthesized compounds 7-18 were screened for in-vitro cytotoxicity potential using the standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay against a panel of three human cancer cell lines: Lung carcinoma A-549, colon carcinoma HT-29 and breast cancer MDA MB-231. DNA binding studies were conducted for three potent molecules by absorption titration method.     

Nitric oxide donors prevent while the nitric oxide synthase inhibitor L-NAME increases arachidonic acid plus CYP2E1-dependent toxicity

Polyunsaturated fatty acids such as arachidonic acid (AA) play an important role in alcohol-induced liver injury. AA promotes toxicity in rat hepatocytes with high levels of cytochrome P4502E1 and in HepG2 E47 cells which express CYP2E1. Nitric oxide (NO) participates in the regulation of various cell activities as well as in cytotoxic events. NO may act as a protectant against cytotoxic stress or may enhance cytotoxicity when produced at elevated concentrations. The goal of the current study was to evaluate the effect of endogenously or exogenously produced NO on AA toxicity in liver cells with high expression of CYP2E1 and assess possible mechanisms for its actions. Pyrazole-induced rat hepatocytes or HepG2 cells expressing CYP2E1 were treated with AA in the presence or absence of an inhibitor of nitric oxide synthase L-N(G)-Nitroarginine Methylester (L-NAME) or the NO donors S-nitroso-N-acetylpenicillamine (SNAP), and (Z)-1-[-(2-aminoethyl)-N-(2-aminoethyl)]diazen-1-ium-1,2-diolate (DETA-NONO). AA decreased cell viability from 100% to 48+/-6% after treatment for 48 h. In the presence of L-NAME, viability was further lowered to 23+/-5%, while, SNAP or DETA-NONO increased viability to 66+/-8 or 71+/-6%. The L-NAME potentiated toxicity was primarily necrotic in nature. L-NAME did not affect CYP2E1 activity or CYP2E1 content. SNAP significantly lowered CYP2E1 activity but not protein. AA treatment increased lipid peroxidation and lowered GSH levels. L-NAME potentiated while SNAP prevented these changes. Thus, L-NAME increased, while NO donors decreased AA-induced oxidative stress. Antioxidants prevented the L-NAME potentiation of AA toxicity. Damage to mitochondria by AA was shown by a decline in the mitochondrial membrane potential (MMP). L-NAME potentiated this decline in MMP in association with its increase in AA-induced oxidative stress and toxicity. NO donors decreased this decline in MMP in association with their decrease in AA-induced oxidative stress and toxicity. These results indicate that NO can be hepatoprotective against CYP2E1-dependent toxicity, preventing AA-induced oxidative stress.     

Synthesis and molecular modelling of novel substituted-4,5-dihydro-(1H)-pyrazole derivatives as potent and highly selective monoamine oxidase-A inhibitors

This report describes novel pyrazoline derivatives investigated for their ability to selectively inhibit the activity of the A and B isoforms of monoamine oxidase. These new synthetic compounds proved to be reversible, potent, and selective inhibitors of monoamine oxidase-A rather than of monoamine oxidase-B, and are promising candidates to further advance drug discovery efforts. The most active compounds show inhibitory activity on monoamine oxidase-A in the 1.0x10(-8)-8.6x10(-9) M range. Moreover, it should be pointed out that for some compounds a high IC50>or=10(-9) M value is associated with a high A-selectivity (Selectivity Index monoamine oxidase-B/monoamine oxidase-A in the 10,000-12,500 range). Further insight to understand enzyme-inhibitor molecular interaction was obtained by docking experiments with the monoamine oxidase-A and monoamine oxidase-B isoforms.     

Thionamides and analogues: A reapraisal of antithyroid and thyroid carcinogenic effects

As commonly depicted, in the thione form, thionamides (including thiourea and its derivatives) bear little resemblance to thyroid hormone. However, if placed in the thiol resonance form, these molecules are noted to structurally mimic the end of the tyrosine molecule (the precursor of thyroid hormone). Alternatively, tyrosine written in the -one configuration resembles the thionamides. This permits a better appreciation of why the thionamides may themselves be iodinated by thyroid peroxidase in some cases, and under other circumstances induce changes in the enzyme. The thiol resonant form can be written for naturally occurring goitrin, and for thiobarbituric acids with antithyroid activity. An hydroxyl resonant configuration can be drawn for the antithyroid compound 3-hydroxy-4-pyridone. Tetramethylthiourea is a thyroid carcinogen in rats. The compound can not be readily placed in the thiol resonant configuration; it also contains 2 methyl groups at both ends of the molecule. The hair dye 2,4-diaminoanisole sulfate induces thyroid neoplasms in rats. A similarity is pointed out both to tyrosine and to lower potency antithyroid aminobenzenes (described by Astwood and coworkers). Pyrazole, known to produce thyroid necrosis, is seen to have a distinct resemblance to the opposite end of several of these compounds.     

Synthesis of new arylazopyrazoles as apoptosis inducers: Candidates to inhibit proliferation of MCF‐7 cells

New 4‐arylazo‐3,5‐diamino‐1H‐pyrazole derivatives substituted in the 4‐aryl ring with the acetyl moiety were designed and synthesized. The antiproliferative activity of the novel arylazopyrazoles was examined against the MCF‐7 cell line. Among all target compounds, 8b (IC₅₀ 3.0 µM) and 8f (IC₅₀ 4.0 µM) displayed higher cytotoxicity as compared with the reference standard imatinib (IC₅₀ 7.0 µM). Further studies to explore the mechanism of action were performed on the most active hit of our library, 8b , via anti‐CDK2 kinase activity. It demonstrated good inhibitory effects for CDK2 (IC₅₀ 0.24 µM) with 62.5% inhibition, compared with imatinib. The cell cycle analysis in the MCF‐7 cell line revealed apoptosis induction by 8b and cell cycle arrest at the S phase. Docking in the CDK2 active site and pharmacophore modeling confirmed the affinity of 8b to the CDK2 active site. Absorption, distribution, metabolism, and excretion studies revealed that our target compounds are orally bioavailable, with no permeation through the blood–brain barrier.     

Design and synthesis of pyrazole–pyrazoline hybrids as cancer‐associated selective COX‐2 inhibitors

In continuation of our previous work on cancer and inflammation, 15 novel pyrazole–pyrazoline hybrids ( WSPP1 – 15 ) were synthesized and fully characterized. The formation of the pyrazoline ring was confirmed by the appearance of three doublets of doublets in ¹H nuclear magnetic resonance spectra exhibiting an AMX pattern for three protons (H_A, H_M, and H_X) of the pyrazoline ring. All the synthesized compounds were screened for their in vitro anticancer activity against five cell lines, that is, MCF‐7, A549, SiHa, COLO205, and HepG2 cells, using the MTT growth inhibition assay. 5‐Fluorouracil was taken as the positive control in the study. It was observed that, among them, WSPP11 was found to be active against A549, SiHa, COLO205, and HepG2 cells, with IC₅₀ values of 4.94, 4.54, 4.86, and 2.09 µM. All the derivatives were also evaluated for their cytotoxicity against HaCaT cells. WSPP11 was also found to be nontoxic against normal cells (cell line HaCaT), with an IC₅₀ value of more than 50 µM. The derivatives were also evaluated for their in vitro anti‐inflammatory activity by the protein (egg albumin) denaturation assay and the red blood cell membrane stabilizing assay, using diclofenac sodium and celecoxib as standard. Compounds that showed significant anticancer and anti‐inflammatory activities were further studied for COX‐2 inhibition. The manifestation of a higher COX‐2 selectivity index of WSPP11 as compared with other derivatives and an in vitro anticancer activity against four cell lines further established that compounds that were more selective toward COX‐2 also exhibited a better spectrum of activity against various cancer cell lines.