Pyridine-4(1H)-one Alkaloids from Waltheria indica as Antitrypanosomatid Agents

Twelve new pyridine-4(1 H )-one derivatives, namely, 8-demethoxywaltherione F ( 1 ), waltheriones R-V ( 2 , 6 , 7 , 10 , and 11 ), 1-methoxywaltherione O ( 3 ), ( S )-15-hydroxywaltherione G ( 4 ), (8 R )-8-hydroxywaltherione M ( 5 ), (9 S ,13 S )-2-hydroxymethylwaltherione C ( 8 ), (9 S ,10 S ,13 S )-10-hydroxywaltherione C ( 9 ), and ( S )-13-methoxywaltherione V ( 12 ), as well as melovinone ( 13 ) and 5'-methoxywaltherione A ( 14 ) were isolated from the CH 2 Cl 2 extract of the aerial parts of Waltheria indica. Their chemical structures were determined by means of a comprehensive analysis including 1 H NMR, DEPTQ, HSQC, HMBC, 1 H- 1 H COSY, ROESY, and HRESIMS data. The absolute configurations were assigned via comparison of the experimental and calculated ECD data. In addition, the isolated constituents as well as the known waltheriones M-Q were evaluated for their in vitro antitrypanosomal activity. Compounds 2 , 5 , and 7 as well as waltheriones M, P, and Q showed potent growth inhibition toward Trypanosoma cruzi with IC 50 values of 2.1, 0.8, 2.1, 1.3, 0.5, and 0.1 μM, respectively, and selectivity indices of >12, >33, >13, 5, 25, and 14. These findings further demonstrate that the waltheriones are a promising class of antichagasic compounds worthy of further investigations.