Synthesis and Bioactivity of Reduced Chalcones Containing Sulfonamide Side Chains

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Organic Synthesis

Background:

• Sulfonamide drugs are known antibacterials.
• Chalcones and their derivatives possess diverse biological activities.
• Lipid solubility is a key factor in drug bioavailability and efficacy.

Purpose of the Study:

• To investigate the impact of increased lipophilicity on the bioactivity of sulfonamide derivatives against malaria and tuberculosis.
• To synthesize novel sulfonamide derivatives by incorporating reduced chalcone moieties.
• To evaluate the structure-activity relationship concerning lipophilicity and biological efficacy.

Main Methods:

• Synthesis of sulfonamide derivatives (8a-8d) via 1,3-diarylpropane scaffolds.
• Preparation of intermediate reduced chalcones and N-alkylated derivatives (5a-7a).
• Determination of ClogP values to assess lipophilicity.
• In vitro testing against Plasmodium falciparum (NF54) and Mycobacterium tuberculosis (H37Rv).

Main Results:

• N-alkylated reduced chalcone derivatives (6 and 7) showed significant antimalarial activity.
• Addition of the sulfonamide group decreased antimalarial activity despite increased lipophilicity.
• Reduced chalcones (5a and 5) demonstrated potent anti-tuberculosis activity, while sulfonamide derivatives (8a, 8d) showed minimal to no activity.
• High ClogP values did not consistently translate to enhanced bioactivity, possibly due to increased molecular weight.

Conclusions:

• Increased lipophilicity through chalcone condensation does not guarantee enhanced bioactivity for sulfonamide derivatives against malaria and tuberculosis.
• The molecular weight of synthesized analogues may counteract the benefits of increased lipophilicity.
• Further optimization is needed to balance lipophilicity and other pharmacokinetic properties for effective drug development.