Synthesis of novel aryl and coumarin substituted pyrazolo[1,5-a]pyrimidine derivatives as potent anti-inflammatory and anticancer agents

Naik, Nirmala S.; Shastri, Lokesh A.; Chougala, Bahubali M.; Samundeeswari, S.; Holiyachi, Megharaja; Joshi, Shrinivas D.; Sunagar, Vinay A.

doi:10.1016/j.cdc.2020.100550

Cited by 19 publications

(10 citation statements)

References 24 publications

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“…Serial dilutions of the investigated compounds and controls (celecoxib, Coxib, and aspirin, Asp) were cultivated with the enzyme-phenotype at 25 °C for 5 min, starting at 0.25 μg/mL and ending at 32 μg/mL. After the gestation time and the addition of chromogenic reagent and arachidonic acid as a substrate, absorbance was measured at 590 nm using a plate reader (Victor Nivo multi-mode computer-aided microplate-scanner, PerkinElmer, USA) [42].…”

Section: The Anti-inflammatory Activity Evaluationmentioning

confidence: 99%

Untitled

2022

J. Med. Chem. Sci.

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The incidence of many human disorders, such as cancer, oxidative stress, diabetes mellitus, and inflammatory diseases, has been mountingly increased because of many factors, including environmental pollution, static lifestyle, and unhealthy feeding. In an attempt to explore a scaffold with multiple biomedical activities, four natural phenolic acids, namely vanillic-, protocatechuic-, ferulic-, and caffeic-acid, were selected to construct twelve derived coumarins. The skeletal formulas of the semi-synthesized coumarins were confirmed by analyzing their spectra afforded via various spectrophotometers. The biomedical characteristics of these coumarins were investigated and included their antioxidant, anti-inflammatory, antidiabetic, and anticancer activities. The antioxidant activity was quantified by monitoring the potential of these coumarins to reduce DPPH and hydroxyl oxidants and provide an electron in the redox reaction. The anti-inflammatory activity was detected by specifying the inhibitory and selectivity of these coumarins on two COX isozymes. The antidiabetic activity was determined by examining the capacity of these coumarins to suppress two enzymes involved in blood glucose regulation. The anticancer activity and cytotoxicity were examined via MTT-based methodology versus four cancer cell lines and one normal cell line. The findings revealed that the semi-synthesized coumarins exhibited potent antioxidant and anticancer activities with low-induced cytotoxicity. Also, these coumarins showed modest antidiabetic potential and inhibitory effects versus the COX isozymes, with some selectivity toward the inhibition of COX-2. The authors concluded that these coumarins, specifically YC11, provide a valid structural template for synthesizing multi-functional agents effective in treating health situations in which oxidative stress, inflammation, diabetes, and cancer are combined.

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Section: The Anti-inflammatory Activity Evaluationmentioning

confidence: 99%

Untitled

2022

J. Med. Chem. Sci.

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“…Similarly, Shastri et al developed a method focused on obtaining derivatives from different arylaldehydes 47a –f . In contrast to the previous example, the synthesis of products 51a –f contemplates mixing all the starting materials in the same vial ( Scheme 16 b) [ 56 ]. In this case, the more extended reaction periods could improve the yields, although aminopyrazole’s stereoelectronic properties could improve selectivity, avoiding side reactions like dimerization or aromatic substitutions.…”

Section: Synthesis and Functionalizationmentioning

confidence: 99%

Functional Pyrazolo[1,5-a]pyrimidines: Current Approaches in Synthetic Transformations and Uses As an Antitumor Scaffold

2021

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Pyrazolo[1,5-a]pyrimidine (PP) derivatives are an enormous family of N-heterocyclic compounds that possess a high impact in medicinal chemistry and have attracted a great deal of attention in material science recently due to their significant photophysical properties. Consequently, various researchers have developed different synthesis pathways for the preparation and post-functionalization of this functional scaffold. These transformations improve the structural diversity and allow a synergic effect between new synthetic routes and the possible applications of these compounds. This contribution focuses on an overview of the current advances (2015–2021) in the synthesis and functionalization of diverse pyrazolo[1,5-a]pyrimidines. Moreover, the discussion highlights their anticancer potential and enzymatic inhibitory activity, which hopefully could lead to new rational and efficient designs of drugs bearing the pyrazolo[1,5-a]pyrimidine core.

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“…[6] Furthermore, the pyrazolo[1,5-a]pyrimidine-fused heterocycle identified in the literature as a privileged structure in drug discovery and exhibited many biological potentials which are anticancerous, [40,41] antioxidant, [42] serotonin antagonist, [43] antimicrobial, [44] and anti-inflammatory. [45,46] Additionally, many approved drugs contain the pyrazolo[1,5-a]pyrimidine nucleus as zaleplon, ocinaplon, and indiplon. [47] Recently, many researchers such as Yewale et al synthesized the pyrazolo-pyrimidine as an anti-inflammatory agent, that synthesized 5-phenyl-6-anilinopyrazolo [3,4-d]pyrimidin-4-ones I and exhibited superior anti-inflammatory activities compared with diclofenac sodium and celecoxib at a dose of 25 mg/kg, as well as inhibit the edema with 77.04 ± 0.5 after 1 h. [48] Additionally, Devesa et al reported that pyrazolo [3,4-d]pyrimidine-4,6-diamine derivative II showed potent and inhibitory activity to COX-1 and COX-2 with (IC 50 = 0.9 nM for COX-2 and IC 50 = 59.6 nM for COX-1) and also showedantiangiogenic activity.…”

Section: Introductionmentioning

confidence: 99%

Discovery of novel pyrazole and pyrazolo[1,5‐a]pyrimidine derivatives as cyclooxygenase inhibitors (COX‐1 and COX‐2) using molecular modeling simulation

Ayman

Radwan

Elmetwally

et al. 2022

Archiv der Pharmazie

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Searching for effective and selective anti-inflammatory agents, our study involved designing and synthesizing new pyrazole and pyrazolo[1,5-a]pyrimidine derivatives 4-11. The structures of the synthesized derivatives were confirmed using different spectroscopic techniques. Virtual screening was achieved for the newly designed derivatives using in silico docking simulation inside the active sites of four proteins classified as two cyclooxygenases (COX)-1 (PDB: 3KK6 and 4OIZ) and two COX-2 (PBD: 1CX2 and 3LN1). Among them, six derivatives 4c, 5b, 6a, 7a, 7b, and 10b displayed the highest binding energy. These derivatives were evaluated for their in vitro COX-1 and COX-2 inhibitory activities and their selectivity indexes were calculated. Additionally, these derivatives displayed IC 50 values ranging between 4.909 ± 0.25 and 57.53 ± 2.91 µM, and 3.289 ± 0.14 and 124 ± 5.32 µM, against COX-1 and COX-2, respectively. Furthermore, the tested derivatives were found to have selective inhibitory activity on the COX-2 enzyme. Surprisingly, the two pyrazole derivatives 4c and 5b were found to be the most active, with IC 50 values of 9.835 ± 0.50 and 4.909 ± 0.25 µM and 4.597 ± 0.20 and 3.289 ± 0.14 µM compared with meloxicam (1.879 ± 0.1 and 5.409 ± 0.23 µM) and celecoxib (5.439 ± 0.28 and 2.164 ± 0.09 µM) against COX-1/-2, respectively. Besides, two pyrazole derivatives, 4c and 5b, displayed a COX-1/COX-2 SI of 2.14 and 1.49. Computational techniques such as molecular docking, density function theory (DFT) calculation, and chemical absorption, distribution, metabolism, excretion, and toxicity evaluation were applied to explain the molecules' binding mode, chemical nature, drug likeness, and toxicity prediction.

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Synthesis of novel aryl and coumarin substituted pyrazolo[1,5-a]pyrimidine derivatives as potent anti-inflammatory and anticancer agents

Cited by 19 publications

References 24 publications

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Functional Pyrazolo[1,5-a]pyrimidines: Current Approaches in Synthetic Transformations and Uses As an Antitumor Scaffold

Discovery of novel pyrazole and pyrazolo[1,5‐a]pyrimidine derivatives as cyclooxygenase inhibitors (COX‐1 and COX‐2) using molecular modeling simulation

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