Insights into Antimalarial Activity of N-Phenyl-Substituted Cinnamanilides

Abstract

Due to the urgent need of innovation in the antimalarial therapeutic arsenal, a series of thirty-seven ring-substituted N-arylcinnamanilides prepared by microwave-assisted synthesis were subjected to primary screening against the chloroquine-sensitive strain of P. falciparum 3D7/MRA-102. The lipophilicity of all compounds was experimentally determined as the logarithm of the capacity factor k, and these data were subsequently used in the discussion of structure-activity relationships. Among the screened compounds, fourteen derivatives exhibited IC50 from 0.58 to 31 µM, whereas (2E)-N-(4-bromo-2-chlorophenyl)-3-phenylprop-2-enamide (24) was the most effective agent (IC50 = 0.58 µM). In addition, (2E)-N-[2,6-dibromo-4-(trifluoromethyl)- phenyl]-3-phenylprop-2-enamide (36), (2E)-N-[4-nitro-3-(trifluoromethyl)phenyl]-3-phenylprop- 2-enamide (18), (2E)-N-(2-bromo-5-fluorophenyl)-3-phenylprop-2-enamide (23), and (2E)-3-phenyl-N-(3,4,5-trichlorophenyl)prop-2-enamide (33) demonstrated efficacy in the IC50 range from 2.0 to 4.3 µM, comparable to the clinically used standard chloroquine. The results of a cell viability screening performed using THP1-Blue™ NF-κB cells showed that none of these highly active compounds displayed any significant cytotoxic effect up to 20 μM, which makes them promising Plasmodium selective substances for further investigations.

Trifluoromethylcinnamanilide Michael Acceptors for Treatment of Resistant Bacterial Infections

“…This supports the theory that our compounds could interact with InhA. -e, 4a-f, 1j,o,p, 2i,p) and antiplasmodial (3f) activity or anti-inflammatory (3g) potential [26][27][28]58,59].…”

“… Structures of investigated ring-substituted cinnamanilides with significant antimicrobial ( 3a – e , 4a – f , 1j , o , p , 2i , p ) and antiplasmodial ( 3f ) activity or anti-inflammatory ( 3g ) potential [ 26 , 27 , 28 , 58 , 59 ]. …”

“…Overall, however, these are electron-deficient (σ range 0.9-1.2) and lipophilic compounds (log k range 1.2-1.4/log P range 5.5-6.5), which penetrate well through the membranes of pathogens and have the ability to bind to electron-rich targets. -e, 4a-f, 1j,o,p, 2i,p) and antiplasmodial (3f) activity or anti-inflammatory (3g) potential [26][27][28]58,59].…”

“…However, in the recently published study describing the antiplasmodial activity of the basic series of cinnamanilides (type 3 compounds), the C (3) /C (3,5) substituted derivatives showed only moderate activity and the compounds having at least one substituent in the C (2) anilide position were the most active [58], e.g., compound 3f with IC 50 = 0.58 µM against Plasmodium falciparum 3D7. Similar findings regarding the need for substitution at the C (2) anilide position were found for NF-κB inhibition, when compound 3g showed the anti-inflammatory potential comparable to that prednisone [59].…”

Towards Arginase Inhibition: Hybrid SAR Protocol for Property Mapping of Chlorinated N-arylcinnamamides

“…In particular, the dependence of the potency to the lipophilicity of the molecules until an optimum log k value, suggesting an increased permeation rate, was already reported for other cinnamic acid derivatives [ 50 ]. It is important to mention that similar dependences on lipophilicity were also obtained for anilides unsubstituted on the cinnamic core [ 51 ]. In addition, the substitution pattern of the N- aryl seemed crucial for the anti- Plasmodium effect since the most efficient structures possessed at least two different halogen substituents.…”