Synthesis and biological activity of cymantrene and cyrhetrene 4-aminoquinoline conjugates against malaria, leishmaniasis, and trypanosomiasis

Abstract

Organometallic analogues of chloroquine show promise as new antimalarial agents capable of overcoming resistance to the parent drug chloroquine. Here, the synthesis and characterization of three new cymantrene (CpMn(CO)(3)) and cyrhetrene (CpRe(CO)(3)) 4-aminoquinoline conjugates with either an amine or amide linker are reported. The antimalarial activity of the new organometallic conjugates N-(2-(7-chloroquinolin-4-ylamino)ethyl)-4-cymantrenylbutanamide (3), N-(2-(7-chloroquinolin-4-ylamino)ethyl)-4-cyrhetrenylbutanamide (4) and N-(7-chloroquinolin-4-yl)-N'-(cymantrenylmethyl)ethane-1,2-diamine (6) was evaluated against a chloroquine-sensitive (CQS) and a chloroquine-resistant strain (CQR) of the malaria parasite Plasmodium falciparum. The cymantrene complex with an amine linker (6) showed good activity against the CQS strain but was inactive against the CQR strain. In contrast, cymantrene and cyrhetrene compounds with an amide linker were active against both the CQS and the CQR strain. In addition, the antibacterial, anti-trypanosomal and anti-leishmanial activity of the compounds was evaluated. Compound 6 showed submicromolar activity against Trypanosoma brucei at a concentration where the toxicity to normal human cells is low. No significant effect was noticed on the exchange of manganese for rhenium in the CpM(CO)(3) moiety in any of the biological assays.

Synthesis, Cellular Uptake and Biological Activity Against Pathogenic Microorganisms and Cancer Cells of Rhodium and Iridium N‐Heterocyclic Carbene Complexes Bearing Charged Substituents

“…Again, only negligible differences in anti‐leishmanial/anti‐trypanosomal activity were observed for the rhodium compound relative to the iridium one. Although these are quite promising results,15 the metal–NHC complexes are still about two orders of magnitude less active than the reference drug pentamidin, which has low nanomolar activity under similar conditions and a selectivity index of approximately 3500. Thus, these metal–NHC compounds miss the definition and activity criteria for hit and lead development as defined by the WHO/TDR (World Health Organization, Special Programme for Research and Training in Tropical Diseases) 16…”

Ferrocenyl Derivatives of the Anthelmintic Praziquantel: Design, Synthesis, and Biological Evaluation

“…[13][14][15][16][17][18][19][20][21][22][23][24][25][26] This strategy was found very successful with ferroquine (FQ), a ferrocenyl analogue of the antimalarial drug chloroquine (CQ), as FQ is active on CQ-resistant Plasmodium falciparum strains. Furthermore, intensive chemical biology studies have recently allowed unveiling additional modes of action for FQ compared to the parent drug in FQ, which were attributed to the presence of the organometallic unit.…”

Cymantrene–Triazole “Click” Products: Structural Characterization and Electrochemical Properties

“…We have reported the facile synthesis of three new triazole-derivatized cymantrene complexes (3)(4)(5) in good yield, all of which have been structurally characterized using a variety of techniques. The incorporation of either a para or meta-amine group into the pendant phenyl ring at the 4-position of the triazole moiety does not adversely affect the "click" reaction used to form it.…”

“…3 Excitingly, we found that all three click products 3-5 were more active than cymantrene 1 at reducing the growth rate of cells by 50% to that of the controls when tested against Trypanosoma brucei (Table 4). The advantage of having a cymantrene spectroelectrochemical redox tag attached to the triazole unit has been pointed out by Geiger,6 allowing for the possibility of spectroscopic or electrochemical monitoring of the compound in cell cultures, and photochemical activation (release) of the pendant CO groups.…”

“…Recently it has found applications in photochemical studies 1 and hydrogen generation via water splitting reactions. 2 Cymantrene derivatives have been combined with known antimalarial drugs such as chloroquine, 3 and have been tested for antiproliferative activity against breast cancer cell lines, 4 to highlight just a few of its many chemical applications.…”