Structural Optimizations of Thieno[3,2-b]pyrrole Derivatives for the Development of Metabolically Stable Inhibitors of Chikungunya Virus

Abstract

Chikungunya virus (CHIKV) is a re-emerging vector-borne alphavirus, and there is no approved effective antiviral treatment currently available for CHIKV. We previously reported the discovery of thieno[3,2-b]pyrrole 1b that displayed good antiviral activity against CHIKV infection in vitro. However, it has a short half-life in the presence of human liver microsomes (HLMs) (T = 2.91 min). Herein, we report further optimization studies in which potential metabolically labile sites on compound 1b were removed or modified, resulting in the identification of thieno[3,2-b]pyrrole 20 and pyrrolo[2,3-d]thiazole 23c possessing up to 17-fold increase in metabolic half-lives in HLMs and good in vivo pharmacokinetic properties. Compound 20 not only attenuated viral RNA production and displayed broad-spectrum antiviral activity against other alphaviruses and CHIKV isolates but also exhibited limited cytotoxic liability (CC > 100 μM). These studies have identified two compounds that have the potential for further development as antiviral drugs against CHIKV infection.

Computer-Aided Design, Synthesis, and Antiviral Evaluation of Novel Acrylamides as Potential Inhibitors of E3-E2-E1 Glycoproteins Complex from Chikungunya Virus

“…Furthermore, studies involving organic synthesis have led to the obtainment of potential hit compounds, with low micromolar ranges. Among these, thiazolidine/rhodanine [ 51 ], peptidomimetic [ 52 ], thienopyrrole [ 53 , 54 ], triazolopyrimidinone [ 31 ], and adenosine analogs [ 55 ] have demonstrated excellent results. Therefore, one of the most promising chemical classes found in the literature is represented by acylhydrazone derivatives (and also acrylamide analogs), which have exhibited high activities with low cytotoxicity [ 56 , 57 , 58 , 59 ].…”

“…Therefore, one of the most promising chemical classes found in the literature is represented by acylhydrazone derivatives (and also acrylamide analogs), which have exhibited high activities with low cytotoxicity [ 56 , 57 , 58 , 59 ]. Essentially, the antiviral compounds can be categorized regarding their biological activity, being ( i ) CHIKV viral entry inhibitors [ 60 , 61 ]; ( ii ) nsP1 inhibitors [ 62 ]; ( iii ) nsP2 inhibitors [ 51 , 56 , 57 , 58 , 59 ]; ( iv ) nsP3 inhibitors [ 38 ]; ( v ) nsP4 inhibitors [ 63 ]; and ( vi ) viral RNA replication inhibitors [ 31 , 53 , 55 , 64 , 65 ]. In Figure 1 , the best compounds found in the literature and their respective biological targets are illustrated.…”

A series of (E)-5-(arylideneamino)-1-tert-butyl-1H-pyrrole-3-carbonitriles and their reduction products to secondary amines: syntheses and X-ray structural studies

“…In recent years, the synthesis of new heterocycles containing two bioactive scaffolds in a single molecule has attained tremendous importance in drug discovery, since numerous bisheterocycles have been identified as lead compounds with novel biological profiles (Zhang et al, 2011;Ching et al, 2015Ching et al, , 2017. Despite these significant achievements, the development of general and efficient methods for the synthesis of novel bis-azaheterocycles from simple and commercially available nonprefunctionalized starting materials is of great interest.…”

Chikungunya virus drug discovery: still a long way to go?

“…Compound 20 (Figure 4A) inhibits protein synthesis and viral RNA synthesis, and showed antiviral activities against other alphaviruses (ONNV and SINV)[65]. Optimization studies in this series has led to compound 21 with improved pharmacokinetic properties and metabolic stability[66]. Time of addition experiments suggest that this series targets the replication stage and/or late stages of the CHIKV life cycle.Wada et al have screened a compound collection against the CHIKV-SL10571 strain to identify a benzimidazole compound(22,…”