Three-Component Synthesis of 2-Amino-3-cyano-4H-chromenes, In Silico Analysis of Their Pharmacological Profile, and In Vitro Anticancer and Antifungal Testing

Abstract

Chromenes are compounds that may be useful for inhibiting topoisomerase and cytochrome, enzymes involved in the growth of cancer and fungal cells, respectively. The aim of this study was to synthesize a series of some novel 2-amino-3-cyano-4-aryl-6,7-methylendioxy-4H-chromenes 4a–o and 2-amino-3-cyano-5,7-dimethoxy-4-aryl-4H-chromenes 6a–h by a three-component reaction, and test these derivatives for anticancer and antifungal activity. Compounds 4a and 4b were more active than cisplatin (9) and topotecan (7) in SK-LU-1 cells, and more active than 9 in PC-3 cells. An evaluation was also made of the series of compounds 4 and 6 as potential antifungal agents against six Candida strains, finding their MIC50 to be less than or equal to that of fluconazole (8). Molecular docking studies are herein reported, for the interaction of 4 and 6 with topoisomerase IB and the active site of CYP51 of Candida spp. Compounds 4a–o and 6a–h interacted in a similar way as 7 with key amino acids of the active site of topoisomerase IB and showed better binding energy than 8 at the active site of CYP51. Hence, 4a–o and 6a–h are good candidates for further research, having demonstrated their dual inhibition of enzymes that participate in the growth of cancer and fungal cells.

Synthesis, In Silico Study, and In Vitro Antifungal Activity of New 5-(1,3-Diphenyl-1H-Pyrazol-4-yl)-4-Tosyl-4,5-Dihydrooxazoles

“…The two series of test compounds and the reference drug all interact with key amino acids of the active site of the CYP51Ca enzyme, such as Thr122, Phe126, Ile131, Tyr132, Phe228, Gly307, and Thr311. All of them also interact with the prosthetic group Hem580, which is known to be essential for the catalytic activity of the enzyme, as previously reported for azole derivatives [14,50,51].…”

The Immobilized Zirconocene Chloride on Magnetite‐reduced Graphene Oxide: A Highly Efficient and Reusable Heterogeneous Nanocatalyst for One‐pot Three‐component Synthesis of Tetrahydrobenzo[b]pyrans and Dihydropyrano[3,2‐c]chromenes

“…[49] These materials have been prepared by one-pot three-component condensation of malononitrile, aryl aldehydes and cyclic 1,3-diketones in the presence of numerous reagents, solvents and catalyst systems. [50][51][52][53][54] The use of piperidine, [55] morpholine, [56] Na 2 SeO 4 , [57] hexadecyldimethylbenzyl ammonium bromide, [58]…”

“…These materials have been prepared by one‐pot three‐component condensation of malononitrile, aryl aldehydes and cyclic 1,3‐diketones in the presence of numerous reagents, solvents and catalyst systems [50–54] . The use of piperidine, [55] morpholine, [56] Na 2 SeO 4 , [57] hexadecyldimethylbenzyl ammonium bromide, [58] Ru(II) complexes, [59] iodine, [60] trisodium citrate [61] tetramethyl ammonium hydroxide (CH 3 ) 4 NOH, [62] TEBA, [63] KF‐montmorillonite, [64] KF‐alumina, [65] ionic liquid, [66] amino functionalized ionic liquids, [67] organocatalysts, [68] TFE, [69] Yb(PFO) 3 , [70] TBAB, [71] melamine‐SO 3 H [72] hydrotalcite, [73] diammonium hydrogen phosphate, [74] potasim phosphate, [75] silica nanopatticles, [76] DBSA, [77] perfluorooctanoate, [78] ( S )‐proline, [79] silica bonded n ‐propyl‐4‐aza‐1‐azoniabicyclo[2.2.2]octane chloride, [80] Co 3 O 4 nano‐flake, [81] nanozeolite clinoptilolite, [82] SO 3 H‐bearing carbonaceous solid catalyst (PEG‐SAC), [83] multi‐walled carbon nanotube supported Fe 3 O 4 nanoparticles, [84] chitosan‐ZnO nanoparticles, [85] acetic acid functionalized imidazolium salts, [86] nano α‐Al 2 O 3 supported ammonium dihydrogenphosphate [87] and driving the reaction in the absence of any catalyst [88] are some of the protocols which have been well documented.…”

Synthesis, Biological and Molecular Docking Studies of New Polysubstituted 2‐Amino‐3‐Cyano‐4H‐Chromene Derivatives

“…[16] Amongst all the chromene derivatives, 2-amino-3cyano-4H-chromene is especially attractive for synthesis because of its high reactivity and excellent medicinal applications such as antioxidant, antimicrobial, anti-inflammatory, antimalarial, antitumor, HIV-fighting and anticancer. [17][18][19][20][21] Also, chromene derivatives shown excellent biological activities like antiproliferative, [22,23] antifungal activities , [24,25] Antiviral activity, [26] antiangiogenic activity. [27] Based on aforementioned information, the present study was attempted to synthesize bioactive chromene derivatives and explore the bioactive potentials of 2amino-3-cyano-4H-chromene derivatives against the virulence factors of P. mirabilis.…”