Discovery of trisubstituted pyrazolines as a novel scaffold for the development of selective phosphodiesterase 5 inhibitors

Abdel‐Halim, Mohammad; Tinsley, Heather N.; Keeton, Adam B.; Weam, Mohammed; Atta, Noha H.; Hammam, Mennatallah A.; Hefnawy, Amr; Hartmann, Rolf W.; Engel, Matthias; Piazza, Gary A.; Abadi, Ashraf H.

doi:10.1016/j.bioorg.2020.104322

Cited by 10 publications

(8 citation statements)

References 36 publications

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“…Heterocyclic analogs such as 1 H -pyrazole-1-carbothioamide/carboxamide are often used to design and develop physiologically active novel medications. 12 − 16 The pyrazoline core showed the potential anticancer activity 17 − 21 , and 1 H -pyrazole-1-carbothioamide types also exhibited biological activities such as antibacterial, 22 antifungal, 23 antiviral, 24 antimalarial, 25 antioxidant, 26 anti-inflammatory, 27 , 28 , and analgesic effects. 29 − 31 Anticancer drugs have DNA as their primary intracellular target.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Carbothioamide/Carboxamide-Based Pyrazoline Analogs as Potential Anticancer Agents: Apoptosis, Molecular Docking, ADME Assay, and DNA Binding Studies

et al. 2022

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To discover anticancer drugs with novel structures and expand our research scope, pyrazoline derivatives ( 3a – 3l ) were designed and synthesized through cyclization of chalcones with thiosemicarbazide/semicarbazide in CH 3 COOH as a solvent. All newly synthesized pyrazoline derivatives were fully characterized using several spectroscopic experiments such as 1 H, 13 C NMR, FT-IR spectroscopy, and mass analysis. By HPLC , the purity of all analogs was found above 95% and both lead compounds ( 3a and 3h ) were also validated by HRMS . Anticancer activity of synthesized pyrazoline derivatives ( 3a – 3l ) was investigated by the MTT assay against the human lung cancer cell (A549), human cervical cancer cell (HeLa), and human primary normal lung cells (HFL-1). Staurosporine (STS) was used as a standard drug. The anticancer results showed that two potent analogs 3a and 3h exhibit excellent activity against A549 (IC 50 = 13.49 ± 0.17 and 22.54 ± 0.25 μM) and HeLa cells (IC 50 = 17.52 ± 0.09 and 24.14 ± 0.86 μM) and low toxicity against the HFL-1 (IC 50 = 114.50 ± 0.01 and 173.20 ± 10 μM). The flow cytometry was further used to confirm the anticancer activity of potent derivatives against the A549 cancer cell line. DNA binding interaction of anticancer agents 3a and 3h with Ct-DNA has been carried out by absorption, fluorescence, EtBr (dye displacement assay), circular dichroism, cyclic voltammetry and time-resolved fluorescence, which showed noncovalent binding mode of interaction. Anticancer activity of both lead compounds ( 3a and 3h ) may be attributed to DNA binding. The evaluation of the antioxidant potential of pyrazoline analogs 3a and 3h by 2,2-diphenyl-1-picrylhydrazyl free radical showed promising antioxidant activity with IC 50 values of 0.132 ± 0.012 and 0.215 ± 0.025 μg/mL, respectively. In silico molecular docking of pyrazoline derivatives was also performed using autodock vina software against the DNA hexamer with PDB ID: 1Z3F and ADMET properties to explore their best hits.

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Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Carbothioamide/Carboxamide-Based Pyrazoline Analogs as Potential Anticancer Agents: Apoptosis, Molecular Docking, ADME Assay, and DNA Binding Studies

et al. 2022

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“…In this work, compound B was selected as a template for optimization and to explore SAR, as discussed in the following sections (Figure ). The details of modifications of celecoxib to compounds A and B have been recently published …”

Section: Resultsmentioning

confidence: 99%

“…These modifications led to compound A (Figure 2) with an IC 50 of 8.4 μM against PDE5, giving more than 4-fold improved potency compared to celecoxib (IC 50 = 37 μM). The subsequent optimization of compound A involved the replacement of the 4-tolyl moiety by several mono-substituted aryls (details are recently published); 29 this led to compound B that has a 4-methoxyphenyl group replacing the 4-tolyl (Figure 2). Compound B showed a further 4-fold increase in potency against PDE5 (IC 50 = 2 μM).…”

Section: ■ Introductionmentioning

confidence: 99%

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From Celecoxib to a Novel Class of Phosphodiesterase 5 Inhibitors: Trisubstituted Pyrazolines as Novel Phosphodiesterase 5 Inhibitors with Extremely High Potency and Phosphodiesterase Isozyme Selectivity

et al. 2021

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A ligand-based approach involving systematic modifications of a trisubstituted pyrazoline scaffold derived from the COX2 inhibitor, celecoxib, was used to develop novel PDE5 inhibitors. Novel pyrazolines were identified with potent PDE5 inhibitory activity lacking COX2 inhibitory activity. Compound d12 was the most potent with an IC50 of 1 nM, which was three times more potent than sildenafil and more selective with a selectivity index of >10,000-fold against all other PDE isozymes. Sildenafil inhibited the full-length and catalytic fragment of PDE5, while compound d12 only inhibited the full-length enzyme, suggesting a mechanism of enzyme inhibition distinct from sildenafil. The PDE5 inhibitory activity of compound d12 was confirmed in cells using a cGMP biosensor assay. Oral administration of compound d12 achieved plasma levels >1000-fold higher than IC50 values and showed no discernable toxicity after repeated dosing. These results reveal a novel strategy to inhibit PDE5 with unprecedented potency and isozyme selectivity.

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“…The general synthesis route of chalcones (3a-3f) and 3,5-diphenyl-4,5-dihydro-1H-pyrazole derivatives (4a-4f) are given in Table 1 and Figure 2. Firstly, the chalcones were synthesized by Claisen-Schmidt condensation among the aromatic aldehydes and the substituted acetophenone utilizing reported methods in the literature (Abdel-Halim et al, 2020;Çelik, 2020). Secondly, for compounds 4a-4f, chalcones have been converted into pyrazoline molecules by intramolecular Michael addition with hydrazine hydrate in refluxing ethanol and acetic acid as a catalyst (Table 1 and Figure 2) (Li et al, 2017;Çelik et al, 2020;Dofe et al, 2020;Farooq and Ngaini, 2020).…”

Section: Resultsmentioning

confidence: 99%

Yeni pirazolin türevlerinin sentezi ve yapı karakterizasyonu

Çelik¹

2021

Gümüşhane Üniversitesi Fen Bilimleri Enstitüsü Dergisi

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Pyrazolines, which are nitrogen including five-membered heterocyclic structures, have been used in the organic and pharmaceutical industries. This study aimed was to synthesize and characterizes new series of 3,5-diphenyl-4,5-dihydro-1H-pyrazole derivatives. The new pyrazoline compounds have been synthesized from chalcones and hydrazine hydrate in two steps. In the first step, chalcones were synthesized from 2-amino acetophenone and various substituted benzaldehyde by Claisen-Schmidt condensation at room temperature. In second step, starting from various substituted chalcones derivatives with hydrazine hydrate and glacial acetic acid in anhydrous ethanol were synthesized six novel 3,5diphenyl-4,5-dihydro-1H-pyrazole derivatives utilizing intramolecular Michael addition reaction in good yields. The structures of the newly synthesized 3,5-diphenyl-4,5-dihydro-1H-pyrazole derivatives are identified via 1H NMR, 13C NMR, FT-IR, and HRMS.

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Discovery of trisubstituted pyrazolines as a novel scaffold for the development of selective phosphodiesterase 5 inhibitors

Cited by 10 publications

References 36 publications

Design and Synthesis of Carbothioamide/Carboxamide-Based Pyrazoline Analogs as Potential Anticancer Agents: Apoptosis, Molecular Docking, ADME Assay, and DNA Binding Studies

Design and Synthesis of Carbothioamide/Carboxamide-Based Pyrazoline Analogs as Potential Anticancer Agents: Apoptosis, Molecular Docking, ADME Assay, and DNA Binding Studies

From Celecoxib to a Novel Class of Phosphodiesterase 5 Inhibitors: Trisubstituted Pyrazolines as Novel Phosphodiesterase 5 Inhibitors with Extremely High Potency and Phosphodiesterase Isozyme Selectivity

Yeni pirazolin türevlerinin sentezi ve yapı karakterizasyonu

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