Series Of Thieno Research Articles

Thieno[3,2-b]thiophene flanked para-azaquinodimethane π-extended aromatic-quinoidal polymers

A series of thieno[3,2-b]thiophene (TT) flanked para-azaquinodimethane (p-AQM) based quinoidal conjugated polymers PAQM2TT-T, PAQM2TT-BT and PAQM3TT were designed in a strategy to extend the aromatic-quinoidal π-system. The three polymers were synthesized by Stille polycondensation, and their opto-electronic properties and device performance in field-effect transistors have been explored. From absorption spectroscopy, the polymers show low bandgaps (1.54–1.57 eV) and high HOMO energy levels. They exhibit typical p-type behavior according to the results of the characterization of the field-effect transistors with average charge carrier mobilities of 0.08 cm2 V−1 s−1 for PAQM2TT-T, 0.12 cm2 V−1 s−1 for PAQM2TT-BT and 0.05 cm2 V−1 s−1 for PAM3TT. This report presents an alternative π-extended quinoidal-donor strategy to control the molecular design and properties of new p-AQM-based conjugated polymers.

Design, synthesis and biological evaluation of novel SIRT3 inhibitors targeting both NAD+ and substrate binding sites for the treatment of acute myeloid leukemia

Acute myeloid leukemia (AML) represents a highly malignant subtype of leukemia with limited therapeutic options. In this study, we propose a novel therapeutic strategy for treating AML by inhibiting SIRT3 to regulate mitochondrial metabolism network involved in energy metabolism and epigenetic modifications essential for AML survival. A series of thieno [3,2-d]pyrimidine-6-carboxamide derivatives were designed and synthesized by structure-based strategy, 17f was documented to be a potent and acceptable selective SIRT3 inhibitor with IC50 value of 0.043 μM and exhibited profound anti-proliferative activity in MOLM13, MV4-11, and HL-60 cells. Through CETSA assay and the degree of deacetylation of intracellular SIRT3 substrates, we confirmed that 17f could effectively bind and inhibit SIRT3 activity in AML cells. Mechanistically, 17f suppressed mitochondrial function, triggered the accumulation of ROS, and significantly inhibited the production of ATP in AML cells. With the breakdown of mitochondrial function, 17f eventually induced apoptosis of AML cells. In addition, 17f also showed excellent anti-AML potential in nude mouse tumor models of HL-60-Luc. Collectively, these results demonstrate that 17f is a potent and acceptable selective SIRT3 inhibitor with promising potential to treat AML.

WLB-87848, a Selective σ1 Receptor Agonist, with an Unusually Positioned NH Group as Positive Ionizable Moiety and Showing Neuroprotective Activity.

The synthesis and pharmacological activity of a new series of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as sigma-1 receptor (σ1R) ligands are reported. A hit from a high-throughput screening program was evolved into a highly potent and selective σ1R agonist (14qR) that contains a free NH group as positive ionizable moiety, not fulfilling the usual pharmacophoric features of the σ1R. The compound shows good physicochemical and ADMET characteristics, displays an agonist profile in the binding immunoglobulin protein/σ1R association assay, induces neuron viability in an in vitro model of β-amyloid peptide intoxication, and presents positive results against recognition memory impairment induced by hippocampal injection of Aβ peptide in rats after oral treatment, altogether making 14qR (WLB-87848) an interesting candidate for neuroprotection.

Designing Potent Anti-Cancer Agents: Synthesis and Molecular Docking Studies of Thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidine Derivatives.

A new series of thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines was designed and synthesized using readily available starting materials, specifically, β-enaminoester. Their cytotoxicity was screened against three cancer cell lines, namely, MCF-7, HCT-116, and PC-3. 2-(4-bromophenyl)triazole 10b and 2-(anthracen-9-yl)triazole 10e afforded excellent potency against MCF-7 cell lines (IC50 = 19.4 ± 0.22 and 14.5 ± 0.30 μM, respectively) compared with doxorubicin (IC50 = 40.0 ± 3.9 μM). The latter derivatives 10b and 10e were further subjected to in silico ADME and docking simulation studies against EGFR and PI3K and could serve as ideal leads for additional modification in the field of anticancer research.

New thieno[2,3‐d]pyrimidine derivatives as EGFRWT and EGFRT790M inhibitors: Design, synthesis, antiproliferative activities, docking studies, ADMET, toxicity, MD simulation studies

AbstractA series of thieno[2,3‐d]pyrimidines were designed and synthesized as epidermal growth factor receptor (EGFR) inhibitors. These compounds were tested for their ability to inhibit MCF‐7 and A549 cancer cells. The most active compound, 12c, inhibited the growth of both cell lines, with IC50 values of 15.67 and 12.16 μM, respectively. It was found that 12c had inhibitory effects on both EGFRWT and EGFRT790M isoforms, with inhibitory partialities of 37.50 and 148.90 nM, respectively. Additionally, 12c was found to be safer than erlotinib against normal cell lines (IC50 = 38.61 μM). Compound 12c induced early and late apoptosis in A549 cells and arrested cell growth at G1 and G2/M phases. 12c was also found to increase caspases 3 and 8 ratios. Molecular docking indicated the correct binding modes of the synthesized compounds. MD simulations, MM‐GBSA, and PLIP studies confirmed the precise binding of 12c to the EGFR protein over 100 ns.

Synthesis of new multitarget-directed ligands containing thienopyrimidine nucleus for inhibition of 15-lipoxygenase, cyclooxygenases, and pro-inflammatory cytokines

A new series of thieno[2,3-d]pyrimidine derivatives 4, 5, 6a-o, and 11 was designed and synthesized starting from cyclohexanone under Gewald condition with the aim to develop multitarget-directed ligands (MTDLs) having anti-inflammatory properties against both 15-LOX and COX-2 enzymes. Moreover, the potential of the compounds against the proinflammatory mediators NO, ROS, TNF-α, and IL-6 were tested in LPS-activated RAW 264.7 macrophages. Compound 6o showed the greatest 15-LOX inhibitory effect (IC50 = 1.17 μM) which was superior to that of the reference nordihydroguaiaretic acid (NDGA, IC50 = 1.28 μM); meanwhile, compounds 6h, 6g, 11, and 4 exhibited potent activities (IC50 = 1.29–1.77 μM). The ester 4 (SI = 137.37) and the phenyl-substituted acetohydrazide 11 (SI = 132.26) showed the highest COX-2 selectivity, which was about 28 times more selective than the reference drug diclofenac (SI = 4.73), however, it was lower than that of celecoxib (SI = 219.25). Interestingly, compound 6o, which showed the highest 15-LOX inhibitory activity and 5 times higher COX-2 selectivity than diclofenac, showed a greater poteny in reducing NO (IC50 = 7.77 μM) than both celecoxib (IC50 = 22.89 μM) and diclofenac (IC50 = 25.34), but comparable activity in inhibiting TNF-α (IC50 = 11.27) to diclofenac (IC50 = 10.45 μM). Similarly, compounds 11 and 6h were more potent in reducing TNF-α and IL6 levels than diclofenac, meanwhile, compound 4 reduced ROS, NO, IL6, and TNF-α levels with comparable potency to the reference drugs celecoxib and diclofenac. Furthermore, docking studies for our compounds within 15-LOX and COX-2 active sites revealed good agreement with the biological evaluations. The proposed compounds could be promising multi-targeted anti-inflammatory candidates to treat resistant inflammatory conditions.

Tandem synthesis and antibacterial screening of new thieno[2,3-b]pyridine-fused pyrimidin-4(3H)-ones linked to thiazole or oxazole units

New two series of thieno[2,3-b]pyridine-fused pyrimidinones 1 and 2 linked to thiazole or oxazole units were prepared utilizing a three-component tandem protocol. Therefore, a mixture of 1 equiv. of 3-aminothieno[2,3-b]pyridine-2-carboxylate was first microwave irradiated with 1.5 equiv. of dimethylformamide-dimethylacetal in toluene was at 110 °C for 15 min. Next, the crude enamine was dissolved in dioxane and 1 equiv. of the respective 4-arylazole-based amines was added. The mixture was microwaved at 100 °C for 20–30 min, resulting in a 74–89% yield of the target pyrimidinones. The new products showed a wide spectrum of antibacterial activity. In general, oxazole-linked pyrimidinones 2 exceeded their analogs 1 attached to thiazole units in antibacterial activity. Hybrids 2d, and 2e, with 4-(p-tolyl)oxazole and 4-(4-methoxyphenyl)oxazole units, demonstrated the best antibacterial potency among the new products with MIC/MBC values of 4.4/8.8 and 4.2/8.5 µM, respectively. According to SwissADME, all new pyrimidinones could be classified as drug-like.

Evaluation of antibacterial and antifungal activities of N-benzylthienopyrimidinone derivatives

This study is part of the biological investigation of the chemical library of molecules already described by the Laboratory of Organic Chemistry and Therapeutic Chemistry of the University of Bordeaux. The main objective was to explore the contribution of a thienyl moiety attached to the pyrimidinone nucleus, in the expression of an antimicrobial activity.
 The structural modifications mainly concerned the conservation or not of the benzo fragment attached to the thienyl, the saturation or not in position-1,2 of the pyrimidinone ring, the substitution on N-benzyl with more or less lipophilic units, the modification of the orientation of the thienyl fragment with, on the one hand, the compounds in which the sulfur is located near the N1 nitrogen (series of thieno[2,3-d]pyrimidin-4-ones) and on the other hand, compounds in which the sulfur is located near the ketone group (series of thieno[3,2-d]pyrimidin-4-ones).
 In general, thienyl fragment with sulfur located near the ketone group and the unsaturated pyrimidinone nucleus in the 1,2-position, seem to promote a broad spectrum of antibacterial activity, with compound 9c which is active on both Gram + bacteria and Gram – bacteria studied. The same pattern was observed for antifungal activity, which is maximum with the compounds of the thieno[3,2-d]pyrimidin-4-ones series for an MIC of 31.25 μg/ml on the strains of Candida albicans and Candida kruzei studied.
 Keywords: Thienopyrimidinones, antibacterial activity, antifungal activity.

Utility of Pyrimidine Thione Derivatives in the Synthesis of Biologically Active Heterocyclic Compounds

A new series of thieno[2,3-b]pyridine-2-carbohydrazide, 2,3 dihydropyrido[3′,2′:4,5]-thieno[3,2-d]pyrimidin-4(1H)-one, thieno[2,3-b]pyridin-2 yl)(3,5-substituted-1H-pyrazol-1-yl)methanone, tetrazolopyrimidine, and triazolopyrimdine derivatives have been synthesized. Molecular docking studies were performed on the most active compounds against the aspartic protease from Candida albicnas (1ZAP) and gram-negative (Salmonella typhimurium) binding protein (3ZQB) revealed the potential binding mode of the ligands to the site of the appropriate targets. To determine the direction of the reaction, compounds (19a) and (20a) were subjected to a computational study. Computational investigations are in complete agreement with experimental findings. Moreover, the selected newly synthesized products were evaluated for their antimicrobial activity.

Thieno[2,3-d]pyrimidine-Based Positive Allosteric Modulators of Human Mas-Related G Protein-Coupled Receptor X1 (MRGPRX1).

Mas-related G protein-coupled receptor X1 (MRGPRX1) is a human sensory neuron-specific receptor and potential target for the treatment of pain. Positive allosteric modulators (PAMs) of MRGPRX1 have the potential to preferentially activate the receptors at the central terminals of primary sensory neurons and minimize itch side effects caused by peripheral activation. Using a high-throughput screening (HTS) hit, a series of thieno[2,3-d]pyrimidine-based molecules were synthesized and evaluated as human MRGPRX1 PAMs in HEK293 cells stably transfected with human MrgprX1 gene. An iterative process to improve potency and metabolic stability led to the discovery of orally available 6-(tert-butyl)-5-(3,4-dichlorophenyl)-4-(2-(trifluoromethoxy)phenoxy)thieno[2,3-d]pyrimidine (1t), which can be distributed to the spinal cord, the presumed site of action, following oral administration. In a neuropathic pain model induced by sciatic nerve chronic constriction injury (CCI), compound 1t (100 mg/kg, po) reduced behavioral heat hypersensitivity in humanized MRGPRX1 mice, demonstrating the therapeutic potential of MRGPRX1 PAMs in treating neuropathic pain.

High birefringence nematic liquid crystals containing both thieno[3,2-b]thiophene core and acetylene bond

ABSTRACT A new series of thieno[3,2-b]thiophene-based liquid crystals with a – C ≡ C- triple bond were synthesised via Sonogashira cross-coupling and characterised. Thermo analysis show that all of these compounds exhibit a stable nematic phase, which is superior to the thieno[3,2-b]thiophene-phenyl and classical tolane anologues. Improved mesophase may be attributing to the increased aspect ratio of molecules and much lower energy barrier of conformation rotation between the aromatic rings than that of the reference compounds. These newly compounds present higher birefringence (0.40 ~ 0.48) than the reference compounds because of the extended π-conjugated. When doped to the mixture, it is found that these new compounds have the advantage of good solubility, higher birefringence, larger dielectric anisotropy and higher clearing point.

Molecular design, synthesis and in vitro biological evaluation of thienopyrimidine–hydroxamic acids as chimeric kinase HDAC inhibitors: a challenging approach to combat cancer

A series of thieno[2,3-d]pyrimidine-based hydroxamic acid hybrids was designed and synthesised as multitarget anti-cancer agents, through incorporating the pharmacophore of EGFR, VEGFR2 into the inhibitory functionality of HDAC6. Three compounds (12c, 15b and 20b) were promising hits, whereas (12c) exhibited potent VEGFR2 inhibition (IC50=185 nM), potent EGFR inhibition (IC50=1.14 µM), and mild HDAC6 inhibition (23% inhibition). Moreover, compound (15c) was the most potent dual inhibitor among all the synthesised compounds, as it exhibited potent EGFR and VEGFR2 inhibition (IC50=19 nM) and (IC50=5.58 µM), respectively. While compounds (20d) and (7c) displayed nanomolar selective kinase inhibition with EGFR IC50= 68 nM and VEGFR2 IC50= 191 nM, respectively. All of the synthesised compounds were screened in vitro for their cytotoxic effect on 60 human NCI tumour cell lines. Additionally, molecular docking studies and ADMET studies were carried out to gain further insight into their binding mode and predict the pharmacokinetic properties of all the synthesised inhibitors.

Discovery of Potent Dual EGFR/HER2 Inhibitors Based on Thiophene Scaffold Targeting H1299 Lung Cancer Cell Line.

Dual targeting of epidermal growth factor receptor (EGFR) and human EGFR-related receptor 2 (HER2) is a proven approach for the treatment of lung cancer. With the aim of discovering effective dual EGFR/HER2 inhibitors targeting non-small cell lung cancer cell line H1299, three series of thieno[2,3-d][1,2,3]triazine and acetamide derivatives were designed, synthesized, and biologically evaluated. The synthesized compounds displayed IC50 values ranging from 12 to 54 nM against H1299, which were superior to that of gefitinib (2) at 40 µM. Of the synthesized compounds, 2-(1H-pyrazolo[3,4-b]pyridin-3-ylamino)-N-(3-cyano4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (21a) achieved the highest in vitro cytotoxic activity against H1299, with an IC50 value of 12.5 nM in situ, and 0.47 and 0.14 nM against EGFR and HER2, respectively, values comparable to the IC50 of the approved drug imatinib (1). Our synthesized compounds were promising, demonstrating high selectivity and affinity for EGFR/HER2, especially the hinge region forming a hydrophobic pocket, which was mediated by hydrogen bonding as well as hydrophobic and electrostatic interactions, as indicated by molecular modeling. Moreover, the designed compounds showed good affinity for T790M EGFR, one of the main mutants resulting in acquired drug resistance. Furthermore, both pharmacokinetic and physicochemical properties of the designed compounds were within the appropriate range for human usage as predicted by the in Silico ADME study. The designed compound (21a) might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR/HER2.

Discovery of new thieno[2,3-d]pyrimidine and thiazolo[5,4-d]pyrimidine derivatives as orally active phosphoinositide 3-kinase inhibitors

As abnormal PI3K signaling is a feature of many types of cancer, the development of orally active PI3K inhibitors is of great significance for targeted cancer therapy. Through integrating strategies of reducing aromatic character/increasing the fraction of sp3 carbons together with scaffold hopping, we designed and synthesized two new series of thieno[2,3-d]pyrimidine and thiazolo[5,4-d]pyrimidine derivatives for use as PI3K inhibitors. Our structure–activity relationship studies led to the identification of thieno[2,3-d]pyrimidine 6a and thiazolo[5,4-d]pyrimidine 7a, which exhibited remarkable nanomolar PI3K potency, good antiproliferative activity, favorable pharmacokinetic properties and significant in vivo anti-cancer efficacy. Notably, thiazolo[5,4-d]pyrimidine 7a had better anti-cancer activity than thieno[2,3-d]pyrimidine 6a and is worthy of further pre-clinical evaluation for its use in cancer treatment.

Thieno[2,3-d]pyrimidin-4(3H)-one Derivatives of Benzimidazole as Potential Anti- Breast Cancer (MDA-MB-231, MCF-7) Agents.

The purpose of this study was the synthesis of some new thienopyrimidine derivatives of 1,3-disubstituted benzimidazoles and the evaluation of their cytotoxicity against MDA-MB-231, MCF-7, and 3T3 cells lines. An overexpression or mutational activation of TK receptors EGFR and HER2/neu is characteristic of tumors. It has been found that some thieno[2,3-d]pyrimidines exhibited better inhibitory activity against Epidermal Growth Factor Receptor (EGFR/ErbB-2) tyrosine kinase in comparison to aminoquinazolines. Breast cancer activity towards MDA-MB-231 and MCF-7 cell lines by inhibiting EGFR was revealed by a novel 2-arylbenzimidazole. This motivated the synthesis of new thienopyrimidines possessing benzimidazole fragments in order to evaluate their cytotoxicity to the above-mentioned cell lines. The objectives of the study were to design and synthesize a novel series of thieno[2,3-d]pyrimidines bearing biologically active moieties, such as 1,3-disubstituted-benzimidazole heterocycle, structurally similar to diaryl ureas in order to evaluate their cytotoxicity against MDA-MB-231, and MCF-7 breast cancer cell lines. N,N-disubstituted benzimidazole-2-one carbonitriles were synthesized by Aza-Michael addition and used as precursors to generate some of the new thieno[2,3-d]pyrimidines in acidic medium The interaction of chloroethyl-2-thienopyrimidines, 2-amino-benzimidazole and benzimidazol-2-one nitriles under solid-liquid transfer catalysis conditions led to new thienopyrimidines. MTT assay for cell survival was performed in order to evaluate the cytotoxicity of the tested compounds. A fluorescence study was conducted to elucidate some aspects of the mechanism of action. The effects of nine synthesized compounds were investigated towards MDA-MB-231, MCF-7 and 3T3 cell lines. Thieno[2,3-d]pyirimidine-4-one 16 (IC50 - 0.058μM) and 21 (IC50 - 0.029μM) possess high cytotoxicity against MDA-MB-231 cells after 24h. The most cytotoxic compounds against breast cancer MCF-7 cells was compound 21 (IC50 - 0.074μM), revealing lower cytotoxicity against mouse fibroblast 3T3 cells with IC50 - 0.20μM. SAR analysis was performed. Fluorescence study of the treatment of MDA-MB cells with compound 21 was carried out in order to clarify some aspects of the mechanism of action. The relationship between cytotoxicity of compounds 14 and 20 against MCF-7 and 3T3 cells can suggest a similar mechanism of action. The antitumor potential of the tested compounds proves the necessity for further investigation to estimate the exact inhibition pathway in the cellular processes. The fluorescence study of the treatment of MDA-MB cells with compound 21 showed a rapid process of apoptosis.

Synthesis and Screening of Some Novel Thieno[2,3-d][1,2,3] triazine Derivatives as Non-sedative H1 Antihistaminics

Histamine receptor H1 antagonists are widely used as antihistamines for allergy conditions. The brain-penetrating antihistamines can cause sedation and some with poor-penetration do not cause sedation potential. In the present study, a new series of thieno[2,3-d][1,2,3]triazine derivatives 7a-e have been synthesized and screened for their H1 antihistaminic activity and sedation potential. Among all the screened compounds, compound 7b, 7c and 7d, show high H1 antihistaminic activity with IC50 value of 0.1 - 0.8 µM, which are comparable with that of the standard drug cetirizine. The sedative potential of the compounds was tested on albino mice using the photoactometer method. All the three compounds show less sedation potential than that of the standard drug diphenhydramine. In conclusion, the novel compounds appear with promising potential as non-sedating antihistamine agents. 

Synthesis, cytotoxicity, in-vitro antibacterial screening and in-silico study of novel thieno[2,3-b]pyridines as potential pim-1 inhibitors

A novel series of thieno[2,3-b]pyridines was prepared via an one-step protocol in excellent yields. The protocol involved the reaction of pyridine-2(1H)-thiones with the appropriate halogen containing reagents in ethanolic sodium ethoxide solution under stirring at 80 °C for 2 h. The new thienopyridines were screened against different bacterial and fungal strains. Thieno[2,3-b]pyridine-2-carboxylate 9a showed the most effective antibacterial activities against each of Staphylococcus aureus and Escherichia coli with MIC/MBC values of 9.9/19.8 and 19.8/39.5 µM, respectively, when compared with Ciprofloxacin. 9a was the most effective compound against MRSA with inhibition zone of 16.2 ± 0.6 mm, when compared with Gentamicin. Moreover, 9a exhibited the best cytotoxic activity against each of HEPG2 and MCF-7 cell lines with IC50 values of 25.7 and 30.53 µM, respectively, when compared with Doxorubicin. The in-silico study was performed to predict the capability of new thienopyridines as potential inhibitors of pim-1 kinase.

Discovery of novel akt1 inhibitor induces autophagy associated death in hepatocellular carcinoma cells

In this study, a series of thieno [2,3-d]pyrimidine derivatives were designed, synthesized and evaluated as novel AKT1 inhibitors. In vitro antitumor assay results showed that compounds 9d-g and 9i potently suppressed the enzymatic activities of AKT1 and potently inhibited the proliferation of HepG2, Hep3B, Huh-7 and SMMC-7721 cancer cell lines. Among these derivatives, the compound 9f demonstrated the best inhibitory activities on AKT1 (IC50 = 0.034 μM) and Huh-7 cell (IC50 = 0.076 μM). A panel of biological assays showed that compound 9f suppressed the cellular proliferation of Huh-7 through Akt/mTOR signaling pathway mediated autophagy mechanism. Furthermore, the antitumor capacity of 9f was validated in the subcutaneous Huh-7 xenograft models. Together, our results demonstrate that a novel small-molecule Akt1 inhibitor induces autophagy associated death in hepatocellular carcinoma, which may afford a potential drug candidate for targeted cancer therapy.

Pharmacophore modeling, 3D-QSAR, synthesis, and anti-lung cancer evaluation of novel thieno[2,3-d][1,2,3]triazines targeting EGFR.

Two series of thieno[2,3-d][1,2,3]triazine derivatives were designed, synthesized, and biologically evaluated as potential epidermal growth factor receptor (EGFR) inhibitors targeting the non-small-cell lung cancer cell line H1299. Most of the synthesized compounds displayed IC50 values ranging from 25 to 58 nM against H1299, which are superior to that of gefitinib (40 µM). 3-(5,6,7,8-Tetrahydro-7H-cyclohexa[4:5]thieno[2,3-d]-1,2,3-triazin-4-ylamino)benzene-1,3-diamine (6b) achieved the highest cytotoxic activity against H1299 with an IC50 value of 25 nM; it had the ability to decrease the EGFR concentration in H1299 cells from 7.22 to 2.67 pg/ml. In vitro, the IC50 value of compound 6b was 0.33 nM against EGFR, which is superior to that of gefitinib at 1.9 nM and erlotinib at 4 nM. The three-dimensional quantitative structure-activity relationships and molecular modeling studies revealed comparable binding modes of compound 6b, gefitinib, and erlotinib in the EGFR active site. The in silico ADME (absorption, distribution, metabolism, and excretion) prediction parameters of this compound revealed promising pharmacokinetic and physicochemical properties. Moreover, DFT (density functional theory) calculations showed the high reactivity of compound 6b toward the EGFR compared with other compounds. The designed compound 6b might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR.

Synthesis and biological activity of thieno[3,2-d]pyrimidines as potent JAK3 inhibitors for the treatment of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a serious and fatal lung disease, with a median survival of only 3–5 years from diagnosis. Janus kinase 3 (JAK3) has a well-established role in the pathogenesis of various autoimmune diseases, including rheumatoid arthritis (RA) and autoimmune-related pulmonary fibrosis. In this study, through the use of a conformationally-constrained design strategy, a series of thieno[3,2-d]pyrimidines were synthesized as potent JAK3 inhibitors for the treatment of IPF. Among them, the most potent JAK3 inhibitor, namely 8e (IC50 = 1.38 nM), significantly reduced the degree of airsacculitis and fibrosis according to hematoxylin-eosin (HE) staining assay for the lung tissue in the bleomycin (BLM)-induced pulmonary fibrosis mouse model. The clear reduction of the lung collagen deposition by the determination of Masson and hydroxyproline (HYP) content also demonstrated its efficacy in the treatment of fibrosis. In addition, 8e also reduced the expression of the inflammatory markers IL-6, IL-17A, TNF-α and malondialdehyde (MDA) in lung tissue, which indicated its higher anti-inflammatory activity compared with that of the reference agents (nintedanib and gefitinib). Furthermore, it possessed low cytotoxicity against normal human bronchial epithelia (HBE) cells (IC50 > 39.0 μM) and C57BL mice. All these evaluated biological properties suggest that 8e may be a potential JAK3 inhibitor for the treatment of IPF.