MedChemComm最新文献

Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for Parkinson's disease. We report herein the discovery of pyrrolopyrimidine analogs as potent and selective LRRK2 kinase inhibitors. Elucidation of the structure–activity relationship (SAR) of the kinase-inhibitor-focused screening lead compound 1 led to the development of compound 39 (GSK3357679) that shows excellent cellular potency, oral bioavailability, brain-penetration, and excellent PK/PD correlation in animal studies. The SAR optimization of the biological and pharmacokinetic profiles of the compounds are described. The pharmacodynamic characteristics for extended oral dosing studies in rodents are also presented.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are closely linked neurodegenerative and metabolic disorders, sharing overlapping pathological mechanisms. In this study, structure-based drug design combined with molecular hybridization strategies was employed to develop dual-acting compounds targeting both conditions. A series of twenty hybrid molecules, comprising 2-oxoindolin-3-thiosemicarbazones (3a–i) and thiazolines (4a–k) were successfully synthesized and characterized using spectroscopic techniques and elemental analysis. Biological evaluations demonstrated that compounds 3d and 3h exhibit potent inhibitory activity against α-glucosidase (α-Glu) and α-amylase (α-Amy), surpassing the efficacy of acarbose. These findings highlight their promising antidiabetic potential and support further investigation into their therapeutic relevance for AD and T2DM comorbidity (3d (α-glucosidase K_i = 41.41 ± 2.53 nM; α-amylase IC₅₀ = 1.25 ± 0.02 nM), 3h (α-glucosidase K_i = 44.19 ± 2.41 nM; α-amylase IC₅₀ = 2.87 ± 0.16 nM and acrabose (α-glucosidase K_i = 101.20 ± 7.53, α-amylase IC₅₀ 9.73 ± 0.20). Furthermore, compounds 3i and 4i exhibited significantly higher inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) compared to the reference drug tacrine. Notably, compound 4i demonstrated exceptional multi-enzyme inhibition, with kinetic parameters indicating strong binding affinity: 3i (AChE K_i = 59.71 ± 2.24 nM; BChE K_i = 8.43 ± 0.97 nM), 4i (AChE K_i = 53.31 ± 1.74 nM; BChE K_i = 10.72 ± 2.19 nM), and tacrine (AChE K_i = 132.35 ± 5.90 nM; BChE K_i = 137.42 ± 4.01 nM). Molecular docking and dynamics simulations corroborated these findings by revealing stable and favorable interactions within the active sites of both enzymes. Additionally, in silico ADME profiling indicated desirable pharmacokinetic properties, further supporting the therapeutic potential of these compounds as dual-action agents for the management of Alzheimer's disease and type 2 diabetes mellitus.

Several first-, second-, and third-generation EGFR-TKIs have proven effective as anti-cancer therapeutics. However, the rapid development of drug resistance and mutations continues to be a major challenge in EGFR-TKI therapy. Addressing both intrinsic and acquired resistance resulting from EGFR mutations requires further exploration and the identification of novel inhibitors. In this study, we identified a new class of pyrido[2,3-b][1,4]oxazine-based inhibitors that exhibited potent EGFR kinase inhibitory activity. These compounds demonstrated significant anti-proliferative effects against EGFR-mutated non-small cell lung cancer (NSCLC) cell lines, including HCC827 (EGFR exon 19 deletion), H1975 (EGFR L858R/T790M double mutation), and A549 (wild-type EGFR overexpression). These novel pyrido[2,3-b][1,4]oxazine analogues were rationally designed and synthesized using the Suzuki cross-coupling reaction in a multi-step synthetic route. Anticancer evaluation of these derivatives using the MTT assay showed promising therapeutic potential. The most promising compounds were 7f, 7g, and 7h, with 7f showing potency (IC₅₀ values: 0.09, 0.89, and 1.10 μM, in the HCC827, NCI-H1975 and A-549 cell lines, respectively) equivalent to clinically approved osimertinib. Interestingly, these compounds are selectively cytotoxic against cancer cells while not harming normal BEAS-2B cells at doses over 61 μM. Mechanistic studies demonstrated that compound 7f acts as an EGFR-TK autophosphorylation inhibitor, causing significant apoptosis (33.7% early and 9.1% late) compared to control conditions (2.4% early and 1.8% late). Molecular docking showed that the compounds scored similar to osimertinib, with the di-fluorophenyl group engaging the glycine-rich loop, pyridine substituents forming front pocket interactions, and essential hinge region interactions maintained, suggesting effective EGFR target engagement. These findings identify pyrido[2,3-b][1,4]oxazine derivatives as potential anticancer candidates worth further exploration for the development of targeted therapies against non-small cell lung cancer.

The exploration of novel three-dimensional scaffolds remains essential for expanding chemical space and discovering new bioactive molecules. Here, we describe a robust synthetic strategy that enables modulation of Janus Kinase activity through systematic diversification of the triquinazine skeleton, a highly sp³-rich scaffold derived from generated databases (GDBs). By employing ring enlargement and deconstruction approaches, four unprecedented chiral scaffolds were accessed, leading to the synthesis of 26 analogues. Biological evaluation against the Janus kinase family demonstrated how subtle modifications to the triquinazine skeleton influence the activity against JAK1, JAK2, JAK3, and TYK2. Notably, compound (S,R,R)-40a emerged as a potent JAK1 inhibitor (IC₅₀ = 18 nM), with similar potency as the FDA-approved inhibitors abrocitinib and upadacitinib. These findings highlight the potential of GDB-inspired molecules as a source for drug discovery.

This study investigates the application of machine learning techniques to predict the toxicity of tetrazole derivatives, aiding in the identification of environmental risks from chemical exposure. Utilizing LD₅₀ data sourced from the scientific literature and the ChemIDplus database, regression models were developed to forecast acute intraperitoneal toxicity in mice. A machine learning regression model for acute intraperitoneal toxicity in mice was constructed and validated on a test dataset, achieving high accuracy (R² = 0.76 and MSE below 10⁻⁴) and surpassing most of the comparable literature models. Molecular descriptors were computed via Mordred software to explore quantitative structure–activity relationships, and additionally, the model's robustness was demonstrated by measuring the acute toxicity of tetrazole derivatives synthesized through the azido-Ugi reaction.

Tissue transglutaminase (TG2) is both an enzyme and a G-protein that is implicated in many diseases, such that small molecule inhibitors of TG2 have broad potential as drugs or research tools. Previous work has demonstrated how the structure of EB-2-16, a highly potent irreversible inhibitor of TG2, has been optimised with respect to its warhead, tether and bridge moieties. In this work, we studied the structure–activity relationships of the pendant hydrophobic group of the scaffold. This confirmed the superior affinity conferred by the parent adamantyl moiety, over other cycloalkyl, aryl, biaryl and bridged biaryl groups. Additionally, some substituted adamantyl derivatives were shown to exhibit superior inhibitory efficiency over the parent inhibitor, with k_inact/K_I values over 10⁶ M⁻¹ min⁻¹. The best inhibitors were shown to exhibit excellent lipid membrane permeability, but evaluation of their human hepatocyte stability revealed a sharp distinction between them. Despite the bromo- and iodoadamantyl derivatives being more efficient inhibitors, chloroadamantyl inhibitor 25b exhibits the best overall properties (k_inact = 1.69 min⁻¹, K_I = 1.79 μM, k_inact/K_I = 941 × 10³ M⁻¹ min⁻¹, P_e = 1.41 × 10⁻⁶ cm s⁻¹, CL_int = 6.91 μL min⁻¹/10⁶ cells) and suitability for potential applications in vivo.

COX-2 enzyme is implicated in Alzheimer's disease (AD) through amyloid beta (Aβ) accumulation, tau aggregation, and neuroinflammation. However, clinical outcomes of COX-2 inhibitors in AD have been inconsistent. This study explores a novel series of pyrazolidinones and pyrazolidinediones as selective COX-2 inhibitors. Among these, 4-hydrazonopyrazolidinediones exhibited potent COX-2 inhibition, reducing PGE2 release in a THP-1 cell model. Compounds 15 and 16 demonstrated multitargeting potential by inhibiting Aβ and tau aggregation (PHF6 and R3) and showed significant neuroprotective effects against Aβ and H₂O₂-induced toxicity in SH-SY5Y cells without cytotoxicity. Additionally, both compounds displayed high permeability in PAMPA and MDCK-MDR1 assays, indicating their potential to cross the blood–brain barrier and reach therapeutic targets. These findings highlight the potential of reviving COX-2 inhibitors as multitargeted therapeutic agents for AD, offering a promising strategy to address multiple pathological aspects of the disease, including neuroinflammation, amyloid aggregation, and tau pathology.

The escalating prevalence of multidrug-resistant tuberculosis (MDR-TB) underscores the urgent need for new classes of antitubercular agents targeting novel pathways. Carbonic anhydrase, a ubiquitous metalloenzyme, catalyses the reversible hydration of carbon dioxide in the CO₂ + H₂O HCO₃⁻ + H⁺ reaction. Suppressing this enzymatic activity has recently been identified as a new pathway for the treatment of Mycobacterium tuberculosis. To address this, a series of isoxazole–sulphonamides was rationally designed, incorporating an isoxazole pharmacophore as the aromatic tail, amide as a linker, and sulphonamide as the zinc-binding group. These compounds were evaluated against Mycobacterium tuberculosis carbonic anhydrases (MtCA 1 and 3) and two human carbonic anhydrases (hCA I and II) to identify selective inhibitors of the bacterial enzymes. The findings indicated that molecules containing an isoxazole pharmacophore with amide-linked benzene-3-sulphonamide were significantly more selective for MtCA 3 than hCA I and II. Among these compounds, 12c, 12e, and 19b had the highest inhibition against the MtCA 3 with K_i values between 0.08–0.09 μM compared to the standard acetazolamide with a K_i value of 0.10 μM. Some of the best compounds exhibited potent and selective inhibition of MtCA 3 over hCA I and II, with the meta- and para-substituted derivatives demonstrating higher selectivity and stronger inhibition. Specifically, compound 19b proved to be 199 and 38 times more selective for MtCA 3 than hCA I and hCA II respectively, compared to the standard drug acetazolamide, which is a non-selective CA inhibitor. The potential of compound 19b as a promising antitubercular agent with a MIC value of 8 μg mL⁻¹ against mc² 6230 was further strengthened by in silico ligand–target interaction studies. Thus, compound 19b is emphasised as a promising lead in the pursuit of new, selective agents targeting MtCA 3.

Chalcone-based derivatives have shown potential anticancer activity via multiple mechanisms including protein kinase inhibition. In the current study, two series of chalcone/2-thiopyrimidine conjugates 4a–4d and 6a–6i were designed, synthesized and screened for their antiproliferative activity in a single-dose assay against NCI-60 cancer cell lines. Ten compounds, 4a–4d, 6a–6c, 6f, 6h, and 6i, were selected for a five-dose assay and their GI₅₀ values were determined. Compound 4c showed potent anticancer activity against LOX IMVI melanoma cell line with a GI₅₀ value of 0.0128 μM. Seven compounds, 4a, 4c, 4d, 6c, 6f, 6h, and 6i, were found to be non-cytotoxic against fibroblast (hFB) normal cell line. Additionally, investigation of the VEGFR-2 inhibitory activity of the ten promising compounds revealed that 4c, 4d and 6i displayed promising VEGFR-2 inhibition (IC₅₀ = 0.144, 0.105, and 0.072 μM, respectively) compared to sorafenib (IC₅₀ = 0.081 μM). Moreover, 4c inhibited BRAF_WT and BRAF_V600E kinases (IC₅₀ = 0.201 and 0.101 μM, respectively) relative to vemurafenib (IC₅₀ = 0.156 and 0.063 μM, respectively). Furthermore, 4c arrested the cell cycle progression at the G₁ phase and induced late apoptosis in LOX IMVI cells. Moreover, evaluation of the effect of 4c on apoptotic markers in the mentioned cells indicated an increase in the Bax/Bcl-2 ratio by 28.12-fold along with upregulation of caspases-3 and -9 by 7.40- and 5.63-fold, respectively, in addition to anti-migratory effect. Molecular docking study of the most promising derivatives revealed a common binding pattern in the binding site of the target kinases that extends from the hinge region through the gate area towards the allosteric back pocket interacting with the key amino acids in a type II inhibitor-like binding pattern.

In this article, we report the design, synthesis, and biological evaluation of a new series of nitroheterocyclic aromatic adamantane amides targeting trypanosomes. These compounds feature diverse substituents on the adamantane scaffold, variations in side chain linker length, and a range of nitroheterocyclic moieties. This work represents a continuation of our previous efforts, with a particular focus on elucidating the structural and functional role of the linker connecting the phenyladamantane core to the nitroheterocyclic ring. The structure–activity relationship data underscore the importance of strategic modifications in enhancing the pharmacological profile of these compounds against trypanosome parasites. Further modifications are recommended to optimize the physicochemical properties of the current derivatives to improve intracellular targeting of trypanosomatids, an important clinical stage in their life cycle.