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Archiv Der Pharmazie Jan 2022Two series comprising 20 novel benzenesulfonamides bearing thioureido-linked pyrazole 8 and amino-1,2,4-thiadiazole 10 were synthesized and assayed as human carbonic...
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.
Topics: Carbonic Anhydrase Inhibitors; Humans; Isoenzymes; Models, Molecular; Pyrazoles; Structure-Activity Relationship; Sulfonamides; Thiadiazoles; Benzenesulfonamides
PubMed: 34596922
DOI: 10.1002/ardp.202100241 -
European Journal of Pharmaceutical... Apr 2023Malaria poses a severe public health risk and a significant economic burden in disease-endemic countries. One of the most severe issues in malaria control is the... (Review)
Review
Malaria poses a severe public health risk and a significant economic burden in disease-endemic countries. One of the most severe issues in malaria control is the development of drug resistance in malaria parasites. The standard treatment for malaria is artemisinin-combination therapy (ACT). Nevertheless, the Plasmodium parasite's extensive resistance to prior drugs and reduced ACT efficiency necessitates novel drug discovery. The progress in discovering novel, affordable, and effective antimalarial agents is significant in combating drug resistance, and the hybrid drug concept can be used to covalently link two or more active pharmacophores that may act on multiple targets. Pyrazole and pyrazoline derivatives are considered pharmacologically necessary active heterocyclic scaffolds that possess almost all types of pharmacological activities. This review summarized recent progress in antimalarial activities of synthesized pyrazole and pyrazoline derivatives. The studies published since 2000 are included in this systematic review. This review is anticipated to be beneficial for future study and new ideas in searching for rational development strategies for more effective pyrazole and pyrazoline derivatives as antimalarial drugs.
Topics: Humans; Antimalarials; Malaria; Pyrazoles; Drug Resistance; Folic Acid Antagonists; Plasmodium falciparum
PubMed: 36563914
DOI: 10.1016/j.ejps.2022.106365 -
Anti-inflammatory & Anti-allergy Agents... 2024Pyrazole is a well-known nucleus in the pharmacy field with a wide range of other activities in addition to anti-inflammatory and analgesic, i.e., anticonvulsant,...
BACKGROUND
Pyrazole is a well-known nucleus in the pharmacy field with a wide range of other activities in addition to anti-inflammatory and analgesic, i.e., anticonvulsant, antiviral, and anticancer activities. There are well-known marketed drugs having pyrazole moiety as celecoxib, and lonazolac as COX-II inhibitors.
AIMS
We aim to synthesize better anti-inflammatory than existing ones. Thiophene is also known for its analgesic and anti-inflammatory action. Thus, the fusion of both gives better anti-inflammatory agents. In the present studies, derivatives from two series of pyrazole were prepared by reacting substituted chalcone (3a-3f) derivatives prepared from 2-acetyl thiophene. They substituted aromatic aldehydes with phenyl hydrazine to form (5a-5f) and with 2, 4-dinitro phenyl hydrazine giving compounds (6a-6f) separately.
METHODS
Purified and characterized pyrazoles have been analyzed for analgesic and anti-inflammatory activities by using standard methods. Compounds 5e, 5f, and 6d were proved to be potent analgesics and series (5a-5f) was found to have anti-inflammatory action, which was further validated using docking and ADME studies.
RESULTS
The ADME profile of synthesized compounds was found to be satisfactory.
CONCLUSION
The synthesized compounds can serve as lead for further drug designing.
Topics: Pyrazoles; Animals; Analgesics; Molecular Docking Simulation; Anti-Inflammatory Agents; Male; Mice; Structure-Activity Relationship; Edema; Humans; Rats; Pain; Rats, Wistar
PubMed: 38828869
DOI: 10.2174/0118715230275741231207115011 -
European Journal of Medicinal Chemistry Sep 2023Chemotherapeutics occupy a pivotal role in the medication of different types of cancers, but the prevalence and mortality rates of cancer remain high. The drug... (Review)
Review
Chemotherapeutics occupy a pivotal role in the medication of different types of cancers, but the prevalence and mortality rates of cancer remain high. The drug resistance and low specificity of current available chemotherapeutics are the main barriers for the effective cancer chemotherapy, evoking an immediate need for the development of novel anticancer agents. Pyrazole is a highly versatile five-membered heterocycle with two adjacent nitrogen atoms and possesses remarkable therapeutic effects and robust pharmacological potency. The pyrazole derivatives especially pyrazole hybrids have demonstrated potent in vitro and in vivo efficacies against cancers through multiple mechanisms, inclusive of apoptosis induction, autophagy regulation, and cell cycle disruption. Moreover, several pyrazole hybrids such as crizotanib (pyrazole-pyridine hybrid), erdafitinib (pyrazole-quinoxaline hybrid) and ruxolitinib (pyrazole-pyrrolo [2,3-d]pyrimidine hybrid) have already been approved for the cancer therapy, revealing that pyrazole hybrids are useful scaffolds to develop novel anticancer agents. The purpose of this review is to summarize the current scenario of pyrazole hybrids with potential in vivo anticancer efficacy along with mechanisms of action, toxicity, and pharmacokinetics, covering papers published in recent 5 years (2018-present), to facilitate further rational exploitation of more effective candidates.
Topics: Humans; Structure-Activity Relationship; Neoplasms; Antineoplastic Agents; Pyrazoles; Azoles
PubMed: 37209450
DOI: 10.1016/j.ejmech.2023.115495 -
Current Organic Synthesis 2021Privileged scaffolds are of high importance for molecules containing the pyrazole subunit due to their broad spectrum of pharmacological activities. For this reason, a...
BACKGROUND
Privileged scaffolds are of high importance for molecules containing the pyrazole subunit due to their broad spectrum of pharmacological activities. For this reason, a method that is more efficient needs to be developed for the preparation of pyrazole derivatives.
OBJECTIVE
The purpose of this study was the optimisation of the conventional synthesis of the pyrazole ring and the oxidation of phenyl-1H-pyrazole-4-carbaldehyde to phenyl-1H-pyrazole-4-carboxylic acid through Microwave- Assisted Organic Synthesis (MAOS).
METHODS
We performed a comparison between conventional synthesis and conventional synthesis with microwave heating using the synthesis method of pyrazole ring described by Finar and Godfrey and for the oxidation of phenyl-1H-pyrazole-4-carbaldehyde, the method described by Shriner and Kleiderer was used.
RESULTS
MAOS reduces the reaction time to obtain all compounds compared to conventional heating. At a temperature of 60°C, 5 minutes of reaction time, and power of 50 W, the yield of phenyl-1H-pyrazoles (3a-m) compounds was in the range of 91 - 98% using MAOS, which is better than conventional heating (72 - 90%, 75ºC, 2 hours). An improvement in the yield for the oxidation reaction was also achieved with MAOS. The compounds (5a-m) were obtained with yields ranging from 62 - 92% (80ºC, 2 minutes, 150 W), while the yields with conventional heating were in the range of 48 - 85% (80ºC, 1 hour). The 26 compounds were achieved through an easy work-up procedure with no chromatographic separation. The pure products were characterised by the spectral data obtained from IR, MS, H and C NMR or HSQC/HMBC techniques.
CONCLUSION
The advantages of MAOS include short reaction time and increased yield, due to which it is an attractive option for pyrazole compounds synthesis.
Topics: Carboxylic Acids; Chemistry Techniques, Synthetic; Microwaves; Pyrazoles
PubMed: 34886771
DOI: 10.2174/1570179418666210618162518 -
Molecules (Basel, Switzerland) Jul 2020The pyrazole nucleus has long been known as a privileged scaffold in the synthesis of biologically active compounds. Within the numerous pyrazole derivatives developed... (Review)
Review
The pyrazole nucleus has long been known as a privileged scaffold in the synthesis of biologically active compounds. Within the numerous pyrazole derivatives developed as potential drugs, this review is focused on molecules characterized by a urea function directly linked to the pyrazole nucleus in a different position. In the last 20 years, the interest of numerous researchers has been especially attracted by pyrazolyl-ureas showing a wide spectrum of biological activities, ranging from the antipathogenic activities (bacteria, plasmodium, toxoplasma, and others) to the anticarcinogenic activities. In particular, in the anticancer field, pyrazolyl-ureas have been shown to interact at the intracellular level on many pathways, in particular on different kinases such as Src, p38-MAPK, TrKa, and others. In addition, some of them evidenced an antiangiogenic potential that deserves to be explored. This review therefore summarizes all these biological data (from 2000 to date), including patented compounds.
Topics: Chemistry Techniques, Synthetic; Chemistry, Pharmaceutical; Humans; Pharmaceutical Preparations; Pyrazoles; Structure-Activity Relationship; Urea
PubMed: 32751358
DOI: 10.3390/molecules25153457 -
Bioorganic Chemistry Apr 2023Cannabinoid receptors (CBs), including CB1 and CB2, are the key components of a lipid signaling endocannabinoid system (ECS). Development of synthetic cannabinoids has...
Cannabinoid receptors (CBs), including CB1 and CB2, are the key components of a lipid signaling endocannabinoid system (ECS). Development of synthetic cannabinoids has been attractive to modulate ECS functions. CB1 and CB2 are structurally closely related subtypes but with distinct functions. While most efforts focus on the development of selective ligands for single subtype to circumvent the undesired off-target effect, Yin-Yang ligands with opposite pharmacological activities simultaneously on two subtypes, offer unique therapeutic potential. Herein we report the development of a new Yin-Yang ligand which functions as an antagonist for CB1 and concurrently an agonist for CB2. We found that in the pyrazole-cored scaffold, the arm of N1-phenyl group could be a switch, modification of which yielded various ligands with distinct activities. As such, the ortho-morpholine substitution exerted the desired Yin-Yang bifunctionality which, based on the docking study and molecular dynamic simulation, was proposed to be resulted from the hydrogen bonding with S173 and S285 in CB1 and CB2, respectively. Our results demonstrated the feasibility of structure guided ligand evolution for challenging Yin-Yang ligand.
Topics: Cannabinoids; Endocannabinoids; Ligands; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Cannabinoid; Yin-Yang
PubMed: 36731294
DOI: 10.1016/j.bioorg.2023.106377 -
International Journal of Molecular... May 20204-Pyrazoles are emerging scaffolds for "click" chemistry. Late-stage fluorination with Selectfluor is found to provide a reliable route to 4-fluoro-4-methyl-4-pyrazoles....
4-Pyrazoles are emerging scaffolds for "click" chemistry. Late-stage fluorination with Selectfluor is found to provide a reliable route to 4-fluoro-4-methyl-4-pyrazoles. 4-Fluoro-4-methyl-3,5-diphenyl-4-pyrazole (MFP) manifested 7-fold lower Diels-Alder reactivity than did 4,4-difluoro-3,5-diphenyl-4-pyrazole (DFP), but higher stability in the presence of biological nucleophiles. Calculations indicate that a large decrease in the hyperconjugative antiaromaticity in MFP relative to DFP does not lead to a large loss in Diels-Alder reactivity because the ground-state structure of MFP avoids hyperconjugative antiaromaticity by distorting into an envelope-like conformation like that in the Diels-Alder transition state. This predistortion enhances the reactivity of MFP and offsets the decrease in reactivity from the diminished hyperconjugative antiaromaticity.
Topics: Chemistry Techniques, Synthetic; Cycloaddition Reaction; Fluorine; Glutathione; Kinetics; Models, Molecular; Molecular Conformation; Molecular Structure; Organic Chemicals; Pyrazoles; Stereoisomerism; Thermodynamics; Ultraviolet Rays
PubMed: 32486503
DOI: 10.3390/ijms21113964 -
Archiv Der Pharmazie Apr 2023Carbonic anhydrase (CA) is a metalloenzyme that catalyzes the interconversion between carbon dioxide and water and dissociated ions of carbonic acid. In addition, CA... (Review)
Review
Carbonic anhydrase (CA) is a metalloenzyme that catalyzes the interconversion between carbon dioxide and water and dissociated ions of carbonic acid. In addition, CA performs various other functions in animals and plants, depending on the part of the living being. CAs have been found in almost all organisms. Besides, CAs are associated with several diseases, such as glaucoma, obesity, epilepsy, cancer, and so on. CAs are also involved in tumor cell growth and angiogenesis. Thus, inhibition of CA may be an attractive way of control of such diseases. Hence, CA inhibitors have been designed and developed to cure CA-associated diseases. Some examples of approved CA inhibitors are dorzolamide, methazolamide, brinzolamide, and dichlorphenamide. Furthermore, various heterocyclic scaffolds were utilized for the design of CA inhibitors. Among those, pyrazole/pyrazoline derivatives have exhibited greater potency toward CA inhibition. Hence, research that took place in the field of drug design and discovery of CA inhibition has been systematically reviewed and collated. Alongside, the structure-activity relationship has been described, followed by a description of the most potent molecules and their structural features.
Topics: Animals; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Neoplasms; Pharmacophore; Pyrazoles; Structure-Activity Relationship
PubMed: 36599496
DOI: 10.1002/ardp.202200562 -
Molecules (Basel, Switzerland) Jan 2023In our initial publication on the in vitro testing of more than 200 compounds, we demonstrated that small molecules can inhibit phagocytosis. We therefore theorized that...
In our initial publication on the in vitro testing of more than 200 compounds, we demonstrated that small molecules can inhibit phagocytosis. We therefore theorized that a small molecule drug discovery-based approach to the treatment of immune cytopenias (ITP, AIHA, HTR, DHTR) is feasible. Those earlier studies showed that small molecules with anti-phagocytic groups, such as the pyrazole core, are good models for producing efficacious phagocytosis inhibitors with low toxicity. We recently screened a chemical library of 80 compounds containing pyrazole/isoxazole/pyrrole core structures and found four hit molecules for further follow-up, all having the pyrazole core structure. Subsequent evaluation via MTT viability, LDH release, and apoptosis, led to the selection of two lead compounds with negligible toxicity and high efficacy. In an in vitro assay for inhibition of phagocytosis, their IC values were 2-4 µM. The rational development of these discoveries from hit to lead molecule stage, viz. independent synthesis/scale up of hit molecules, and in vivo activities in mouse models of autoimmune disease, will result in the selection of a lead compound(s) for further pre-clinical evaluation.
Topics: Mice; Animals; Phagocytosis; Drug Discovery; Pyrazoles; Structure-Activity Relationship
PubMed: 36677815
DOI: 10.3390/molecules28020757