Phthalimide Derivatives with Bioactivity against Plasmodium falciparum: Synthesis, Evaluation, and Computational Studies Involving bc₁ Cytochrome Inhibition

Abstract

We describe herein the design and synthesis of N -phenyl phthalimide derivatives with inhibitory activities against Plasmodium falciparum (sensitive and resistant strains) in the low micromolar range and noticeable selectivity indices against human cells. The best inhibitor, 4-amino-2-(4-methoxyphenyl)isoindoline-1,3-dione ( 10 ), showed a slow-acting mechanism similar to that of atovaquone. Enzymatic assay indicated that 10 inhibited P. falciparum cytochrome bc 1 complex. Molecular docking studies suggested the binding mode of the best hit to Qo site of the cytochrome bc 1 complex. Our findings suggest that 10 is a promising candidate for hit-to-lead development.

Antimalarial Inhibitors Targeting Epigenetics or Mitochondria in Plasmodium falciparum: Recent Survey upon Synthesis and Biological Evaluation of Potential Drugs against Malaria

“…In 2018, Okada-Junior et al reported [ 102 ] their study on phthalimide derivatives with activities on P. falciparum and targeting the bc1 cytochrome complex. In search of surrogates of atovaquone ( Figure 13 ), the authors described the synthesis and activities of a series of N -phenyl substituted phthalimides.…”

Molecular Docking: Considerations of a Low Cost and Suitable Methodology and Some Successful Applications

“…The first example herein presented of successful molecular docking application is a study by Okada-Junior, et al [32] targeting malaria disease through the cytochrome bc1 complex of P. falciparum, a protozoa from the Plasmodium spp associated with severe malaria [33]. Atovaquone (1) is a first line treatment for malaria disease but resistance has been reported since the early 1990s, thus making the search for new treatments of paramount importance [34].…”

Dual Parasiticidal Activities of Phthalimides: Synthesis and Biological Profile against Trypanosoma cruzi and Plasmodium falciparum

“…[12] Phthalimides, thiosemicarbazones and 1,3thiazoles nucleus are found in several natural products and have also been utilized to develop synthetic drugs and druglike molecules with a variety of pharmacological effects, binding to a plethora of different targets across target families. [13,14] Phthalimides, thiosemicarbazones, and 1,3-thiazoles nucleus have been used as platform types to obtains antiplasmodial and anti-T. cruzi agents. [15][16][17][18][19][20][21][22] Our research group has explored the pharmacological properties of phthalimide derivatives, and as a result, phthalimido-thiazole derivatives were identified as building blocks to promising anti-T. cruzi candidates.…”

“…There is a recognized need to identify new chemical entities (NCEs) as drug candidates in order to both improve patient care and meet targets for elimination, particularly of neglected parasitic diseases [12] . Phthalimides, thiosemicarbazones and 1,3‐thiazoles nucleus are found in several natural products and have also been utilized to develop synthetic drugs and drug‐like molecules with a variety of pharmacological effects, binding to a plethora of different targets across target families [13,14] …”