AIM: A new series of pyrazolo[1,5-c]pyrimidines were synthesized by different hybridization strategies. METHODOLOGY: All structures were confirmed by IR, H, C, H-C heteronuclear multiple-quantum correlation (HMQC) spectra and microanalysis. They were evaluated for their in vitro antileishmanial activity against miltefosine and amphotericin B deoxycholate as reference drugs. RESULTS: The most active compounds 2a and 9a demonstrated superior potencies to miltefosine by ten- and six-fold, respectively, for the promastigote form, and by 5.5-fold for the amastigote form. Their binding scenario to Leishmania major pteridine reductase was rationalized by docking experiments. In addition, all compounds were safe for the experimental animals orally up to 150 mg/kg and parenterally up to 75 mg/kg. CONCLUSION: This study provides novel chemotype class for antileishmanial activity. [Formula: see text].