Design, Synthesis and Antimalarial Evaluation of New Trimethoxy Benzaldehyde Chalcones

Abstract

Proteases are validated drug target for inhibition of Plasmodium falciparum, the most virulent malaria parasite. This study guided by previous reports, designed trimethoxy benzaldehyde chalcone derivatives as potential protease inhibitors and antimalarial agents. They were synthesized by Schmidt-Claisen condensation reaction. The structures of these compounds were established using Fourier transform infrared (FT-IR), Proton, Carbon-13, as well as twodimensional nuclear magnetic resonance (NMR) spectroscopy, and Mass Spectrometry (MS). The synthesized compounds were screened for in-vivo antimalarial activity in mice infected with Plasmodium berghei parasite, using curative model. (E)-1-(2,4-dimethoxyphenyl)-3-(2,3,4trimethoxy-phenyl) prop-2-en-1-one (P2) displayed a significant activity, with activity comparable to that of quinine (10 mgkg-1) and chloroquine (25 mg kg-1) at a dose of 100 mgkg-1 in the curative test. However, (E)-1,3-bis(2,3,4-trimethoxyphenyl) prop-2-en-1-one (P1) and (E)-1-(2,4-dichlorophenyl)-3-(2,3,4-trimethoxyphenyl) prop-2-en-1-one (P13) did not show any significant activity (p < 0.05). Compound P2 was found to be devoid of electron deficient ring A (benzaldehyde ring). This suggests that, electron density on the rings are not determinants for antimalarial activity of the chalcone as proposed earlier and, present compound P2 as a candidate for further optimization and evaluation for prophylactic and suppressive activities.

Therapeutic Potency of Mono- and Diprenylated Acetophenones: A Case Study of In-Vivo Antimalarial Evaluation

“…Structure-activity relationship (SAR) evaluation shows that the size and hydrophobicity of the substituents attached on the acetophenone are critical parameters for regulating the activity of the ring. 10 In this work, two prenylated acetophenones, 3,5-diprenyl acetophenone (I) and 5-diprenyl acetophenone (II), were chosen to assess their antimalarial activity to correlate the theoretical studies, e.g., rule of three (Ro3) for active fragment and rule of five (Ro5) for orally bioavailable agents, and in silico pharmacokinetic (PK) studies with their experimental activity, and deduce further insights into their SAR. This is the first report of the in vivo antimalarial activity of the two prenylated acetophenones.…”

“…Structure–activity relationship (SAR) evaluation shows that the size and hydrophobicity of the substituents attached on the acetophenone are critical parameters for regulating the activity of the ring. 10…”

Therapeutic Potency of Mono and Diprenylated Acetophenone: A Case Study of in-vivo Antimalarial Evaluation

“…The presence of electrondonating groups on the acetophenone ring, according to Li et al [14] is advantageous to antimalarial activity. Structure-activity relationship (SAR) evaluation shows that the size and hydrophobicity of the attached substituents on the acetophenone are critical parameters regulating the activity of the ring [15] .…”