ChemMedChem最新文献

Efficient synthesis in aqueous media is employed to prepare targeted compounds to evaluate antiproliferative, antibacterial, and antiviral activity in vitro. The biological activity is influenced by the type and number of substituents placed at phenyl or benzoxazole ring. Acrylonitriles substituted with 3,4-dihydroxy 50, 51, 3,4,5-tryhidroxy 52, 53, and 4-N,N-diethyl-amino 55 groups demonstrate potent antiproliferative effects against cancer cell lines, with IC₅₀ values from 0.7 to 5.8 μM. Their impact on normal cell viability is assessed. The most active benzoxazoles induce DNA damage and are analyzed for their interaction with ct-DNA. UV/Vis titrations, thermal melting assays, and circular dichroism suggest an intercalative mode for the 4-N,N-diethylamino 55 and partial intercalation for the 3,4-dihydroxy 50 and 3,4,5-tryhidroxy derivative 52. Derivative 55 induces apoptosis and cell cycle arrest in cancer cells. Among tested benzoxazoles, significant antiviral activity against HCoV OC43 is observed for the 2-naphthyl 32, 3-indolyl 41 and 42 and p-hydroxy derivative 48 (EC₅₀ from 2.1 to 8.5 μM). Furthermore, antibacterial activity is most effective for the 3,4-dihydroxy and bromine substituted acrylonitrile 51 against S. aureus (MIC 8 μM) and the efflux pump-deleted mutant of E. coli (MIC 4 μM), which is also observed for the hydroxy and bromine substituted 49.

Caerulomycin A, a marine-derived natural product featuring a bipyridinic core and a substituted oxime functional group, was originally isolated from Streptomyces caeruleus and is known for its antibiotic, antifungal, and cytotoxic properties. In this study, we report the efficient synthesis of caerulomycin A and a series of novel analogs via a five-step synthetic route using readily available reagents. The structural diversification focused on the replacing the methoxy group with various benzyl ether substituents at C-4 and subsequent oxidation and condensation steps at C-6 to generate caerulomycin E and caerulomycin A analogs. These compounds were evaluated for their cytotoxic activity against six human cancer cell lines. Notably, several benzyl ether derivatives exhibited significantly enhanced cytotoxicity compared to the parent compound, with some analogs demonstrating greater potency than the reference drug ellipticine. The structure–activity relationship (SAR) analysis revealed that halogenated substituted benzyl ether groups at C-4 positions played a critical role in modulating cytotoxic activity and selectivity. These findings underscore the potential of synthetic caerulomycin derivatives as promising lead compounds for further development in cancer therapeutics.

Toward the discovery of novel efficient repellents, protein-directed dynamic combinatorial chemistry (pdDCC) coupled to saturation-transfer difference (STD) NMR spectroscopy was initially employed to identify modulators of the malaria vector Anopheles gambiae Odorant Binding Protein 1 (AgamOBP1). A library of potential binders of AgamOBP1 (secondary amines) generated from two amines and seven aldehydes was designed aiming to enable interactions with critical amino acids at the DEET-site and to bridge the DEET- and Icaridin sIC-binding pockets, both implicated in repellents recognition. Solubility issues hindered the clear identification of binders among the DCL members, except for one sublibrary, leading us to shift our strategy towards the synthesis of the designed amines, followed by direct evaluation of their binding to AgamOBP1 using ¹H STD NMR spectroscopy. The identified binders were further validated in vitro by fluorescence competition assays, and the most potent compounds which also possessed suitable vapor pressure were evaluated as repellents in arm-in-cage behavioral assays against Aedes albopictus. Amines 2A, 3A, 4A, and 6A showed significant repellent activity. The most potent was compound 4A (4-methyl-N-(pyridin-4-ylmethyl)aniline) which acted as a a DEET-like repellent at 0.4 μL cm⁻² dose. Thus, our strategy showcased a promising scaffold for further optimization toward efficient mosquito repellents.

A novel chemotype of nitrile-containing azolopyrimidines with potential antitumor activity has been proposed, and a method for the synthesis of the corresponding 5-amino-7-oxoazolo[1,5-a]pyrimidine-6-carbonitriles by cyclocondensation of various aminoazoles and ethyl 2-cyano-3-R-amino-3-(methylsulfanyl)acrylates has been developed. Cytotoxic effects of the obtained azolopyrimidines against glioblastoma (A-172), bladder carcinoma (T-24), lung carcinoma (A-549), and human embryonic kidney (HEK-293) cells have been investigated, and structure–activity relationships have been identified. 2-Phenyl-5-(morpholin-4-yl)-7-oxo-1,2,4-triazolo[1,5-a]pyrimidine-6-carbonitrile 5j has been found to exhibit selective cytotoxic activity against the T-24 cells (IC₅₀ = 14.68 µM), whereas 3-bromo-5-(morpholin-4-yl)-7-oxopyrazolo[1,5-a]pyrimidine-6-carbonitrile 5v has shown selective toxicity against the A-172 cells (IC₅₀ = 18.38 µM). Further studies on heterocycle 5j in the annexin V apoptosis assay indicate that the primary mechanism involves inhibition of proliferative activity rather than induction of cell death. The cyclin-dependent kinase 2 protein is suggested as a possible target for the cytotoxic action of the studied compounds 5 on the T-24 cell line according to the notable correlation between docking studies and MTT assay results.

An icosahedral glimmer in the dark: Carborane-modified halogenated naphthyridinones illuminate the path towards CB₂R-selective PET imaging agents, with a brown (bromine) and a purple (iodine) companion. The determination of CB₂R overexpression in pathological conditions with PET requires radiotracers. In article 10.1002/cmdc.202500251, Evamarie Hey-Hawkins and co-workers report carborane-based CB₂R ligands with different carborane isomers and halogene substituents as potential CB₂R-PET tracers. Art by Dr. Christoph Selg.

The Bcl-2 protein family plays a critical role in regulating apoptosis, making it a key target for cancer therapy. In this study, a series of novel Bcl-2 inhibitors have been designed, synthesized, and evaluated. To disrupt the interactions between anti-apoptotic Bcl-2 and pro-apoptotic proteins, compounds were developed based on essential pharmacophoric features. Among the tested compounds, R4, R14, R17, and R23 demonstrated potent anticancer activity with sub-micromolar IC₅₀ concentrations across various Bcl-2 expressing human cancer cell lines (IC₅₀ ranges: 1.46–7.67 µM for cancer cells). ELISA binding assays further validated the efficacy of R4, R14, and R23, showcasing their potency with IC₅₀ values ranging from 0.25 to 0.63 µM, compared to gossypol and ABT-199 (venetoclax), with IC₅₀ values of 0.6 and 0.038 µM, respectively. Furthermore, the R23 revealed a significant induction of late and early apoptosis and cell cycle arrest at G1 phase. Noteworthy, R23 emerged as a promising candidate with unique computational analysis, showing superior displacement of hydration sites and higher ΔG values in WaterMap studies. Moreover, molecular dynamics simulations reveal low root mean square deviation fluctuations, indicating strong and stable interactions with Bcl-2. These findings underscore the therapeutic potential of R23 as a Bcl-2 inhibitor.

Drug discovery and development is a complex, arduous and uncertain activity that is more likely to fail than succeed. To improve the odds of success, numerous dogmas have become entrenched in medicinal chemistry. This has unwittingly led to stifling of creativity and innovation, rather than improve the practice of medicinal chemistry. It is time to let go of these dogmas and embrace an open mindset for discovery and knowledge creation.

Proteolysis targeting chimeras (PROTACs) offer a promising therapeutic approach by leveraging the ubiquitin–proteasome system (UPS) to degrade target proteins. These heterobifunctional molecules consist of a target protein ligand, an E3 ligase ligand, and a linker. Among the limited E3 ligase ligands available, cereblon (CRBN) ligands are the most widely used. However, the stability and racemization of current chiral CRBN ligands pose challenges for developing CRBN-recruiting PROTAC therapeutics. Herein, a partial PROTAC library is reported incorporating an aldehyde motif and various linkers into previously developed achiral phenyl dihydrouracil CRBN ligands, which offer improved stability and eliminate racemization issues. This library enables the rapid generation of fully functional PROTACs targeting Bruton's tyrosine kinase (BTK) by coupling the aldehyde motif with a hydrazide-containing BTK ligand. Initial HiBiT assay (Promega) screening identifies nine hits capable of significant BTK degradation, with compound B1 emerging as the most potent degrader. A stable amide bioisostere, AM-B1, is further developed, which induces significant antiproliferation and BTK degradation. Mechanistic studies confirm BTK degradation via the UPS. This study highlights the development of an achiral CRBN-based partial PROTAC library and demonstrates a two-stage strategy for rapid PROTAC development against BTK.

Despite significant advancements in antituberculosis (TB) drug discovery, considerable scope remains for novel therapeutic development. Molecular hybridization represents a promising strategy for generating new anti-TB agents. In this study, in silico molecular docking is employed to design novel isoniazid–sulfonamide hybrids connected via a hydrazone bridge, designated as series 7j–r and 8a–i. Docking analysis reveals that these compounds interact significantly with the active site of InhA, particularly engaging the catalytic triad residues Y158, F149, and K165, as well as the cofactor NAD. Subsequently, both series are synthesized and evaluated against Mycobacterium tuberculosis. Generally, compounds from both series (7 and 8) exhibit enhanced activity compared to their precursors. Notably, compound 8a demonstrated approximately twofold greater potency ( minimum inhibitory concentration (MIC) = 0.156 µg mL⁻¹) with respect to compound 7j (MIC = 0.313 µg mL⁻¹). However, these compounds lose efficacy against INH-resistant M. tuberculosis strains harboring katG mutations and remain ineffective against multidrug-resistant and extensively drug-resistant strains of M. tuberculosis. Encouragingly, the tested compounds exhibit little cytotoxicity against the THP-1 human monocytic cell line at a concentration of 20 µg mL⁻¹. Additionally, the structural stability studies using ¹H NMR confirm the structural integrity of these compounds. Overall, these molecular hybrids are promising for further development as anti-TB agents after relevant structural optimizations.

Multiple myeloma is a rare blood cancer that develops from abnormal plasma cells in the bone marrow. Treatment of multiple myeloma remains an enormous challenge. In this work, hybrid compounds are developed and studied for their potential use against multiple myeloma. The compounds are designed to act by a dual mechanism of action, activation of the p53 pathway, and inhibition of the ataxia telangiectasia and Rad3-related protein (ATR). To evaluate the selectivity for the p53 pathway, the compounds are first evaluated in an isogenic pair of HCT116 colon cancer cell lines, with and without p53, and in two breast cancer cell lines expressing different forms of p53. Then, the growth inhibitory effect of the hybrid compounds is tested against the multiple myeloma cell lines RPMI 8226 (mutant p53) and MM.1S (wild-type p53). At the same time, compound 15 is confirmed to inhibit doxorubicin- but not UV-induced DNA damage response via the ATR/Chk1 signaling pathway. The hybrids show lower IC₅₀ values compared to the fragments alone, highlighting the potential for using hybrid molecules containing two pharmacophores with complementary activities. These results suggest that novel hybrid molecules may serve as new leads against multiple myeloma.