Synthesis and Evaluation of 1,1′-Hydrocarbylenebis(indazol-3-ols) as Potential Antimalarial Drugs

Bis(indazol‐3‐ol) derivatives (5, 30–38) were prepared by alkylation of 3‐alkoxyindazoles with α,ω‐dibromides, followed by removal of the O‐protecting groups. These compounds were subsequently evaluated as inhibitors of biocrystallization of ferriprotoporphyrin IX (heme) to hemozoin, a Plasmodium detoxification specific process. Most bis(5‐nitroindazol‐3‐ols) were good inhibitors, however, a denitro analogue (38), the intermediate bis(3‐alkoxyindazoles) (15–29) as well as bis(indazolin‐3‐ones) (39–42) were not active, showing the importance of the NO2 and OH groups in the inhibition process. 1,1′‐Hydrocarbylenebis(5‐nitroindazol‐3‐ols) are inhibitors of biocrystallization of heme to hemozoin, a Plasmodium specific detoxification process and therefore they are good leads for the development of new antimalarial drugs. Acidic OH groups with adequate pKa values provided by NO2 substituents seem to be essential for activity.