QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP (QSAR) ANALYSIS, SYNTHESIS AND HEME POLYMERIZATION INHIBITION ACTIVITY (HPIA) ASSAY OF XANTHONE DERIVATIVES AS ANTIMALARIA

Fitriastuti, Dhina, Jumina

2016 | Disertasi | FMIPA

Research on Quantitative Structure Activity Relationship (QSAR) analysis and synthesis of xanthone derivatives had been conducted to obtain new antimalaria active compounds. The HPIA assay of the synthesized xanthones was also conducted. The QSAR analysis was carried out using the semi empirical method of AM1 with the descriptors of atomic net charge, log P, dipole moment, polarizability, mass and volume. Statistical analysis was performed using the multilinear regression analysis. Then, the xanthone was designed using the validated best QSAR equation. 2,3,4-Trihydroxy-5-methylxanthone and 1,3,6-trihydroxy xanthone had the IC50 prediction of 3.79 and 6.96 ?g/mL, respectively, and were decided to be synthesized. Synthesis of xanthone was conducted from the raw material of hydroxybenzoic acid and phenol derivatives using Eaton’s reagent. The synthesized xanthone in this research was 1,3,6-trihydroxyxanthone and 2,3,4-trihydroxy-5-methyl xanthone. The initial step of synthesis of 1,3,6-trihydroxyxanthone was carboxylation of resorcinol using KHCO3 and CO2 gas. The mixture of resorcinol and KHCO3 in water was refluxed for 4 h and was passed a rapid stream of CO2 for 1 h to afford 2,4-dihydroxybenzoic acid as white solid in 53% (m.p. 213.7-217.6 °C). Carboxylation product was then mixed with phloroglucinol and Eaton’s reagent. The mixture was heated for 3 h at 80 °C to yield 1,3,6-trihydroxyxanthone in the form of yellowish solid (56%), 322-323 °C (dec.). The synthesis of 2,3,4-trihydroxy-5-methyl xanthone was carried out using gallic acid, o-cresol and Eaton’s reagent with the same procedure as the first xanthone. This reaction produced 2,3,4-trihydroxy-5-methyl xanthone in 43% yield as dark red viscous liquid. The QSAR equation describing the relationship between antimalarial activity and parameter of lipophilicity, electronic and steric properties of xanthone was: Log (1/IC50) = (2.726)qC1 + (1.783)qC10 + (0.2387)log P + 5.282 (n = 17, r2 = 0.683, Fcalc/Ftable = 4.309, PRESS = 0.652). The results of HPIA assay of xanthone derivatives showed that the compound 1,3,6-trihydroxy xanthone, 2,3,4-trihydroxy-5-methyl xanthone and chloroquine has IC50 values of 1.985, 0.755 and 1.462 mg/mL or 8.13, 2.92 and 4.57 mM, respectively. 2,3,4-Trihydroxy-5-methyl xanthone displayed better antimalarial activity than chloroquine and 1,3,6-trihydroxy xanthone.

Kata Kunci : QSAR; xanthone; synthesis; HPIA assay