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 ...
In this paper, using AI78-38, an andrographolide analog with novel skeleton, as the lead compound, we designed and synthesized fifteen amide derivatives at the 17 position of AI78-38. In the synthesis of key intermediate IM4, the low yield of the SeO2 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 firstly reported that White reagent possessed the ability of oxidating the cyclic substrates. Compared with SeO2 oxidative approach, the modified synthetic method utilized by White reagent increased the yield from 32.0% to 53.6%. The anti-influenza A virus (H3N2) results showed that 4-methoxy derivative 10 offered the greatest inhibitory ability, with an IC50 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 AI78-38.
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