MedChemComm最新文献

Designed polypharmacology aims to exploit additive or synergistic effects of simultaneous multi-target modulation. Multifactorial diseases like metabolic dysfunction requiring multi-drug treatment may significantly benefit from this concept. To identify multi-target lead pharmacophores for the development of designed dual ligands, we performed a focused two-stage screening of fatty acid mimetic fragments for modulation of the nuclear receptors THR, PPAR, FXR and RXR which are involved in transcriptional regulation of metabolic balance. Dual, multiple and pan-agonist hits were retrieved for various combinations of these targets of interest and preliminary SAR evaluation yielded dual agonist and pan-agonist fragments with attractive potency and efficacy as valuable leads for polypharmacology.

A series of novel bis(indolyl)-tetrazine derivatives were designed and synthesized to develop potential anti-breast cancer agents. The compounds were characterized by spectral analysis using ¹H NMR, ¹³C NMR spectroscopy, and HRMS. Further, the structure of one of the derivatives 5b was confirmed by single crystal X-ray diffraction technique. The compounds exhibited good to moderate anti-proliferative activity against MCF-7 and MDA-MB-231 cell lines, showing IC₅₀ values of 7.57–22.52 μM and 10.08–21.49 μM, respectively. However, only four compounds, 5b, 5f, 5i, and 5j were found to be active against the T-47D cell line. Particularly, compounds 5b and 5f demonstrated the most promising anti-proliferative activity as compared to standard drug bazedoxifene (IC₅₀ = 12.78 ± 0.92 μM), with IC₅₀ values of 5.11 ± 0.16 and 4.69 ± 0.51 μM, respectively against estrogen receptor-alpha (ER-α) dominant (ratio of ER-α/ER-β is 9/1) T-47D cell line. Further, compound 5b exhibited binding affinity towards ER-α with an IC₅₀ value of 1729 ± 24 nM when assessed for its affinity towards ER-α through a competitive ER-α binding assay. The Western blot analysis confirmed that compound 5b reduced the ER-α protein's expression, impeding its subsequent transactivation and signalling pathway within T-47D cells. Current findings imply that compound 5b, which exhibits significant ER-α antagonistic activity, can be a potential lead compound for developing anti-breast cancer agents.

We report the design and synthesis of thieno[3,2-b]pyridin-5(4H)-one derivatives exhibiting site-dependent modulation of both antitumor activity and fluorescence, enabled by a regioselective BOP-promoted aza-[3 + 3] cycloaddition. The reaction proceeds between thiophen-3-amines and α,β-unsaturated carboxylic acids, followed by base-induced dehydrogenation. Mechanistic studies reveal that the head-to-tail aza-[3 + 3] annulation involves a C-1,4 conjugate addition, leading to an intramolecular amide coupling. Evaluation of the photophysical properties and antitumor activities demonstrated that the biological and optical behaviours of the thieno[3,2-b]pyridin-5(4H)-one scaffold are dependent on the aryl substitution site. Specifically, 3-aryl derivatives exhibited notable antitumor activity, whereas 2-aryl analogues displayed strong fluorescence, highlighting the potential of this scaffold for dual-function applications. DFT calculations supported the observed divergence in fluorescence by revealing differences in orbital conjugation and HOMO–LUMO gaps. In addition, selected compounds showed low cytotoxicity toward MRC-9 cells, indicating favourable cancer cell selectivity.

The C–X–C motif chemokine receptor 4 (CXCR4) is overexpressed by pancreatic cancer cells. This work developed a CXCR4 antagonistic peptide P12, which was identified by pancreatic-cell-based selection from among the de novo designed peptides and was able to specifically bind to the pancreatic cancer cells as well as fibroblasts and macrophages in vitro and in vivo. CXCL12-mediated migration of tumor cells and adhesion to stromal cells were effectively inhibited by P12, and the phosphorylation of Erk and P38 was down-regulated. P12 increased the sensitivity of the tumor cells and fibroblasts to gemcitabine (GEM). The combination of P12 with GEM (P12+GEM) increased the infiltration of CD8⁺ T cells and reduced fibroblasts in the tumor microenvironment, as well as increasing the toxicity of the lymphocytes to the tumor cells with upregulated blood levels of INF-γ and TNF-α. Collectively, P12+GEM decreased the tumor weight and prolonged the survival of tumor-bearing mice significantly. In conclusion, P12 is a potent and selective CXCR4 antagonist that effectively enhances anti-tumor immune responses and overcomes the gemcitabine resistance of pancreatic cancer.

Breast cancer is the most frequently diagnosed malignancy in women. Invasive breast cancer will be diagnosed in approximately one in every eight women during their lifetime. Quinazoline-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines were designed and synthesized using a pharmacophore hybridization technique that combined biologically active scaffolds. In vitro assays of the synthesized compounds' cancer activity against three breast cancer cell lines: MCF-7, MDA-MB-231, and MDA-MB-468, compounds 6i, 6k, and 6l exhibited significant activity. Compounds 6j and 6m exhibited equivalent efficacy relative to the standard drug against the MDA-MB-231 cell line, but compound 6i showed significant activity against the MDA-MB-468 cell line. Moreover, compound 6i (IC₅₀ = 0.37 ± 0.03 μM) demonstrated superior efficacy compared to the standard erlotinib (IC₅₀ = 0.42 ± 0.01 μM) in vitro, based on EGFR inhibitory assays and compound 6k (IC₅₀ = 0.51 ± 0.04 μM) showed good EGFR inhibitory activity. To validate the activity data and the drug-likeness of the compounds, six potent compounds were subjected to in silico molecular docking investigations using the Discovery Studio 2021 methodology.

We compute the different thermodynamic interaction parameters between afatinib, a tyrosine kinase inhibitor, and the epidermal growth factor receptor (EGFR) protein found in the cell membrane of lung epidermal cells and primarily responsible for non-small cell lung cancer (NSCLC). We compare the interaction entropy component (−TΔS) of the binding energy obtained through normal mode or Nmode analysis (NMA), interaction entropy (IE), and C2 methods. We observe a much closer value of the binding free energy of the hydrated complex (−19.86 kcal mol⁻¹) with the experimental value (about −13.00 kcal mol⁻¹) compared to those obtained through newly developed IE and C2 methods (about −32.96 kcal mol⁻¹ and −35.47 kcal mol⁻¹, respectively). The present study with molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) shows the standard deviation of binding energies (σ_IE = 3.54 kcal mol⁻¹) which is an indication of the convergence of binding entropy with a lower value of energy. Advancement in structural biology with appropriate simulation techniques is an essential feature to meet challenges in covalent drug discovery as such drugs have been used to treat various types of cancers.

A series of hydrazinyl-oxoacetamide linked 4-aminoquinoline-phthalimides were synthesized and assayed for their anti-plasmodial activities against the chloroquine-resistant W2 strain of P. falciparum. The synthesized compounds exhibited activity in the low nanomolar range with eight compounds being more active than the standard drug, chloroquine (CQ). Structure–activity relationship studies indicated the dependence of anti-plasmodial activity on the length of the alkyl chain used as a spacer with two of the most promising compounds of the series exhibiting an IC₅₀ value of 0.037 μM. Inhibition of hemozoin formation proved to be the primary mechanism of action of the most promising compound of the series with superior binding affinity toward heme compared to CQ.

Carbonic anhydrases (CAs) are crucial for cancer cells to survive in hypoxia. Here we show that our newly synthesised 1,8-naphthalimide-piperazine-amidobenzenesulfonamide derivative, namely compound Q, specifically targets CA IX and causes cell death in colorectal cancer. Compound Q stably binds to the zinc atom in the active pocket of CA IX and selectively inhibits the activity of this enzyme. It kills SW480 cells under normoxic and hypoxic conditions, with an IC₅₀ of 17.03 ± 1.09 μM and 10.90 ± 0.46 μM, respectively. The inhibitory effect of compound Q against CA IX activity is better under hypoxic conditions and it has low toxicity on normal colon with an IC₅₀ of 38.83 ± 1.98 μM. Compound Q also inhibits tumour growth in the colorectal cancer SW480 xenograft model and it shows no adverse effects on nude mice body weight. Our analyses also demonstrate that compound Q induces ferroptosis, apoptosis and autophagy in colorectal cancer and we believe that these are the main mechanisms by which it promotes cell death in this cancer. Taken together, our data indicate that compound Q is a potent and selective CA IX inhibitor that is promising for the treatment of colorectal cancer.

Previous studies have shown that the palindromic peptide RWQWRWQWR derived from bovine lactoferricin (LfcinB) has exhibited selective in vitro cytotoxic effects against multiple cancer cells such as cervical, breast, and prostate cancer. We designed and synthesized peptides based on this palindromic sequence conjugated with non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen and ibuprofen to obtain novel hybrid peptides that could trigger inflammatory processes within cancer cells. Incorporating the non-natural amino acid ornithine as a spacer was done to improve the aqueous solubility of the NSAID–peptide conjugates. The antibacterial activity of the conjugated peptides was evaluated, and these peptides showed significant activity against E. coli strain ATCC 25922, with MIC values of 12 μM. Cytotoxicity was assessed in human cervical cancer cells (HeLa) and human melanoma cells (A375), showing that the NSAID-conjugated peptides retained and even exhibited better anticancer activity compared to the palindromic peptide from which they were derived. The NSAID-LfcinB conjugates showed good selectivity towards cancer cells in the concentration ranges evaluated, being non-hemolytic. The cytotoxic effect of the IBU-Orn₃-1 and NAP-Orn₃-1 peptides was rapid and selective, inducing severe morphological changes, including rounding, shrinkage, and vacuole formation, which are associated with apoptosis. Flow cytometry assays revealed that the ibuprofen-conjugated palindromic sequence induced apoptosis independently of peptide concentration and treatment duration. These results suggest that the palindromic peptide RWQWRWQWR could be used for new applications in cancer research, such as delivering small molecules with anti-inflammatory activity in tumoral environments. The conjugation of NSAIDs to anticancer peptide sequences is a novel, viable, and rapid strategy that facilitates the synthesis of hybrid peptides with enhanced anticancer activity, thereby expanding the pool of promising molecules for preclinical and clinical studies in cancer therapy development.

The prevalence of human fungal infections (FIs) is rapidly increasing worldwide, posing substantial challenges to public health. The underestimation of FIs risk led to a limited knowledge of the fungal pathogenicity and a concomitant paucity of antimycotic drugs that are increasingly unable to effectively address resistance liabilities. The identification of innovative antifungal drugs is therefore an urgent need. Natural products have always been under scrutiny in the drug discovery process. Of these, usnic acid (UA) represents a compelling starting point for antifungal drug development due to its natural occurrence as a secondary metabolite in various lichen species, where it serves as a natural defence mechanism against fungal invasion. This dibenzofuran derivative possesses an intrinsically rigid three-dimensional architecture with stereogenic center, providing a pre-organized chiral scaffold with potential for selective interaction with fungal targets. Despite its high therapeutic potential as antimicrobial agent, UA suffers from poor solubility and hepatotoxicity issues. The proposed research explores the modification of UA scaffold to generate the series of semisynthetic compounds 1–9 by derivatizing the (R)- and (S)-UA as enamines. Considering the inherent chirality of UA, this work aims to identify structure–activity relationships that optimize antifungal efficacy while improving the pharmacokinetic properties of UA. The resulting compounds were evaluated for their antifungal activity against three strains, showing significant differences in potency concerning their absolute configuration. This research addresses the urgent need for novel antifungal agents in an era of increasing resistance to conventional treatments, identifying (9bS,15S)-1, 3, 4, and 8 compounds as promising compounds for developing antifungal therapeutics.