Hemozoin inhibiting 2-phenylbenzimidazoles active against malaria parasites

Abstract

The 2-phenylbenzimidazole scaffold has recently been discovered to inhibit β-hematin (synthetic hemozoin) formation by high throughput screening. Here, a library of 325,728 N-4-(1Hbenzo[d]imidazol-2-yl)aryl)benzamides was enumerated, and Bayesian statistics used to predict β-hematin and Plasmodium falciparum growth inhibition. Filtering predicted inactives and compounds with negligible aqueous solubility reduced the library to 35,124. Further narrowing to compounds with terminal aryl ring substituents only, reduced the library to 18, 83% of which were found to inhibit β-hematin formation <100 μM and 50% parasite growth <2 μM. Four compounds showed nanomolar parasite growth inhibition activities, no cross-resistance in a chloroquine resistant strain and low cytotoxicity. QSAR analysis showed a strong association of parasite growth inhibition with inhibition of β-hematin formation and the most active compound inhibited hemozoin formation in P. falciparum, with consequent increasing exchangeable heme. Pioneering use of molecular docking for this system demonstrated predictive ability and could rationalize observed structure activity trends.

Virtual screening as a tool to discover new β-haematin inhibitors with activity against malaria parasites

“…It should be noted, however, that while the strongest interaction is predicted to be with the [001] face, this does not imply that no interaction occurs with other faces. Indeed, in a recent investigation of benzimidazole haemozoin inhibitors we found that docking to both the [001] and [011] faces needed to be considered to explain observed activity 21 . experimental tests.…”

“…It was found that 103 of 155 compounds with this fingerprint were active in the β-haematin inhibition assay while 194 of 194 compounds were active in the parasite growth inhibition activity assay 31 . That study led to the synthesis of benzimidazole analogues, 83% of which were found to inhibit β-haematin formation and 50% inhibited parasite growth 21 . Although 9 showed one of the best β-haematin inhibitory activities, curiously, three out the five benzimidazole compounds identified in this series (compound 5, 7, and 14) were β-haematin and parasite inactive (with compound 14 weakly active against P. falciparum).…”

Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites

“…A molecular docking study conducted to attempt to rationalise these findings indicated that the lack of activity of the smaller fragments was probably a result of fewer contacts with the crystal surface, even though the benzimidazole fragment was the key pharmacophore. The most active benzimidazoles had a higher number of π-stacking interactions with the β-haematin crystal [21].…”

“…It should also be noted that while the strongest interaction is predicted to be with the [001] face, this does not necessarily imply that no interaction occurs with other faces. In a recent investigation of benzimidazole haemozoin inhibitors, we found that not only docking to the [001] face of β-haematin but also to the second fastest growing [011] face had to be considered to explain the observed activity [21]. The absence of these additional binding modes may play a role in reducing the accuracy of the model, as may the absence of solvents and lack of steps and kinks at the surface of the crystal, which are known to represent sites of drug binding [4].…”

Recent Highlights in Anti‐infective Medicinal Chemistry from South Africa

“…Following the application of Bayesian statistics and docking simulations, L′abbate et al. selected benzimidazole 51 for optimisation, culminating in a handful of compounds including 54 , whose excellent β‐hematin inhibitory activity translated into sub‐micromolar anti‐plasmodial activity …”