Structure−Activity Relationships of Cinnamate Ester Analogues as Potent Antiprotozoal Agents

Abstract

Protozoal infections are still a global health problem, threatening the lives of millions of people around the world, mainly in impoverished tropical and sub‐tropical regions. Thus, in view of the lack of efficient therapies and increasing resistances against existing drugs, this study describes the antiprotozoal potential of synthetic cinnamate ester analogues and their structure‐activity relationships. In general, Leishmania donovani and Trypanosoma brucei were quite susceptible to the compounds in a structure‐dependent manner. Detailed analysis revealed a key role of the substitution pattern on the aromatic ring and a marked effect of the side chain on the activity against these two parasites. The high antileishmanial potency and remarkable selectivity of the nitro‐aromatic derivatives suggested them as promising candidates for further studies. On the other hand, the high in vitro potency of catechol‐type compounds against T. brucei could not be extrapolated to an in vivo mouse model.

A Comprehensive QSAR Study on Antileishmanial and Antitrypanosomal Cinnamate Ester Analogues

“…Those bits from the MACCS fingerprint would be likely responsible for the activity. Such features are related to the number of oxygen atoms in the molecule and to the existence of linear alkyl chains, which is in perfect agreement with the previously published qualitative SAR results [25], but also led to inferring that the antileishmanial activity is overall affected by changes in polarity. The same analysis for the antitrypanosomal activity-based model (Figure 2C) indicated that the most important keys in that case are 54, 131, 127, and 72 (Figure 2E), which are mainly related to the presence of geminal oxygens (i.e., carboxyl, nitro, etc.)…”

“…The noteworthy antileishmanial and antitrypanosomal activity of various cinnamate ester analogues among compounds 1 – 34 , in addition to the outstanding selectivity of some of those compounds against the parasites under study in comparison with mammalian cells [25], encouraged the detailed QSAR study presented here. A new set of scoring functions was defined to help selecting the best models within large model populations obtained by GA/MLR with very similar statistical validation parameters.…”

“…Compounds 1 – 34 were recently prepared, characterized, and tested for their activity against Leishmania donovani and Trypanosoma brucei rhodesiense within our working group [25]. Three-dimensional molecular representations of each compound were created using MOE, Montreal, QC, Canada (version 2018.01) [28] and subsequently optimized by energy minimization using the AMBER10: EHT force field, which is adequately parameterized for small molecules and provided better outcome than typical force fields like MMFF94x (the latter caused torsion of the double bond of the cinnamate, resulting in twisted structures lacking co-planarity of the π orbitals of the conjugated phenyl-acrylate system).…”

“…On the other hand, the potential of natural derivatives and synthetic analogues of cinnamic acid for combating leishmaniasis and trypanosomiasis have been widely described in the few past years [13,14,15,16,17,18,19,20,21,22,23,24,25]. Therefore, and as part of our continuous efforts to fight NTDs, we present a comprehensive QSAR study on a set of synthetic esters of the natural product cinnamic acid, which we recently described as potent and selective agents against L. donovani and T. brucei rhodesiense [25]. Even though those compounds may not strictly fulfill the stringent criteria for “hits” proposed by Katsuno et al [26], a deeper understanding of the underlying structure-activity relationships (SARs) from the quantitative point of view together with the predictive ability of robust QSAR models may result in an actual hit compound.…”

Alkyl and Aryl Derivatives Based on p-Coumaric Acid Modification and Inhibitory Action against Leishmania braziliensis and Plasmodium falciparum

“…Butyl p -coumarate ( 6 ) being compared to compound 1 , presented the lowest leishmanicidal potency, with an EC 50 of 323.29 ± 50.04 μg/mL. Interestingly, Bernal et al (2019) [ 49 ] found that groups with a medium length linear alkyl chain exhibited higher activity against L. donovani when compared to groups presenting short chains [ 50 ]. Meanwhile, pentyl p -coumarate ( 7 ) was five times less potent than isopentyl p -coumarate ( 8 ) (32.03 ± 5.054.3 μg/mL, 6.02 ± 0.22 μg/mL, respectively), possibly due to compound 8 branching.…”