Interrogating alkyl and arylalkylpolyamino (bis)urea and (bis)thiourea isosteres as potent antimalarial chemotypes against multiple lifecycle forms of Plasmodium falciparum parasites

Abstract

A new series of potent potent aryl/alkylated (bis)urea- and (bis)thiourea polyamine analogues were synthesized and evaluated in vitro for their antiplasmodial activity. Altering the carbon backbone and terminal substituents increased the potency of analogues in the compound library 3-fold, with the most active compounds, 15 and 16, showing half-maximal inhibitory concentrations (IC50 values) of 28 and 30 nM, respectively, against various Plasmodium falciparum parasite strains without any cross-resistance. In vitro evaluation of the cytotoxicity of these analogues revealed marked selectivity towards targeting malaria parasites compared to mammalian HepG2 cells (>5000-fold lower IC50 against the parasite). Preliminary biological evaluation of the polyamine analogue antiplasmodial phenotype revealed that (bis)urea compounds target parasite asexual proliferation, whereas (bis)thiourea compounds of the same series have the unique ability to block transmissible gametocyte forms of the parasite, indicating pluripharmacology against proliferative and non-proliferative forms of the parasite. In this manuscript, we describe these results and postulate a refined structure-activity relationship (SAR) model for antiplasmodial polyamine analogues. The terminally aryl/alkylated (bis)urea- and (bis)thiourea-polyamine analogues featuring a 3-5-3 or 3-6-3 carbon backbone represent a structurally novel and distinct class of potential antiplasmodials with activities in the low nanomolar range, and high selectivity against various lifecycle forms of P. falciparum parasites.

Antibacterial Diamines Targeting Bacterial Membranes

“…20,39 However, this toxicity can be effectively managed when compounds related to 3 are used at lower doses as antimicrobial agents. 40,41 Hit-to-lead optimization of antimicrobial diamines such as 3 is an ongoing concern in our laboratories.…”

“…Experimental details and analytical data for compounds 1 – 12 appear in previous publications. 18,40 …”

Resisting resistance: is there a solution for malaria?

“…Polyamines and their analogues have been shown to be readily taken up by malaria infected erythrocytes [67] and analogues with (bis)urea and (bis)thiourea substituents are potently and selectively active on the parasite (IC 50 = 26 nM; selectivity indexes >7000-fold) [68]. Pluriplarmacology is further evident with the (bis)urea polyamine chemotype targeting parasite asexual proliferation through multiple mechanisms, and (bis)thiourea analogues uniquely blocking transmissible sexual forms of the malaria parasite [69]. Importantly, when asexual parasites are exposed to this pleiotropic scaffold, no recrudescence or viable resistant mutants were generated (unpublished results), suggesting that these promising multitarget inhibitors may serve as "resistance-refractory" antimalarial candidates.…”

Bis‐thiourea Derivatives and Their Utility in Synthesis of Mono‐heterocyclic, Bis‐heterocyclic, and Fused Heterocyclic Systems

“…They have also demonstrated interesting pharmacological activities. They have been reported to display potent antitumor as well as antimalarial activities. Bis‐thioureas were extensively employed as organocatalysts in several asymmetric organic reaction providing high reactivity and enantioselectivity .…”