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.
Background and Purpose
Alveolar macrophages (AMs) contribute to airway inflammation and remodelling in allergic asthma. Calcaratarin D (CalD), a labdane diterpenoid from rhizomes of the medicinal plant Alpinia calcarata, has recently been shown to possess anti‐inflammatory properties. The present study evaluated protective effects of CalD in a house dust mite (HDM)‐induced asthma mouse model.
Experimental Approach
The effects of CalD on AMs in contributing to anti‐inflammatory effects in asthma were investigated through in vivo, ex vivo, and in vitro experiments.
Key Results
CalD reduced total bronchoalveolar lavage fluid and differential cell count, serum IgE levels, mucus hypersecretion, and airway hyperresponsiveness in HDM‐challenged mice. Additionally, CalD affected a wide array of pro‐inflammatory cytokines and chemokines and oxidative damage markers in isolated lung tissues. CalD suppressed the HDM‐induced increase in Arg1 (M2 macrophage marker) in AMs from lung tissue and reduced lung polyamine levels. CalD weakened antigen presentation capability of AMs by reducing CD80 expression, reduced AM‐derived CCL17 and CCL22 levels, and lessened Th2 cytokines from CD4+ T‐cells from asthma lung digest. CalD blocked the HDM‐induced FoxO1/IRF4 pathway and restored impaired the Nrf2/HO‐1 antioxidant pathway in lung tissues. CalD inhibited IL‐4/IL‐13‐stimulated JAK1/STAT6 pathway, FoxO1 protein expression, and chemokine production in primary AMs. Structure–activity relationship study revealed the α,β‐unsaturated γ‐butyrolactone in CalD is capable of forming covalent bonds with cellular protein targets essential for its action.
Conclusion and Implications
Our results demonstrate for the first time that CalD is a novel anti‐inflammatory natural compound for allergic asthma that modulates AM function.
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