Synthesis of 3-aryl-4-(N-aryl)aminocoumarins via photoredox arylation and the evaluation of their biological activity

• Published in: Bioorganic chemistry Vol. 114; p. 105141
• Main Authors: Carneiro, Leonardo S.A., Almeida-Souza, Fernando, Lopes, Yanne S.C., Novas, Rachel C.V., Santos, Kaique B.A., Ligiero, Carolina B.P., Calabrese, Kátia da S., Buarque, Camilla D.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.09.2021; Elsevier
• Subjects: ADMET; Aminocoumarin; Aminocoumarins - chemical synthesis; Aminocoumarins - chemistry; Aminocoumarins - pharmacology; Animals; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Arylation; Arylcoumarin; Biochemistry & Molecular Biology; Cell Proliferation - drug effects; Chemistry; Chemistry, Organic; Cytotoxicity; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; In silico; Leishmania - drug effects; Leishmaniasis; Life Sciences & Biomedicine; Mice; Mice, Inbred BALB C; Molecular Structure; Oxidation-Reduction; Parasitic Sensitivity Tests; Photochemical Processes; Photoredox catalysis; Physical Sciences; Science & Technology; Structure-Activity Relationship; Tumor Cells, Cultured; X-ray diffraction; Photoredox catalysis; Arylation; Aminocoumarin; X-ray diffraction; Cytotoxicity; In silico; Arylcoumarin; Leishmaniasis; ADMET; DESIGN; ANALOGS; CANCER; BREAST; IN-VITRO; POTENT; AMASTIGOTES; 4-SUBSTITUTED COUMARINS; DERIVATIVES; ACCESS
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105141

[Display omitted] •The synthesis of 18 new 3-aryl-4-(N-aryl)aminocoumarins was achieved in two steps.•The key step of the proposed route is a photoredox arylation.•Compound 17x was more selective to L. amazonensis than miltefosine.•In silico analysis suggested that 17x is a candidate for anti-leishmaniasis drugs. A new series of 3-aryl-4-(N-aryl)aminocoumarins was synthesized in two steps starting from the natural product 4-hydroxycoumarin using the photoredox catalysis for the key step. These conditions reactions allowed to make CC bonds is up to 95% yields in mild conditions, easy operation, in an environmentally benign way, and are compatible with several patterns of substitution. The biological activity of the new compounds was tested in vitro against MCF-7, MDA-MB-231, and CCD-1072Sk cancer cell lines, as soon as to promastigotes and intracellular amastigotes of Leishmania amazonensis. Compounds 17d, 17s and 17x showed activity against promastigote forms (IC50 = 5.96 ± 3.210, 9.05 ± 2.855 and 5.65 ± 2.078 μM respectively), and compound 17x presented the best activity against L. amazonensis amastigote intracellular form (IC50 = 9.6 ± 1.148 μM), no BALB/c peritoneal macrophage cytotoxicity at assayed concentrations (CC50 > 600 μM), and high selectivity to parasites over the mammalian cells (Selectivity Index > 62.2). There was no expressive activity for the cancer cell lines. Single crystal X-ray diffraction analysis was employed for structural elucidation of compounds 17a and 17s. In silico analyses of physicochemical, pharmacokinetic, and toxicological properties suggest that compound 17x is a potential candidate for anti-leishmaniasis drugs.