Cinnamon extracts, trans-cinnamaldehyde and trans-cinnamic acid inhibit HDAC 1 activity.

Histone deacetylase (HDAC) enzymes play a key role in cell function and are implicated in several diseases such as inflammation, cancer, and neurodegeneration. Studies on natural products have revealed their potential and have led to increased research on natural HDAC inhibitors. Since the progression of these diseases is a prolonged process, dietary supplements and nutraceuticals consisting of plant extracts may be beneficial against HDAC related diseases. Beyond nutritional purposes, cinnamon (Cinnamomum cassia (L.) J. Presl), as a regularly consumed dietary additive due to its rich flavor, may present co-benefits during lifelong use. In this study, cinnamon extracts of differing polarities, trans-cinnamaldehyde and trans-cinnamic acid were evaluated for HDAC 1 inhibitory activity. The total phenol and flavonoid contents were quantified by spectrophotometry, while cinnamaldehyde and cinnamic acid analyses were performed using UPLC-DAD, ESI-MS/MS. Ethanol and dichloromethane extracts yielded the highest cinnamaldehyde and cinnamic acid contents of 389.17 mg per g extract and 11.85 mg per g extract, respectively. The essential oil (IC50: 51.11 µg ml-1) and 70% ethanol extract (IC50: 107.90 µg ml-1) showed the most potent HDAC 1 inhibitory activity. Individually, cinnamaldehyde and cinnamic acid were determined to have IC50 values of 7.58 µg ml-1 and 9.15 µg ml-1, respectively. As the 70% ethanol extract was able to yield remarkably lower cinnamaldehyde and cinnamic acid amounts, the potential of other moderately polar phenolic compounds for HDAC 1 inhibitory activity was revealed. The essential oil and 70% ethanol extracts of Cinnamomum cassia bark can be further evaluated in future studies for use in products against HDAC 1 related diseases.

Discovery of selective TYK2 inhibitors: Design, synthesis, in vitro and in silico studies of promising hits with triazolopyrimidinone scaffold.

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway mediates many cytokine and growth factor signals. Tyrosine kinase 2 (TYK2), one of the members of this pathway and the first described member of the JAK family. TYK2 associates with inflammatory and autoimmune diseases, cancer and diabetes. Here, we present novel compounds as selective inhibitors of the canonical kinase domain of TYK2 enzyme. These compounds were rationally designed and synthesized with appropriate reactions. Molecular modeling techniques were used to design and optimize the candidates for TYK2 inhibition and to determine the estimated binding orientations of them inside JAKs. Designed compounds potently inhibited TYK2 with good selectivity against other JAKs as determined by in vitro assays. In order to verify its selectivity properties, compound A8 was tested against 58 human kinases (KinaseProfiler™ assay). The effects of the selected seven compounds on the protein levels of members of the JAK/STAT family were also detected in THP-1 monocytes although the basal level of these proteins is poorly detectable. Therefore, their expression was induced by lipopolysaccharide treatment and compounds A8, A15, A18, and A19 were found to be potent inhibitors of the TYK2 enzyme, (9.7 nM, 6.0 nM, 5.0 nM and 10.3 nM, respectively), and have high selectivity index for the JAK1, JAK2, and JAK3 enzymes. These findings suggest that triazolo[1,5-a]pyrimidinone derivatives may be lead compounds for developing potent TYK2-selective inhibitors targeting enzymes' active site.

The Effects of Novel Triazolopyrimidine Derivatives on H2S Production in Lung and Vascular Tonus in Aorta.

INTRODUCTION: Hydrogen sulfide (H2S), known as a third gasotransmitter, is a signaling molecule that plays a regulatory role in physiological and pathophysiological processes. Decreased H2S levels were reported in inflammatory respiratory diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary hypertension. H2S donors or drugs that increase H2S have emerged as novel treatments for inflammatory respiratory diseases. We previously showed that resveratrol (RVT) causes vascular relaxation and antioxidant effects by inducing H2S production. In the current study, we synthesized a new molecule Cpd2, as an RVT analog. We examined the effect of Cpd2 and its precursor chalcone compound (Cpd1) on H2S formation under both healthy and oxidative stress conditions in the lung, as well as vascular relaxation in the aorta. METHODS: Cpd2 synthesized from Cpd1 with microwaved in basic conditions. H2S formation was measured by H2S biosensor in the mice lungs under both healthy and pyrogallol-induced oxidative stress conditions in the presence/absence of H2S synthesis inhibitor aminooxyacetic acid (AOAA). The effect of compounds on vascular tonus is investigated in mice aorta by DMT myograph. RESULTS: RVT and Cpd2 significantly increased l-cysteine (l-cys) induced-H2S formation in the lung homogenates of healthy mice, but Cpd1 did not. Superoxide anion generator pyrogallol caused a decrease in H2S levels in mice lungs and Cpd2 restored it. Inhibition of Cpd2-induced H2S formation by AOAA confirmed that Cpd2 increases endogenous H2S formation in both healthy and oxidative stress conditions. Furthermore, we found that both Cpd1 and Cpd2 (10-8-10-4 M) caused vascular relaxation in mice aorta. DISCUSSION AND CONCLUSION: We found that Cpd2, a newly synthesized RVT analog, is an H2S-inducing molecule and vasorelaxant similar to RVT. Since H2S has antioxidant and anti-inflammatory effects, Cpd2 has a potential for the treatment of respiratory diseases where oxidative stress and decreased H2S levels are present.

Design, synthesis, and in vitro biological evaluation of novel thiazolopyrimidine derivatives as antileishmanial compounds.

A series of thiazolopyrimidine derivatives was designed and synthesized as a Leishmania major pteridine reductase 1 (LmPTR1) enzyme inhibitor. Their LmPTR1 inhibitor activities were evaluated using the enzyme produced by Escherichia coli in a recombinant way. The antileishmanial activity of the selected compounds was tested in vitro against Leishmania sp. Additionally, the compounds were evaluated for cytotoxic activity against the murine macrophage cell line RAW 264.7. According to the results, four compounds displayed not only a potent in vitro antileishmanial activity against promastigote forms but also low cytotoxicity. Among them, compound L16 exhibited an antileishmanial activity for both the promastigote and amastigote forms of L. tropica, with IC50 values of 7.5 and 2.69 µM, respectively. In addition, molecular docking studies and molecular dynamics simulations were also carried out in this study. In light of these findings, the compounds provide a new potential scaffold for antileishmanial drug discovery.