Incorporation of an intramolecular hydrogen bonding motif in the side chain of antimalarial benzimidazoles

Abstract

Analogues of a novel class of benzimidazoles with an intramolecular hydrogen bonding motif have been synthesized and evaluated in vitro for their antiplasmodium activity against chloroquine-sensitive (NF54) and multi-drug resistant (K1) strains of the human malaria parasite Plasmodium falciparum.

Recent Highlights in Anti‐infective Medicinal Chemistry from South Africa

“…However, a reduction in activity was observed for all compounds when assessed against a chloroquine‐resistant strain, indicating a degree of cross sensitivity. While β‐hematin inhibition assays did not correlate with anti‐plasmodial activity, the most promising compound from this study ( 59 ) was found to have superior β‐hematin inhibitory activity to chloroquine, indicating that inhibition of this pathway likely contributes the anti‐plasmodial activity of these compounds …”

“…Atram et al., designed a series of related compounds, featuring a basic nitrogen, in close enough proximity to a hydroxy functionality to facilitate the formation of intramolecular hydrogen bonds . The shielding of hydrogen bond donors and acceptors from interacting with water as a result of intramolecular hydrogen bonds reduces the energy penalty of desolvation, which would usually occur as a result of moving from an aqueous to a lipid environment .…”

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

“…In particular, the exhibition of the internal hydrogen bond between the phenolic hydroxyl and amino nitrogen groups is crucial for the antiplasmodial activity of α-aminocresols. [21] Additionally, Chinnapattu et al found that constraining the rotatability of the bond between the α-carbon and the amino nitrogen atom by introducing an amide bond led to a decrease in activity of the resulting compounds. [20] Therefore, in order to comprehensively elucidate the structure-activity relationship (SAR) profile of the pursued ferrocenyl α-aminocresols, the phenolic hydroxy group (OH) and the rotatable α-CÀ NH bond were modified by synthesizing non-phenolic benzylamines 12 a-d and salicylamides 14 a-g as non-rotatable aminocresol congeners, respectively.…”

“…[19] Additionally, α-aminocresols have attracted renewed research interest in the recent years as antimalarial agents. [20,21] By conjugating the adamantane motif to the α-aminocresol scaffold, Chinnapattu et al generated a series of adamantane aminomethylphenols (4) with 3D geometry possessing impressive plasmocidal activity against chemosusceptible (NF54) and multidrug-resistant (K1) Plasmodium falciparum strains in the nanomolar range. [20] Similarly, Chibale and co-workers incorporated the α-aminocresol moiety into the benzimidazole scaffold to produce α-aminocresol-benzimidazole conjugates (5) that were active against the same strains of the malaria parasite.…”

“…[20] Similarly, Chibale and co-workers incorporated the α-aminocresol moiety into the benzimidazole scaffold to produce α-aminocresol-benzimidazole conjugates (5) that were active against the same strains of the malaria parasite. [21] Several αaminocresol derivatives are featured in the Open-Access Box of Medicines for Malaria Venture (MMV) as important structural motifs for investigation and development in antimalarial drug research. [22] Despite these successes, there are no accounts of organometallic derivatives of the α-amino-o-cresol scaffold presented in literature to our knowledge.…”