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Synthesis and effects of pyrazolines and isoxazoles on the phagocytic chemotaxis and release of reactive oxygen species by zymosan stimulated human neutrophils

Bukhari SN, Jantan I, Wai LK, Lajis NH, Abbas F, Jasamai M

Med Chem, 2013 Dec;9(8):1091-8.
PMID: 23092331

A series of novel isoxazole and pyrazoline derivatives has been synthesized and evaluated for their effects on the chemiluminescence and chemotactic activity of human phagocytes. Their effects on the chemotactic migration of isolated polymorphonuclear leukocytes (PMNs) and on the release of reactive oxygen species (ROS) during respiratory burst of human whole blood and PMNs were carried out using the Boyden chamber technique and luminol-based chemiluminescence assay, respectively. Of the compounds tested, compounds 8, 9, 11 and 12 exhibited higher inhibitory activity on the release of ROS (with IC50 values ranging from 5.6 to 8.4 μM) than acetylsalicylic acid (IC50 = 9.5 μ M). These compounds also showed strong inhibitory activity on the migration of PMNs with compound 8 exhibiting an IC50 value lower than that of ibuprofen. The results suggest that some of these isoxazole and pyrazoline derivatives have ability to modulate the innate immune response of phagocytes at different steps, indicating their potential as a source of new immunomodulatory agents.

Matched MeSH terms: Pyrazoles/chemical synthesis; Pyrazoles/pharmacology*; Pyrazoles/chemistry
In silico studies, nitric oxide, and cholinesterases inhibition activities of pyrazole and pyrazoline analogs of diarylpentanoids

Mohd Faudzi SM, Leong SW, Auwal FA, Abas F, Wai LK, Ahmad S, et al.

Arch Pharm (Weinheim), 2021 Jan;354(1):e2000161.
PMID: 32886410 DOI: 10.1002/ardp.202000161

A new series of pyrazole, phenylpyrazole, and pyrazoline analogs of diarylpentanoids (excluding compounds 3a, 4a, 5a, and 5b) was pan-assay interference compounds-filtered and synthesized via the reaction of diarylpentanoids with hydrazine monohydrate and phenylhydrazine. Each analog was evaluated for its anti-inflammatory ability via the suppression of nitric oxide (NO) on IFN-γ/LPS-activated RAW264.7 macrophage cells. The compounds were also investigated for their inhibitory capability toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), using a modification of Ellman's spectrophotometric method. The most potent NO inhibitor was found to be phenylpyrazole analog 4c, followed by 4e, when compared with curcumin. In contrast, pyrazole 3a and pyrazoline 5a were found to be the most selective and effective BChE inhibitors over AChE. The data collected from the single-crystal X-ray diffraction analysis of compound 5a were then applied in a docking simulation to determine the potential binding interactions that were responsible for the anti-BChE activity. The results obtained signify the potential of these pyrazole and pyrazoline scaffolds to be developed as therapeutic agents against inflammatory conditions and Alzheimer's disease.

Matched MeSH terms: Pyrazoles/chemical synthesis; Pyrazoles/pharmacology*; Pyrazoles/chemistry
Fulltext Insecticide Residues on Poultry Manures: Field Efficacy Test on Selected Insecticides in Managing Musca Domestica Population

Ong SQ, Ab Majid AH, Ahmad H

Trop Life Sci Res, 2017 Jul;28(2):45-55.
PMID: 28890760 MyJurnal DOI: 10.21315/tlsr2017.28.2.4

In this study, bifenthrin (Maxxthor SC, Ensystex Australasia Pty Ltd), imidacloprid (Prothor SC, Ensystex Australasia Pty Ltd) and fipronil (Regent(®)50SC, Bayer) were applied on the natural infest manures according to the manufacturer rate during a broiler breeding cycle. Solvent direct-immersion extraction (SDIE) was used in detecting the target compound and later, quantification of the insecticide residues in field condition was investigated. The samples were prior cleaned up by solid-phase extraction (SPE) and analysed by Ultra-Performance Liquid Chromatography (UPLC) - photodiode array (PDA) system. In the field trial, three insecticides were showed accumulation during the broiler breeding period and it is suggested that they acted as adulticides when applied on the poultry manures, this is supported by the significant correlation between the increment of insecticide residues to the reduction percentage of adult flies (<0.05). Fipronil showed significantly greater reduction on the adult fly compared to the other insecticides, in which the reduction rate compared to control population at the end of the broiler breeding period; fipronil, imidaclopril and bifenthrin reduced 51.51%, 28.30% and 30.84% of adult flies, respectively.

Matched MeSH terms: Pyrazoles
Fulltext The Effect of Temperature on the Development of Trilocha varians (Lepidoptera: Bombycidae) and Control of the Ficus Plant Pest

Basari N, Mustafa NS, Yusrihan NEN, Yean CW, Ibrahim Z

Trop Life Sci Res, 2019 Jan;30(1):23-31.
PMID: 30847031 MyJurnal DOI: 10.21315/tlsr2019.30.1.2

Ficus plants are commonly planted as ornamentals along roadsides in Malaysia. In 2010, Ficus plants in Kuala Terengganu were found to be attacked by a moth, identified as Trilocha varians. The larvae of this moth fed on Ficus leaves causing up to 100% defoliation. This study was conducted to determine the life cycle of T. varians under two different environmental temperatures and to control this pest using two different insecticides. Our findings showed that there were significant differences in the time taken for eggs to hatch and larval and pupation period between low and high environmental temperatures. Results also showed that fipronil had lower LT50 and LT95 than malathion. This study provides new information on the life history of T. varians under two different conditions and the efficiency in controlling T. varians larvae using insecticides. The results of this study are important for future management in controlling T. varians population especially in Kuala Terengganu, Malaysia.

Matched MeSH terms: Pyrazoles
Development and investigation of thiazolidinedione and pyrazoline compounds as antiangiogenic weapons targeting VEGFR-2

Upadhyay N, Tilekar K, Safuan S, Kumar AP, Schweipert M, Meyer-Almes FJ, et al.

Future Med Chem, 2021 11;13(22):1963-1986.
PMID: 34581188 DOI: 10.4155/fmc-2021-0139

Background: Angiogenesis deregulation is often linked to cancer and is thus an essential target. Materials & methods: Twenty-nine compounds were developed as VEGFR-2 inhibitors. Compounds were evaluated to determine their antiangiogenic activity. Results: B1, PB11 and PB16 showed HUVEC's IC50 scores in the submicromolar range. B1, B2 and PB16 reduced cellular migration and capillary tube formation of HUVECs. VEGFR-2 inhibitory activity was found in the nanomolar range: 200 nM of B1, 500 nM of B2 and 600 nM of PB16. B1 and PB16 suppressed the formation of new capillaries on growing CAMs. B1 and PB16 occupied the ATP site and allosteric pocket of VEGFR-2 in docking studies. Conclusion: These compounds can target VEGFR-2 and are endowed with in vitro and in vivo antiangiogenic activity.

Matched MeSH terms: Pyrazoles/chemical synthesis; Pyrazoles/pharmacology*; Pyrazoles/chemistry
Fulltext A Novel Hydrazinecarbothioamide as a Potential Corrosion Inhibitor for Mild Steel in HCl

Al-Amiery AA, Kadhum AAH, Mohamad AB, Junaedi S

Materials (Basel), 2013 Apr 02;6(4):1420-1431.
PMID: 28809218 DOI: 10.3390/ma6041420

2-(1-methyl-4-((E)-(2-methylbenzylidene)amino)-2-phenyl-1H-pyrazol-3(2H)-ylidene)-hydrazineecarbothioamide (HCB) was synthesized as a corrosion inhibitor from the reaction of 4-aminoantipyrine, thiosemicarbazide and 2-methylbenzaldehyde. The corrosion inhibitory effects of HCB on mild steel in 1.0 M HCl were investigated using potentiodynamic polarization (PDP) and electrochemical impedance spectroscopy (EIS). The results showed that HCB inhibited mild steel corrosion in acidic solution and inhibition efficiency increased with an increase in the concentration of the inhibitor. The inhibition efficiency was up to 96.5% at 5.0 mM. Changes in the impedance parameters suggested that HCB adsorbed on the surface of mild steel, leading to the formation of a protective film. The novel corrosion inhibitor synthesized in the present study was characterized using Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR) spectral data.

Matched MeSH terms: Pyrazoles
Infrared spectrum, structural and optical properties and molecular docking study of 3-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-1-carbaldehyde

Mary YS, Panicker CY, Sapnakumari M, Narayana B, Sarojini BK, Al-Saadi AA, et al.

Spectrochim Acta A Mol Biomol Spectrosc, 2015 Mar 5;138:529-38.
PMID: 25528512 DOI: 10.1016/j.saa.2014.11.041

The optimized molecular structure, vibrational frequencies, corresponding vibrational assignments of 3-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-1-carbaldehyde have been investigated experimentally and theoretically. The title compound was optimized using at HF and DFT levels of calculations. The B3LYP/6-311++G(d,p) (5D,7F) results and in agreement with experimental infrared bands. The normal modes are assigned using potential energy distribution. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using natural bonding orbital analysis. The frontier molecular orbital analysis is used to determine the charge transfer within the molecule. From molecular electrostatic potential map, it is evident that the negative electrostatic potential regions are mainly localized over the carbonyl group and mono substituted phenyl ring and are possible sites for electrophilic attack and, positive regions are localized around all para substituted phenyl and pyrazole ring, indicating possible sites for nucleophilic attack. First hyperpolarizability is calculated in order to find its role in nonlinear optics. The geometrical parameters are in agreement with experimental data. From the molecular docking studies, it is evident that the fluorine atom attached to phenyl ring and the carbonyl group attached to pyrazole ring are crucial for binding and the results draw us to the conclusion that the compound might exhibit phosphodiesterase inhibitory activity.

Matched MeSH terms: Pyrazoles/chemistry*
Fulltext Endocannabinoid system and cardio-metabolic risk

Loh KY, Kew ST

Med J Malaysia, 2008 Oct;63(4):348-50; quiz 351.
PMID: 19385504 MyJurnal

Recent research in bio-medical science has shown an integral role of endocannabinoid system (ECS) in determining cardio-metabolic risk of human body. The mechanism is mediated through binding of endocannabinoids at the CB1 receptors. The stimulation of CB1 receptor in the brain is believed to control and mediate the effects on appetite. In normal physiology, CB1 receptors activation is responsible for energy homeostasis, govern emotions and behaviors such as anxiety, fear, appetite, food and water intake. CB1 receptors also found in peripheral tissues like liver, pancreas, skeletal muscles and adipose tissues, which play an important role in lipid and glucose metabolism. Over-activation of ECS is associated with various metabolic diseases such as dyslipidemia, insulin resistance, lipogenesis, excessive weight gain and increasing intra-abdominal obesity. All these events lead to increased cardiovascular risk. Use of selective CB1 receptor blocker such as rimonabant has shown to reduced waist circumference, better glycemic control, lower triglyceride levels, raise HDL cholesterol and over all reduction in total body fat. This drug has been recommended for patients with metabolic syndrome.

Matched MeSH terms: Pyrazoles/therapeutic use
Metal-ion permeation in congested nanochannels: the exposure effect of Ag+ ions on the phosphorescent properties of a gold(I)-pyrazolate complex that is confined in the nanoscopic channels of mesoporous silica

Lintang HO, Kinbara K, Yamashita T, Aida T

Chem Asian J, 2012 Sep;7(9):2068-72.
PMID: 22431445 DOI: 10.1002/asia.201200041

An organometallic/silica nanocomposite of a 1D cylindrical assembly of a trinuclear gold(I)-pyrazolate complex ([Au(3)Pz(3)]) that was confined inside the nanoscopic channels of hexagonal mesoporous silica ([Au(3)Pz(3)]/silica(hex)), emitted red light with a luminescence center at 693 nm upon photoexcitation at 276 nm owing to a Au(I)-Au(I) metallophilic interaction. When a film of [Au(3)Pz(3)]/silica(hex) was dipped into a solution of Ag(+) in tetrahydrofuran (THF), the resulting nanocomposite material (Ag@[Au(3)Pz(3)]/silica(hex)) emitted green light with a new luminescence center at 486 nm, which was characteristic of a Au(I)-Ag(I) heterometallic interaction. Changes in the emission/excitation and XPS spectra of Ag@[Au(3)Pz(3)]/silica(hex) revealed that Ag(+) ions permeated into the congested nanochannels of [Au(3)Pz(3)]/silica(hex), which were filled with the cylindrical assembly of [Au(3)Pz(3)].

Matched MeSH terms: Pyrazoles/chemistry*
Effects of termiticide exposure on mutual interactions between the treated and untreated workers of the Asian subterranean termite Coptotermes gestroi

Neoh KB, Lee CC, Lee CY

Pest Manag Sci, 2014 Feb;70(2):240-4.
PMID: 23554339 DOI: 10.1002/ps.3544

Mutual interactions, including reciprocal food sharing and grooming between chlorantraniliprole- and fipronil-treated, and untreated Asian subterranean termites, Coptotermes gestroi (Wasmann), were examined using rubidium as a tracer. Two questions were addressed in this study: (1) After insecticide treatment, does the mutual interaction between termiticide-treated termites and untreated nestmates increase? (2) Does the nutritional status of both termiticide-treated termites and untreated nestmates affect the mutual interaction?

Matched MeSH terms: Pyrazoles/pharmacology
Fipronil resistance in the diamondback moth (Lepidoptera: Plutellidae): inheritance and number of genes involved

Sayyed AH, Wright DJ

J Econ Entomol, 2004 Dec;97(6):2043-50.
PMID: 15666763

Bioassays (at generation 1, G1) using fipronil, spinosad, indoxacarb, and Bacillus thuringiensis toxins Cry1Ac and Cry1Ca with a newly collected field population of Plutella xylostella (L.) from farmers fields in the Cameron Highlands, Malaysia, indicated a resistance ratio of approximately 400-, 1,170-, 330-, 2,840-, and 1,410-fold, respectively, compared with a laboratory-susceptible population of P. xylostella (ROTH). At G3, the field-derived population was divided into two subpopulations, one was selected (G3 to G7) with fipronil (fip-SEL), whereas the second was left unselected (UNSEL). Bioassays at G8 found that selection with fipronil gave a resistance ratio of approximately 490 compared with UNSEL and approximately 770 compared with ROTH. The resistance ratio for fipronil, spinosad, indoxacarb, Cry1Ac, and Cry1Ca in the UNSEL population declined significantly by G8. Logit regression analysis of F1 reciprocal crosses between fip-SEL (at G8) and UNSEL indicated that resistance to fipronil in the fip-SEL population was inherited as an autosomal, incompletely recessive (D(LC) = 0.37) trait. At the highest dose of fipronil tested, resistance was completely recessive, whereas at the lowest dose it was incompletely recessive. A direct test of monogenic inheritance based on a backcross of F1 progeny with fip-SEL suggested that resistance to fipronil was controlled by a single locus. The fip-SEL population at G8 showed little change in its response to spinosad and indoxacarb compared with G1, whereas its susceptibility to Cry1Ac and Cry1Ca increased markedly over the selection period. This suggests that there may be some low level of cross-resistance between fipronil, spinosad, and indoxacarb.

Matched MeSH terms: Pyrazoles*
Field efficacy of fipronil 3G, lambda-cyhalothrin 10%CS, and sumithion 50EC against the dengue vector Aedes albopictus in discarded tires

Sulaiman S, Pawanchee ZA, Wahab A, Jamal J, Sohadi AR

J Vector Ecol, 1999 Dec;24(2):154-7.
PMID: 10672544

The efficacy of three insecticides, fipronil 3G, lambda-cyhalothrin 10%CS, and sumithion 50EC were evaluated against the dengue vector Aedes albopictus in discarded tires in Kuala Lumpur, Malaysia. The dosage given for each insecticide was 0.01 g of active ingredient/m2. Fipronil 3G was the most effective larvicide with a residual activity of up to two weeks, causing 88% mortality in Aedes albopictus. Lambda-cyhalothrin 10%CS was effective for one week causing 92% larval mortality and two weeks with 63% larval mortality. Sumithion 50EC had a residual efficacy of one week with 79% larval mortality.

Matched MeSH terms: Pyrazoles*
Fulltext Randomised, open label, controlled trial of celecoxib in the treatment of acute migraine

Loo CY, Tan HJ, Teh HS, Raymond AA

Singapore Med J, 2007 Sep;48(9):834-9.
PMID: 17728965

INTRODUCTION: Migraine is a common disabling condition that results in considerable socioeconomic loss. The role of non-steroidal anti-inflammatory drugs (NSAIDs) in acute migraine has been well-established. We compared the efficacy of the cyclooxygenase-2 inhibitor celecoxib with the NSAID, naproxen sodium, in the treatment of acute migraine.
METHODS: This was a randomised, open label, controlled trial. We selected patients with a diagnosis of migraine, based on the International Headache Society revised criteria. 60 patients were randomised to either celecoxib 400 mg (30 patients) or naproxen sodium 550 mg (30 patients). Patients took the study medicine for the first acute migraine episode that occurred during the study period and reported the headache reduction based on a visual analogue score (VAS). Patients were reviewed after a month to check on VAS at one and two hours, compared to the baseline. Any side effects of the medication were also recorded.
RESULTS: Of the 52 patients who completed the study, eight did not experience any headaches. The mean VAS in the celecoxib group improved significantly from baseline (6.48 +/- 1.53) to one hour (4.28 +/- 2.11) and two hours (2.24 +/- 2.57) (p-value is less than 0.0005). The mean VAS in the naproxen sodium group also improved significantly from baseline (7.30 +/- 1.66) to one hour (4.81 +/- 2.50) and two hours (2.63 +/- 2.65) (p-value is less than 0.0005). However, there was no significant difference between the magnitudes of improvement between the treatment groups. The incidence of gastric pain was significantly higher in the naproxen sodium group (p-value is equal to 0.029).
CONCLUSION: In comparison with naproxen sodium, celecoxib was equally effective in relieving pain in acute migraine and caused significantly less gastric pain.

Study site: neurology outpatient clinic in Pusat Perubatan
Universiti Kebangsaan Malaysia (PPUKM)

Matched MeSH terms: Pyrazoles/therapeutic use*
Synthesis and Staphylococcus aureus biofilm inhibitory activity of indolenine-substituted pyrazole and pyrimido[1,2-b]indazole derivatives

Yap CH, Ramle AQ, Lim SK, Rames A, Tay ST, Chin SP, et al.

Bioorg Med Chem, 2023 Nov 15;95:117485.
PMID: 37812886 DOI: 10.1016/j.bmc.2023.117485

Staphylococcus aureus is a highly adaptable opportunistic pathogen that can form biofilms and generate persister cells, leading to life-threatening infections that are difficult to treat with antibiotics alone. Therefore, there is a need for an effective S. aureus biofilm inhibitor to combat this public health threat. In this study, a small library of indolenine-substituted pyrazoles and pyrimido[1,2-b]indazole derivatives were synthesised, of which the hit compound exhibited promising antibiofilm activities against methicillin-susceptible S. aureus (MSSA ATCC 29213) and methicillin-resistant S. aureus (MRSA ATCC 33591) at concentrations significantly lower than the planktonic growth inhibition. The hit compound could prevent biofilm formation and eradicate mature biofilms of MSSA and MRSA, with a minimum biofilm inhibitory concentration (MBIC50) value as low as 1.56 µg/mL and a minimum biofilm eradication concentration (MBEC50) value as low as 6.25 µg/mL. The minimum inhibitory concentration (MIC) values of the hit compound against MSSA and MRSA were 50 µg/mL and 25 µg/mL, respectively, while the minimum bactericidal concentration (MBC) values against MSSA and MRSA were > 100 µg/mL. Preliminary structure-activity relationship analysis reveals that the fused benzene ring and COOH group of the hit compound are crucial for the antibiofilm activity. Additionally, the compound was not cytotoxic to human alveolar A549 cells, thus highlighting its potential as a suitable candidate for further development as a S. aureus biofilm inhibitor.

Matched MeSH terms: Pyrazoles/pharmacology
Fulltext Characterization of the inheritance of field-evolved resistance to diamides in the fall armyworm (Spodoptera frugiperda) (Lepidoptera: Noctuidae) population from Puerto Rico

Posos-Parra O, Mota-Sanchez D, Pittendrigh BR, Wise JC, DiFonzo CD, Patterson E

PLoS One, 2024;19(2):e0295928.
PMID: 38394153 DOI: 10.1371/journal.pone.0295928

The fall armyworm (Spodoptera frugiperda) is one of the most destructive pests of corn. New infestations have been reported in the East Hemisphere, reaching India, China, Malaysia, and Australia, causing severe destruction to corn and other crops. In Puerto Rico, practical resistance to different mode of action compounds has been reported in cornfields. In this study, we characterized the inheritance of resistance to chlorantraniliprole and flubendiamide and identified the possible cross-resistance to cyantraniliprole and cyclaniliprole. The Puerto Rican (PR) strain showed high levels of resistance to flubendiamide (RR50 = 2,762-fold) and chlorantraniliprole (RR50 = 96-fold). The inheritance of resistance showed an autosomal inheritance for chlorantraniliprole and an X-linked inheritance for flubendiamide. The trend of the dominance of resistance demonstrated an incompletely recessive trait for H1 (♂ SUS × ♀ PR) × and an incompletely dominant trait for H2 (♀ SUS × ♂ PR) × for flubendiamide and chlorantraniliprole. The PR strain showed no significant presence of detoxification enzymes (using synergists: PBO, DEF, DEM, and VER) to chlorantraniliprole; however, for flubendiamide the SR = 2.7 (DEM), SR = 3.2 (DEF) and SR = 7.6 (VER) indicated the role of esterases, glutathione S- transferases and ABC transporters in the metabolism of flubendiamide. The PR strain showed high and low cross-resistance to cyantraniliprole (74-fold) and cyclaniliprole (11-fold), respectively. Incomplete recessiveness might lead to the survival of heterozygous individuals when the decay of diamide residue occurs in plant tissues. These results highlight the importance of adopting diverse pest management strategies, including insecticide rotating to manage FAW populations in Puerto Rico and other continents.

Matched MeSH terms: Pyrazoles*
Synthesis, Biological Evaluation and Molecular Docking Studies of New Pyrazolines as an Antitubercular and Cytotoxic Agents

Lokesh BVS, Prasad YR, Shaik AB

Infect Disord Drug Targets, 2019;19(3):310-321.
PMID: 30556506 DOI: 10.2174/1871526519666181217120626

BACKGROUND: Many synthetic procedures were reported till date to prepare pyrazoline derivatives. Some have published pyrazolines from different chalcone derivatives in the literature.
OBJECTIVE: A series of new pyrazolines containing novel 2,5-dichloro-3-acetylthiophene chalcone moiety (PZT1-PZT20) have been synthesized, characterized by 1HNMR and 13CNMR and evaluated for them in vitro antitubercular activity against M. tuberculosis H37Rv strain and in vitro anticancer activity against DU-145 prostate cancer cell lines and all compounds were also screened for molecular docking studies against specific targeted protein domains.
METHODS: All compounds were screened for potential activity against Mycobacterium tuberculosis H37Rv (MTB) strain and anticancer activity against DU-149 prostate cancer cell lines using MTT cytotoxicity assay.
RESULTS: Among the series, compound PZT5 with 2", 4"-dichlorophenyl group at 5-position on the pyrazoline ring exhibited the most potent antitubercular activity (MIC=1.60 µg/mL) and compounds PZT2, PZT9, PZT11, PZT15, and PZT20 showed similar antitubercular activity against standard pyrazinamide (MIC=3.12 µg/mL) by broth dilution assay. PZT15 and PZT17 with 4"- pyridinyl and 2"-pyrrolyl groups on pyrazoline ring were found to exhibit better anticancer activity against DU-149 prostate cancer cell lines with IC50 values of 2.0±0.2 µg/mL and 6.0±0.3 µg/mL respectively by MTT assay. The preliminary structure-activity relationship has been summarized. The molecular docking studies with crystalline structures of enoyl acyl carrier protein reductase InhA interaction with target protein (2NSD; PDB and 3FNG; PDB) of Mycobacterium tuberculosis H37Rv (MTB) strain have also exhibited good ligand interaction and binding affinity. Ligand interaction and binding affinity were estimated using crystal structures of both types of enoyl acyl carrier protein reductase InhA (3FNG.pdb) and found to be much higher (-16.70 to - 19.20 kcal/mol) compared with pyrazinamide (-10.70 kcal/mol) as a standard target molecule. Whereas the binding affinities of six active compounds with crystal structure of other type of enoyl acyl carrier protein reductase InhA (2NSD.pdb) were much similar and higher (-9.30 to - 11.20 kcal/mole) than pyrazinamide (-11.10 kcal/mole).
CONCLUSION: These new pyrazolines would be promising potent inhibitors of drug sensitive and drug resistant Mycobacterium tuberculosis strain and potential anticancer agents against prostate cancer and other prototypes of cancers.

Matched MeSH terms: Pyrazoles/chemical synthesis*; Pyrazoles/pharmacology*
Discovery of mixed type thymidine phosphorylase inhibitors endowed with antiangiogenic properties: synthesis, pharmacological evaluation and molecular docking study of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones. Part II

Bera H, Ojha Pk, Tan BJ, Sun L, Dolzhenko AV, Chui WK, et al.

Eur J Med Chem, 2014 May 6;78:294-303.
PMID: 24686016 DOI: 10.1016/j.ejmech.2014.03.063

In our drug discovery program, a series of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones were designed, synthesized and evaluated for their TP inhibitory potential. All the synthesized analogues conferred a varying degree of TP inhibitory activity, comparable or better than positive control, 7-deazaxanthine (7-DX, 2) (IC50 value = 42.63 μM). A systematic approach to the lead optimization identified compounds 3c and 4a as the most promising TP inhibitors, exhibiting mixed mode of enzyme inhibition. Moreover, selected compounds demonstrated the ability to attenuate the expression of the angiogenic markers (viz. MMP-9 and VEGF) in MDA-MB-231 cells at sublethal concentrations. In addition, molecular docking studies revealed the plausible binding orientation of these inhibitors towards TP, which was in accordance with the experimental results. Taken as a whole, these compounds would constitute a new direction for the design of novel TP inhibitors with promising antiangiogenic properties.

Matched MeSH terms: Pyrazoles/chemical synthesis; Pyrazoles/pharmacology*; Pyrazoles/chemistry
Effect of non-phospholipid-based cationic and phospholipid-based anionic nanosized emulsions on skin retention and anti-inflammatory activity of celecoxib

Tamilvanan S, Baskar R

Pharm Dev Technol, 2013 Jul-Aug;18(4):761-71.
PMID: 23668371 DOI: 10.3109/10837450.2011.586038

Celecoxib (CXB, 0.2 g)-loaded anionic and cationic nanosized emulsions were prepared by a well-established combined emulsification method.

Matched MeSH terms: Pyrazoles/administration & dosage; Pyrazoles/pharmacokinetics; Pyrazoles/pharmacology*
Stress induces reinstatement of extinguished cocaine conditioned place preference by a sequential signaling via neuropeptide S, orexin, and endocannabinoid

Chou YH, Hor CC, Lee MT, Lee HJ, Guerrini R, Calo G, et al.

Addict Biol, 2020 Oct 19.
PMID: 33078457 DOI: 10.1111/adb.12971

Neurons containing neuropeptide S (NPS) and orexins are activated during stress. Previously, we reported that orexins released during stress, via orexin OX1 receptors (OX1 Rs), contribute to the reinstatement of cocaine seeking through endocannabinoid/CB1 receptor (CB1 R)-mediated dopaminergic disinhibition in the ventral tegmental area (VTA). Here, we further demonstrated that NPS released during stress is an up-stream activator of this orexin-endocannabinoid cascade in the VTA, leading to the reinstatement of cocaine seeking. Mice were trained to acquire cocaine conditioned place preference (CPP) by context-pairing cocaine injections followed by the extinction training with context-pairing saline injections. Interestingly, the extinguished cocaine CPP in mice was significantly reinstated by intracerebroventricular injection (i.c.v.) of NPS (1 nmol) in a manner prevented by intraperitoneal injection (i.p.) of SHA68 (50 mg/kg), an NPS receptor antagonist. This NPS-induced cocaine reinstatement was prevented by either i.p. or intra-VTA microinjection (i.vta.) of SB-334867 (15 mg/kg, i.p. or 15 nmol, i.vta.) and AM 251 (1.1 mg/kg, i.p. or 30 nmol, i.vta.), antagonists of OX1 Rs and CB1 Rs, respectively. Besides, NPS (1 nmol, i.c.v.) increased the number of c-Fos-containing orexin neurons in the lateral hypothalamus (LH) and increased orexin-A level in the VTA. The latter effect was blocked by SHA68. Furthermore, a 30-min restraint stress in mice reinstated extinguished cocaine CPP and was prevented by SHA68. These results suggest that NPS is released upon stress and subsequently activates LH orexin neurons to release orexins in the VTA. The released orexins then reinstate extinguished cocaine CPP via an OX1 R- and endocannabinoid-CB1 R-mediated signaling in the VTA.

Matched MeSH terms: Pyrazoles
Fulltext Molecular Hybrids Integrated with Benzimidazole and Pyrazole Structural Motifs: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies

Sivaramakarthikeyan R, Iniyaval S, Saravanan V, Lim WM, Mai CW, Ramalingan C

ACS Omega, 2020 May 05;5(17):10089-10098.
PMID: 32391496 DOI: 10.1021/acsomega.0c00630

Synthesis of a series of benzimidazole-ornamented pyrazoles, 6a-6j has been obtained from arylhydrazine and aralkyl ketones via a multistep synthetic strategy. Among them, a hybrid-possessing para-nitrophenyl moiety connected to a pyrazole scaffold (6a) exerted the highest anti-inflammatory activity, which is superior to the standard, diclofenac sodium. While executing the 2,2-diphenyl-1-picrylhydrazyl radical-scavenging activity, a hybrid-possessing para-bromophenyl unit integrated at the pyrazole structural motif (6i) exhibited the highest activity among the hybrids examined. Besides, evaluation of anticancer potency of the synthesized hybrids revealed that the one containing a para-fluorophenyl unit tethered at the pyrazole nucleus (6h) showed the highest activity against both the pancreatic cancer cells (SW1990 and AsPCl) investigated. Considerable binding affinity between B-cell lymphoma and the hybrid, 6h has been reflected while performing molecular docking studies (-8.65 kcal/mol). The outcomes of the investigation expose that these hybrids could be used as effective intermediates to construct more potent biological agents.

Matched MeSH terms: Pyrazoles

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