Benzo-ring modification on Malaria Box hit MMV008138: effects on antimalarial potency and microsomal stability.

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Tetrahydro-β-carboline 1 (MMV008138) is an antimalarial compound targeting the MEP pathway enzyme IspD.
• Previous studies focused on the B, C, and D rings; this study examines the A-ring (benzo-ring).

Purpose of the Study:

• To investigate the structure-activity relationship (SAR) of the benzo-ring of Tetrahydro-β-carboline 1.
• To enhance *in vitro* antimalarial potency and metabolic stability of the compound.

Main Methods:

• Synthesis of 19 benzo-ring substitution variants of Tetrahydro-β-carboline 1.
• Testing derivatives against multidrug-resistant *Plasmodium falciparum* (Dd2 strain).
• Evaluation of microsomal stability and plasma exposure in mouse models.

Main Results:

• Extreme sensitivity to substitution was observed in the benzo-ring.
• Three derivatives (20a, 20c, 20d) retained asexual blood-stage (ABS) activity within a 3-fold range of the parent compound.
• Analog 20c demonstrated improved microsomal stability but did not enhance plasma exposure or oral efficacy.

Conclusions:

• Benzo-ring substitution of Tetrahydro-β-carboline 1 offers limited improvement in antimalarial potency and metabolic stability.
• Further optimization is needed to achieve enhanced plasma exposure and oral efficacy for malaria treatment.