Synthesis and anti-influenza virus activity evaluation of novel andrographolide derivatives

Abstract

In this paper, using AI78-38, an andrographolide analog with novel skeleton, as the lead compound, we designed and synthesized fteen amide derivatives at the 17 position of AI78-38. In the synthesis of key intermediate IM4, the low yield of the SeO 2 oxidation step impeded the further study. Aiming at improving the yield, White reagent was applied to furnish IM4 by catalyzing the allylic C-H oxidation at the 7, 8, 17 position. It is also rstly reported that White reagent possessed the ability of oxidating the cyclic substrates. Compared with SeO 2 oxidative approach, the modi ed synthetic method utilized by White reagent increased the yield from 32.0% to 53.6%. The anti-in uenza A virus (H3N2) results showed that 4methoxy derivative 10 offered the greatest inhibitory ability, with an IC 50 value of 90.2 mg/ml, slightly more potent than ribavirin. Furthermore, the drug likeness and ADMET properties of compound 10 and AI78-38 were evaluated using the Discovery Studio 2.1 software and the online SwissADME. The results showed that compound 10 offered good bioavailability and overcame the disadvantages of the ADMET properties in , as well as 1, 2-ole nation [38] and terpene ring expansion [39]. These methods have enriched the structural diversity of andrographolide and laid a solid foundation for elucidating the accurate SAR of andrographolide.Although many andrographolide derivatives with various structural characteristics have been successfully synthesized, active analogues with anti-viral activities, especially anti-in uenza virus effects, remain scarce. Most of these analogues belong to the 3, 14, and 19-hydroxyl groups' functional and Δ 12, 13 -alkene isomerized derivatives. Among them, only DASS, AL-1, and DAP have presented de nite antiin uenza viral activities [40,41]. Other compounds showed inhibitory capabilities against Zika, hepatis B, and HIV virus, respectively [26] (Fig. 2). Therefore, it is vital to search for an andrographolide-type antiin uenza viral-active compound with a novel skeleton structure.In previous work, our group successfully semi-synthesized two microbial transformative products, AI78 and AI89, with new structural fragments in which the Δ 8,17 double bond migrated into the ring. Taking AI78 as the lead compound, we synthesized a series of 17-substituted derivatives. Further bioactivity evaluations showed that AI78-38, a 17-benzylamine derivative of AI78, offered the best anti-in uenzavirus H3N2 activity among all derivatives and was superior to the positive control-drug, Lianbizhi (Fig. 3) [42]. This result indicated that this type of substitution at the 17 position can help enhance anti-in uenzavirus effects and suggested that structural optimization at the 17 position in AI78 may offer signi cant advantages in the inhibitory activity of in uenza virus.To further improve the anti-in uenza viral potency of AI78-38, we expanded our research on the reported active compounds. Based on an extensive literature review, we found that the amide group appeared in most active molecules exhibiting ...