Synthesis of Baicalein derivatives as anti-dengue agents

Abstract

Dengue, a mosquito-borne viral disease, is now considered a major international health concern, and hence the development of a new anti-dengue drug is highly desirable. Baicalein is a flavone isolated from the roots of Scutellaria baicalensis and Scutellaria lateriflora. Baicalein derivatives have been shown previously to exhibit a promising anti-dengue activity. In this study, five novel and thirteen known baicalein derivatives were synthesized via semi synthesis from baicalein with modifications at C-5, -6, -7, and -8 positions on ring A and a six-step total synthesis with modifications at the para position on the ring B with a range of electron-withdrawing or electron-donating groups. The structures of the synthesized derivatives were confirmed by 1H and 13C NMR. Most of the compounds exhibited the anti-dengue activity (DENV2) in LLC/MK2 cell at the concentration of 10 µM, except for the 8-bromo-5,6,7-tripropionyl (1h) and 4'-amino (6d) derivatives. Strikingly, the presence of propionyl derivatives (1d, EC50 = 0.070 ± 0.015 µM and 1e, EC50 = 0.068 ± 0.040 µM) showed efficiently inhibited DENV2 activity with great viability (1d, viability = 83.79±2.61 and 1e, viability = 89.62±5.95). The structure-activity relationship (SAR) of these compounds demonstrated that electron-withdrawing substituents could Improve anti-dengue activity, especially at the C-6, -7, and -8 positions on ring A and para position on ring B. Moreover, most of the synthetic baicalein compounds have good physicochemical properties and drug-likeness according to Lipinski's rule of five and Verber parameters. In conclusion, modification on both ring A and B of baicalein can potentially enhance the efficiency of dengue inhibition and the derivatives with electron-withdrawing substituents could become interesting candidates for anti-dengue agents in the future.