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Novel semicarbazides and ureas of primaquine with bulky aryl or hydroxyalkyl substituents: synthesis, cytostatic and antioxidative activity.

European journal of medicinal chemistry (2014-09-10)
K Pavić, I Perković, M Cindrić, M Pranjić, I Martin-Kleiner, M Kralj, D Schols, D Hadjipavlou-Litina, A-M Katsori, B Zorc
ABSTRACT

Novel primaquine semicarbazides 7a-l and ureas 9a-g with modified benzhydryl, trityl, phenyl or hydroxyalkyl substituents were prepared and evaluated for cytostatic and antioxidative activities. Two synthetic approaches for preparation of the title semicarbazides were applied, both having certain advantages. In the first approach, the products grew from the semicarbazide side and the primaquine residue entered the molecule the last. In the second approach, semicarbazide grew from the primaquine side. This method was more convenient for synthesis of a series of semicarbazides: various products could be obtained from the same precursor N-(4-((6-methoxyquinolin-8-yl)amino)pentyl)hydrazinecarbox-amide (10). Primaquine ureas 9a-f were prepared from primaquine benzotriazolide 8 and corresponding amines and urea 9g directly from primaquine and 4-chloro-3-(fluoromethyl)phenyl isocyanate. All primaquine semicarbazide derivatives showed either prominent cytostatic activity towards all the tested cell lines (benzhydryl or trityl derivatives 7a-e) or high selectivity towards MCF-7 cells (hydroxyalkyl derivatives 7h-l), with IC50 values in the low micromolar range. The highest selectivity exerted symmetric bisprimaquine derivative 7f, with an IC50 0.2 μM against MCF-7 cells and practically no activity against other seven tested cancer cell lines. Urea derivatives 9a-f were generally less active than their semicarbazide analogues, but still selective towards MCF-7 cells. Urea 9g with the similar structure to cytostatic drug sorafenib, was the most active urea derivative. Semicarbazides 7g and 10 showed the best antioxidative activity as measured by DPPH (64% at 20 min and 90% at 60 min), while urea derivatives 9a-g, especially 9d, and semicarbazides 7a-g with lipophilic substituents exerted better LP antioxidant activity. Both semicarbazides and ureas with methoxy or chloro benzhydryl substituents and high Clog P values showed significant LOX inhibition.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
2,2-Diphenyl-1-picrylhydrazyl
Supelco
Benzotriazole, analytical standard
Sigma-Aldrich
Hydrazine hydrate solution, puriss. p.a., 24-26% in H2O (RT)
Sigma-Aldrich
Triphosgene, reagent grade, 98%
Sigma-Aldrich
Hydrazine monohydrate, N2H4 64-65 %, reagent grade, 98%
Sigma-Aldrich
1,1-Diphenyl-2-picrylhydrazine, 97%
Sigma-Aldrich
Benzotriazole, ReagentPlus®, 99%
Sigma-Aldrich
Triethylamine, ≥99%
Sigma-Aldrich
Bis(trichloromethyl) carbonate, purum, ≥99.0% (AT)
Sigma-Aldrich
Nordihydroguaiaretic acid, ≥97.0% (HPLC)
Sigma-Aldrich
Triethylamine, ≥99.5%
Sigma-Aldrich
Primaquine bisphosphate, 98%
Sigma-Aldrich
Hydrazine hydrate, reagent grade, N2H4 50-60 %
Sigma-Aldrich
Triethylamine, for amino acid analysis, ≥99.5% (GC)
Sigma-Aldrich
Triethylamine, BioUltra, ≥99.5% (GC)
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Triethylamine, puriss. p.a., ≥99.5% (GC)
Sigma-Aldrich
Triethylamine, for protein sequence analysis, ampule, ≥99.5% (GC)
Sigma-Aldrich
Triethylamine, ≥99.5%
Supelco
Triethylamine, analytical standard
USP
Primaquine phosphate, United States Pharmacopeia (USP) Reference Standard
Primaquine diphosphate, European Pharmacopoeia (EP) Reference Standard