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. 2022 Mar 30;27(7):2240.
doi: 10.3390/molecules27072240.

Design, Synthesis, Pharmacodynamic and In Silico Pharmacokinetic Evaluation of Some Novel Biginelli-Derived Pyrimidines and Fused Pyrimidines as Calcium Channel Blockers

Ahmed M Farghaly  1 , Ola H Rizk  1   2 , Inas Darwish  3   4 , Manal Hamza  3 , Mezna Saleh Altowyan  5 , Assem Barakat  6   7 , Mohamed Teleb  1
Affiliations

Design, Synthesis, Pharmacodynamic and In Silico Pharmacokinetic Evaluation of Some Novel Biginelli-Derived Pyrimidines and Fused Pyrimidines as Calcium Channel Blockers

Ahmed M Farghaly et al. Molecules. .

Abstract

Some new pyrimidine derivatives comprising arylsulfonylhydrazino, ethoxycarbonylhydrazino, thiocarbamoylhydrazino and substituted hydrazone and thiosemicarbazide functionalities were prepared from Biginelli-derived pyrimidine precursors. Heterocyclic ring systems such as pyrazole, pyrazolidinedione, thiazoline and thiazolidinone ring systems were also incorporated into the designed pyrimidine core. Furthermore, fused triazolopyrimidine and pyrimidotriazine ring systems were prepared. The synthesized compounds were evaluated for their calcium channel blocking activity as potential hypotensive agents. Compounds 2, 3a, 3b, 4, 11 and 13 showed the highest ex vivo calcium channel blocking activities compared with the reference drug nifedipine. Compounds 2 and 11 were selected for further biological evaluation. They revealed good hypotensive activities following intravenous administration in dogs. Furthermore, 2 and 11 displayed drug-like in silico ADME parameters. A ligand-based pharmacophore model was developed to provide adequate information about the binding mode of the newly synthesized active compounds 2, 3a, 3b, 4, 11 and 13. This may also serve as a reliable basis for designing new active pyrimidine-based calcium channel blockers.

Keywords: Biginelli; calcium channel blockers; hypotensive activity; pyrimidines.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Pyrimidine-derived cardiovascular agents.
Figure 2
Figure 2
The design strategy of the target Biginelli-derived pyrimidines and fused pyrimidines.
Scheme 1
Scheme 1
Synthesis of the desired compounds 2–8.
Scheme 2
Scheme 2
Synthesis of the desired compounds 9–14.
Figure 3
Figure 3
(a) HMBC spectrum of compound 13; (b) HMBC spectrum of compound 14b.
Figure 4
Figure 4
(a) The best query displaying pharmacophoric features shared by representative DHP, DHPM and pyrimidine-based CCBs as colored spheres (green for hydrophobic feature, cyan for H-bond acceptor and pink for H-bond acceptor/donor as well as hydrophobic centers with H-bond acceptor or donor functions. (b) Linear distances between various pharmacophore features are measured in angstroms and displayed as green lines.
Figure 5
Figure 5
(a) Mapping of compound 2 on the pharmacophore model. (b) Mapping of compound 3a on the pharmacophore model. (c) Mapping of compound 3b on the pharmacophore model. (d) Mapping of compound 4 on the pharmacophore model. (e) Mapping of compound 11 on the pharmacophore model.
Figure 5
Figure 5
(a) Mapping of compound 2 on the pharmacophore model. (b) Mapping of compound 3a on the pharmacophore model. (c) Mapping of compound 3b on the pharmacophore model. (d) Mapping of compound 4 on the pharmacophore model. (e) Mapping of compound 11 on the pharmacophore model.
Figure 5
Figure 5
(a) Mapping of compound 2 on the pharmacophore model. (b) Mapping of compound 3a on the pharmacophore model. (c) Mapping of compound 3b on the pharmacophore model. (d) Mapping of compound 4 on the pharmacophore model. (e) Mapping of compound 11 on the pharmacophore model.
Figure 6
Figure 6
Summarized SAR pattern of the Biginelli-derived pyrimidine and fused pyrimidine CCBs.
See this image and copyright information in PMC

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