The in Vitro Antiplasmodial and Antiproliferative Activity of New Ferrocene‐Based α‐Aminocresols Targeting Hemozoin Inhibition and DNA Interaction

Abstract

The conjugation of organometallic complexes to known bioactive organic frameworks is a proven strategy revered for devising new drug molecules with novel modes of action. This approach holds great promise for the generation of potent drug leads in the quest for therapeutic chemotypes with the potential to overcome the development of clinical resistance. Herein, we present the in vitro antiplasmodial and antiproliferative investigation of ferrocenyl α‐aminocresol conjugates assembled by amalgamation of the organometallic ferrocene unit and an α‐aminocresol scaffold possessing antimalarial activity. The compounds pursued in the study exhibited higher toxicity towards the chemosensitive (3D7) and ‐resistant (Dd2) strains of the Plasmodium falciparum parasite than to the human HCC70 triple‐negative breast cancer cell line. Indication of cross‐resistance was absent for the compounds evaluated against the multi‐resistant Dd2 strain. Structure‐activity analysis revealed that the phenolic hydroxy group and rotatable σ bond between the α‐carbon and NH group of the α‐amino‐o‐cresol skeleton are crucial for the biological activity of the compounds. Spectrophotometric techniques and in silico docking simulations performed on selected derivatives suggest that the compounds show a dual mode of action involving hemozoin inhibition and DNA interaction via minor‐groove binding. Lastly, compound 9 a, identified as a possible lead, exhibited preferential binding for the plasmodial DNA isolated from 3D7 P. falciparum trophozoites over the mammalian calf thymus DNA, thereby substantiating the enhanced antiplasmodial activity of the compounds. The presented research demonstrates the strategy of incorporating organometallic complexes into known biologically active organic scaffolds as a viable avenue to fashion novel multimodal compounds with potential to counter the development drug resistance.

Ferrocene-Based Drugs, Delivery Nanomaterials and Fenton Mechanism: State of the Art, Recent Developments and Prospects

“…The preferential binding affinity of 53 for the plasmodial DNA over the mammalian DNA, together with hemozoin inhibitory affinity, substantiated the higher selectivity of the compounds for the P. falciparum strains. The aminocresol 54 was the most potent compound against the CQS 3D7 strain in the rich series with an IC 50 value of 0.98 ± 0.10 µM [114]. Several other antimalarial ferrocene-containing drugs have recently been reported, including betulinic acid/betulin-derived dimers and hybrids [115] and amino-artemisininferrocene derivatives [116][117][118].…”

“…The preferential binding affinity of 53 for the plasmodial DNA over the mammalian DNA, together with hemozoin inhibitory affinity, substantiated the higher selectivity of the compounds for the P. falciparum strains. The aminocresol 54 was the most potent compound against the CQS 3D7 strain in the rich series with an IC 50 value of 0.98 ± 0.10 μM [ 114 ].…”

Thermal and thermo-oxidative stability of a series of palladium and platinum ferrocenylamine sulfides and selenides

“…22 Industrial applications involve production of redox-active anion sensors, 23 supercapacitor electrodes, 24 corrosion inhibitors, 25 and electro-and photoresponsive materials. 26 In addition, the biological impact of ferrocenylamine derivatives has been explored and they were found to exhibit anticancer, 1,[27][28][29] antimalarial, 30 antifungal, 31 antibacterial, 29 antiplasmodial, and antiproliferative activities, 32 in addition to being carbonic anhydrase inhibitors 33 and being able to electrochemically determine β-galactosidase 34 and alkaline phosphatase activities. 35 In this study, 20 ferrocenylamine complexes with systematic structural variations have been prepared and examined for their thermal (under nitrogen) and thermo-oxidation (under atmospheric air) stability.…”

“…In addition, the biological impact of ferrocenylamine derivatives has been explored and they were found to exhibit anticancer, 1,27–29 antimalarial, 30 antifungal, 31 antibacterial, 29 antiplasmodial, and antiproliferative activities, 32 in addition to being carbonic anhydrase inhibitors 33 and being able to electrochemically determine β-galactosidase 34 and alkaline phosphatase activities. 35…”