Discovery and Structural Optimization of 4-(Aminomethyl)benzamides as Potent Entry Inhibitors of Ebola and Marburg Virus Infections

Abstract

The recent Ebola epidemics in West Africa underscore the great need for effective and practical therapies for future Ebola virus outbreaks. We have discovered a new series of remarkably potent small molecule inhibitors of Ebola virus entry. These 4-(aminomethyl)­benzamide-based inhibitors are also effective against Marburg virus. Synthetic routes to these compounds allowed for the preparation of a wide variety of structures, including a conformationally restrained subset of indolines (compounds 41–50). Compounds 20, 23, 32, 33, and 35 are superior inhibitors of Ebola (Mayinga) and Marburg (Angola) infectious viruses. Representative compounds (20, 32, and 35) have shown good metabolic stability in plasma and liver microsomes (rat and human), and 32 did not inhibit CYP3A4 nor CYP2C9. These 4-(aminomethyl)­benzamides are suitable for further optimization as inhibitors of filovirus entry, with the potential to be developed as therapeutic agents for the treatment and control of Ebola virus infections.

Discovery and structural optimization of 3-O-β-chacotriosyl oleanane-type triterpenoids as potent entry inhibitors of SARS-CoV-2 virus infections

“…For studies of other highly pathogenic enveloped viruses such as HIV, H5N1 and EBOV/MARV, this obstacle has been circumvented by a surrogate pseudovirus (PsV) system, which can be widely utilized to not only identify antiviral agents but also study the entry mechanisms [ [33] , [34] , [35] ]. It has been proved that viral PsV systems for CoVs such as SARS-CoV and MERS-CoV are also valid surrogate assays [ 36 , 37 ]. Based on our previous study [ 13 ], we utilized a robust HIV pseudotype model with the SARS-CoV-2-S to screen the OA triterpenoids library for discovering entry inhibitors.…”

Anno 2021: Which antivirals for the coming decade?

“… 117 Using various filoviral replication-defective and replicative infectivity assays, Gaisina et al discovered compounds sharing a common 4-(aminomethyl)benzamide core with broad spectrum activity against both EBOV (Mayinga) and MARV (Angola). 118 In addition to low micromolar potency (EC 50 < 1 μM), these compounds (exemplified by 23 ) exhibited favorable pharmacokinetic and pharmacological properties without detected cytotoxicity. Preliminary mechanistic studies suggested that the inhibitory activity of these compounds resulted from the direct binding and inhibition of the EBOV envelope glycoprotein (GP) protein, clearly indicating GP as an attractive target for therapeutic intervention other than the key immunogen for eliciting antibody responses.…”

Estrogen Receptor Modulators in Viral Infections Such as SARS−CoV−2: Therapeutic Consequences

“…These mechanisms were also dependent on the interaction of hormones with their receptors. The inhibitory effect of estrogens on replication was documented [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ]. in a panel of viruses (for particulars see Table 1 ).…”