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ChemMedChem Nov 2021Inhibition of membrane-bound pyrophosphatase (mPPase) with small molecules offer a new approach in the fight against pathogenic protozoan parasites. mPPases are absent...
Inhibition of membrane-bound pyrophosphatase (mPPase) with small molecules offer a new approach in the fight against pathogenic protozoan parasites. mPPases are absent in humans, but essential for many protists as they couple pyrophosphate hydrolysis to the active transport of protons or sodium ions across acidocalcisomal membranes. So far, only few nonphosphorus inhibitors have been reported. Here, we explore the chemical space around previous hits using a combination of screening and synthetic medicinal chemistry, identifying compounds with low micromolar inhibitory activities in the Thermotoga maritima mPPase test system. We furthermore provide early structure-activity relationships around a new scaffold having a pyrazolo[1,5-a]pyrimidine core. The most promising pyrazolo[1,5-a]pyrimidine congener was further investigated and found to inhibit Plasmodium falciparum mPPase in membranes as well as the growth of P. falciparum in an ex vivo survival assay.
Topics: Dose-Response Relationship, Drug; Humans; Molecular Structure; Pyrazoles; Pyrimidines; Pyrophosphatases; Structure-Activity Relationship
PubMed: 34459148
DOI: 10.1002/cmdc.202100392 -
Chimia 2015Sedaxane (SDX) 1, isopyrazam (IZM) 2 and Solatenol™ (STL) 3 are broad-spectrum pyrazole carboxamides, which originate from novel chemical classes of fungicides. Their... (Review)
Review
Sedaxane (SDX) 1, isopyrazam (IZM) 2 and Solatenol™ (STL) 3 are broad-spectrum pyrazole carboxamides, which originate from novel chemical classes of fungicides. Their mode of action (MoA) is inhibition of succinate dehydrogenase (SDH), which was recognized for a long time to deliver only compounds with a narrow biological spectrum. This view changed with the market introduction of BASF's boscalid in 2003. All major agro-companies subsequently worked in parallel on this MoA successfully and recently introduced new compounds to the market. Syngenta entered the SDHI area in 1998 and was able to introduce three complementary compounds to the market between 2010 and 2012. In this short review some synthesis challenges and biological effects of SDX 1, IZM 2 and STL 3 will be covered. New cost-efficient synthesis strategies for the preparation of o-biscyclopropyl-aniline, new benzonorbornene intermediates and the key pyrazole carboxylic acid intermediate which is essential for all three Syngenta SDHIs, will be in the focus of this review.
Topics: Anilides; Animals; Antifungal Agents; Enzyme Inhibitors; Fungi; Fungicides, Industrial; Humans; Norbornanes; Pyrazoles; Succinate Dehydrogenase
PubMed: 26507595
DOI: 10.2533/chimia.2015.425 -
International Journal of Molecular... Jun 2024This paper presents the work performed to transition a lab-scale synthesis (1 g) to a large-scale (400 g) synthesis of the 3-5-diamino-1H-Pyrazole Disperazol, a new...
This paper presents the work performed to transition a lab-scale synthesis (1 g) to a large-scale (400 g) synthesis of the 3-5-diamino-1H-Pyrazole Disperazol, a new pharmaceutical for treatment of antibiotic-resistant biofilm infections. The potentially hazardous diazotisation step in the lab-scale synthesis was transformed to a safe and easy-to-handle flow chemistry step. Additionally, the paper presents an OSHA-recommended safety assessment of active compound , as performed by Fauske and Associates, LLC, Burr Ridge, IL, USA.
Topics: Pyrazoles; Pseudomonas aeruginosa; Anti-Bacterial Agents; Biofilms; Humans; Pseudomonas Infections; Risk Assessment
PubMed: 38928443
DOI: 10.3390/ijms25126737 -
European Journal of Medicinal Chemistry May 2016The features of the chemistry of 4-thiazolidinone and pyrazole/pyrazolines as pharmacologically attractive scaffolds were described in a number of reviews in which the... (Review)
Review
The features of the chemistry of 4-thiazolidinone and pyrazole/pyrazolines as pharmacologically attractive scaffolds were described in a number of reviews in which the main approaches to the synthesis of mentioned heterocycles and their biological activity were analyzed. However, the pyrazole/pyrazoline-thiazolidine-based hybrids as biologically active compounds is poorly discussed in the context of pharmacophore hybrid approach. Therefore, the purpose of this review is to summarize the data about the synthesis and modification of heterocyclic systems with thiazolidine and pyrazoline or pyrazole fragments in molecules as promising objects of modern bioorganic and medicinal chemistry. The description of biological activity was focused on SAR analysis and mechanistic insights of mentioned hybrids.
Topics: Chemistry, Pharmaceutical; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Thiazolidines
PubMed: 26922234
DOI: 10.1016/j.ejmech.2016.02.030 -
Molecules (Basel, Switzerland) Sep 2022A small library of highly functionalized phenylaminopyrazoles, bearing different substituents at position 1, 3, and 4 of the pyrazole ring, was prepared by the one-pot...
A small library of highly functionalized phenylaminopyrazoles, bearing different substituents at position 1, 3, and 4 of the pyrazole ring, was prepared by the one-pot condensation of active methylene reagents, phenylisothiocyanate, and substituted hydrazine (namely, methyl- and benzyl-hydrazine). The identified reaction conditions proved to be versatile and efficient. Furthermore, the evaluation of alternative stepwise protocols affected the chemo- and regio-selectivity outcome of the one-pot procedure. The chemical identities of two -methyl pyrazole isomers, selected as prototypes of the whole series, were unambiguously identified by means of NMR and mass spectrometry studies. Additionally, semiempirical calculations provided a structural rationale for the different chromatographic behavior of the two isomers. The prepared tetra-substituted phenylaminopyrazoles were tested in cell-based assays on a panel of cancer and normal cell lines. The tested compounds did not show any cytotoxic effect on the selected cell lines, thus supporting their pharmaceutical potentials.
Topics: Antineoplastic Agents; Drug Design; Hydrazines; Molecular Structure; Pharmaceutical Preparations; Pyrazoles; Structure-Activity Relationship
PubMed: 36144549
DOI: 10.3390/molecules27185814 -
Biochemical Pharmacology Mar 2024Cancer is a disease with a high mortality rate characterized by uncontrolled proliferation of abnormal cells. The hallmarks of cancer evidence the acquired cells... (Review)
Review
Cancer is a disease with a high mortality rate characterized by uncontrolled proliferation of abnormal cells. The hallmarks of cancer evidence the acquired cells characteristics that promote the growth of malignant tumours, including genomic instability and mutations, the ability to evade cellular death and the capacity of sustaining proliferative signalization. Poly(ADP-ribose) polymerase-1 (PARP1) is a protein that plays key roles in cellular regulation, namely in DNA damage repair and cell survival. The inhibition of PARP1 promotes cellular death in cells with homologous recombination deficiency, and therefore, the interest in PARP protein has been rising as a target for anticancer therapies. There are already some PARP1 inhibitors approved by Food and Drug Administration (FDA), such as Olaparib and Niraparib. The last compound presents in its structure an indazole core. In fact, pyrazoles and indazoles have been raising interest due to their various medicinal properties, namely, anticancer activity. Derivatives of these compounds have been studied as inhibitors of PARP1 and presented promising results. Therefore, this review aims to address the importance of PARP1 in cell regulation and its role in cancer. Moreover, it intends to report a comprehensive literature review of PARP1 inhibitors, containing the pyrazole and indazole scaffolds, published in the last fifteen years, focusing on structure-activity relationship aspects, thus providing important insights for the design of novel and more effective PARP1 inhibitors.
Topics: Adenosine Diphosphate Ribose; Cell Cycle; Indazoles; Neoplasms; Pyrazoles; United States; Humans; Animals; Poly (ADP-Ribose) Polymerase-1
PubMed: 38336156
DOI: 10.1016/j.bcp.2024.116045 -
Molecules (Basel, Switzerland) Nov 2021Chagas disease, a chronic and silent disease caused by , is currently a global public health problem. The treatment of this neglected disease relies on benznidazole and...
Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against .
Chagas disease, a chronic and silent disease caused by , is currently a global public health problem. The treatment of this neglected disease relies on benznidazole and nifurtimox, two nitroheterocyclic drugs that show limited efficacy and severe side effects. The failure of potential drug candidates in Chagas disease clinical trials highlighted the urgent need to identify new effective chemical entities and more predictive tools to improve translational success in the drug development pipeline. In this study, we designed a small library of pyrazole derivatives (44 analogs) based on a hit compound, previously identified as a cysteine protease inhibitor. The in vitro phenotypic screening revealed compounds , , and as promising candidates, with IC values of 6.09 ± 0.52, 2.75 ± 0.62, and 3.58 ± 0.25 µM, respectively, against intracellular amastigotes. All pyrazole derivatives have good oral bioavailability prediction. The structure-activity relationship (SAR) analysis revealed increased potency of 1-aryl-1-pyrazole-imidazoline derivatives with the Br, Cl, and methyl substituents in the -position. The compound stands out for its trypanocidal efficacy in 3D microtissue, which mimics tissue microarchitecture and physiology, and abolishment of parasite recrudescence in vitro. Our findings encourage the progression of the promising candidate for preclinical in vivo studies.
Topics: Cell Culture Techniques; Chagas Disease; Humans; Models, Molecular; Parasitic Sensitivity Tests; Printing, Three-Dimensional; Pyrazoles; Trypanocidal Agents; Trypanosoma cruzi
PubMed: 34771151
DOI: 10.3390/molecules26216742 -
Haematologica Dec 2016
Topics: Adenine; Age Factors; Clinical Studies as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Sweden; United Kingdom
PubMed: 27903711
DOI: 10.3324/haematol.2016.155986 -
Synthesis of Novel Pyrazole Derivatives Containing Phenylpyridine Moieties with Herbicidal Activity.Molecules (Basel, Switzerland) Sep 2022To discover new compounds with favorable herbicidal activity, a range of phenylpyridine moiety-containing pyrazole derivatives were designed, synthesized, and identified...
To discover new compounds with favorable herbicidal activity, a range of phenylpyridine moiety-containing pyrazole derivatives were designed, synthesized, and identified via NMR and HRMS. Their herbicidal activities against six species of weeds were evaluated in a greenhouse via both pre- and post-emergence treatments at 150 g a.i./hm. The bioassay revealed that a few compounds exhibited moderate herbicidal activities against , , and in post-emergence treatment. For instance, compounds and demonstrated 50% inhibition activity against , which was slightly superior to pyroxasulfone. Thus, compounds and may serve as the new possible leading compounds for the discovery of post-emergence herbicides.
Topics: Digitaria; Herbicides; Plant Weeds; Pyrazoles; Structure-Activity Relationship
PubMed: 36234814
DOI: 10.3390/molecules27196274 -
European Journal of Medicinal Chemistry Jul 2021A collection of potent antimicrobials consisting of novel 1,3-bis-benzoic acid and trifluoromethyl phenyl derived pyrazoles has been synthesized and tested for...
A collection of potent antimicrobials consisting of novel 1,3-bis-benzoic acid and trifluoromethyl phenyl derived pyrazoles has been synthesized and tested for antibacterial activity. The majority of trifluoromethyl phenyl derivatives are highly potent growth inhibitors of Gram-positive bacteria and showed low toxicity to human cultured cells. In particular, two compounds (59 and 74) were selected for additional studies. These compounds are highly effective against Staphylococcus aureus as shown by a low minimum inhibitory concentration (MIC), a bactericidal effect in time-kill assays, moderate inhibition of biofilm formation as well as biofilm destruction, and a bactericidal effect against stationary phase cells representing non-growing persister cells. Multistep resistance assays showed a very low tendency for S. aureus and Enterococcus faecalis to develop resistance through mutation. Additionally, in vivo mouse model studies showed no harmful effects at doses up to 50 mg/kg using 14 blood plasma organ toxicity markers or TUNEL assay in liver and kidney. Investigations into the mode of action by performing macromolecular synthesis inhibition studies showed a broad range of inhibitory effects, suggesting targets that have a global effect on bacterial cell function.
Topics: Aniline Compounds; Anti-Bacterial Agents; Biofilms; Cell Line; Cell Survival; Drug Resistance, Bacterial; Enterococcus faecalis; Gram-Positive Bacteria; Humans; Liver; Microbial Sensitivity Tests; Pyrazoles; Staphylococcus aureus; Structure-Activity Relationship
PubMed: 33845234
DOI: 10.1016/j.ejmech.2021.113402