MedChemComm最新文献

A series of Meldrum's acid, 7-azaindole and 1,2,3-triazole hybrids were synthesized and evaluated for their in vitro anticancer activity against five different cancer cell lines viz. MCF-7 (breast cancer), HeLa (cervical cancer), DU-145 (prostate cancer), HepG2 (liver cancer) and K562 (myelogenous leukemia cell). Among the series, compound 6b containing a 4-methyl substitution showed potent activity against HeLa cell line. Cell cycle analysis revealed that compound 6b induced cell cycle arrest at the G2/M phase and induced apoptosis. Apoptotic activity was further confirmed by Hoechst staining and Annexin V-FITC assay. Compound 6b has been found to exhibit higher activity in all four cell lines, with IC₅₀ values of 6.67 ± 0.39 μM, 4.44 ± 0.32 μM, 12.38 ± 0.51 μM and 9.97 ± 0.25 μM against MCF-7, HeLa, DU-145 and HepG2 cell lines respectively. Compounds 6m (9.68 ± 0.10 μM) and 6n (9.52 ± 0.38 μM), which have dimethoxy and trimethoxy substitutions, respectively, have demonstrated significant anticancer activity against HeLa cells compared to the other cells. The molecular docking study of ligand 6b against the crystal structure of EGFR and Mcl-1 scored notable binding energy values and displayed important interactions like H-bond, π–cation and other hydrophobic interactions.

We have developed a novel chemical handle (PFI-E3H1) and a chemical probe (PFI-7) as ligands for the Gid4 subunit of the human E3 ligase CTLH degradation complex. Through an efficient initial hit-ID campaign, structure-based drug design (SBDD) and leveraging the sizeable Pfizer compound library, we identified a 500 nM ligand for this E3 ligase through file screening alone. Further exploration identified a vector that is tolerant to addition of a linker for future chimeric molecule design. The chemotype was subsequently optimized to sub-100 nM Gid4 binding affinity for a chemical probe. These novel tools, alongside the suitable negative control also identified, should enable the interrogation of this complex human E3 ligase macromolecular assembly.

PD-L1 is a transmembrane protein overexpressed by tumor cells. It binds to PD-1 on the surface of T-cells, suppresses T-cell activity and hinders the immune response against cancer. Clinically, several monoclonal antibodies targeting PD-1/PD-L1 have achieved significant success in cancer immunotherapy. Nevertheless, their disadvantages, such as unchecked immune responses, high cost and long half-life, stimulated pharmacologists to develop small-molecule inhibitors targeting PD-1/PD-L1. After a batch of excellent inhibitors with a biphenyl core structure were firstly reported by BMS, more and more researchers focused on small-molecule inhibitors targeting PD-L1 rather than PD-1. Numerous small-molecule inhibitors were extensively designed and synthesized in the past few years. In this paper, the structural characteristics of PD-L1 and complexes of PD-L1 with its inhibitors are elaborated and small molecule inhibitors developed in the last decade are summarized as well. This paper aims to provide insights into further designing and synthesis of small molecule inhibitors targeting PD-L1.

Arginase, a difficult-to-target metalloenzyme, is implicated in a wide range of diseases, including cancer, infectious, and cardiovascular diseases. Despite the medical need, existing inhibitors have limited structural diversity, consisting predominantly of amino acids and their derivatives. The search for innovative arginase inhibitors has now extended to screening approaches. Due to the small and narrow active site of arginase, screening must meet the criteria of fragment-based screening. However, the limited binding capacity of fragments requires working at high concentrations, which increases the risk of interference and false positives. In this study, we investigated three colorimetric assays and selected one based on interference for screening under these challenging conditions. The subsequent adaptation and application to the screening a library of metal chelator fragments resulted in the identification of four compounds with moderate activity. The synthesis and evaluation of a series of compounds from one of the hits led to compound 21a with an IC₅₀ value of 91.1 μM close to the reference compound piceatannol. Finally, molecular modelling supports the potential binding of aurones and chalcones to the active site of arginase, suggesting them as new candidates for the development of novel arginase inhibitors.

Multidrug resistance (MDR) remains a challenging issue in cancer treatment. Aiming at finding anticancer agents to overcome MDR, the triacetyl derivative (2) of the labdane diterpenoid lactone andrographolide (1) underwent the Michael-type addition reaction followed by elimination, yielding twenty-three new derivatives, bearing nitrogen-containing substituents (3–25). Their structures were assigned, mainly, by 1D and 2D NMR experiments. The MDR reversal potential of compounds 1–25 was assessed, by functional and chemosensitivity assays, using resistant human ABCB1-gene transfected L5178Y mouse lymphoma cells as a model. Several derivatives exhibited remarkable P-glycoprotein (P-gp) inhibitory ability. Compounds 13 and 20, bearing thiosemicarbazide moieties, were the most active exhibiting a strong MDR reversal effect at 2 μM. Some compounds showed selectivity towards the resistant cells, with compound 5 exhibiting a collateral sensitivity effect associated with significant antiproliferative activity (IC₅₀ = 5.47 ± 0.22 μM). Moreover, all selected compounds displayed synergistic interaction with doxorubicin, with compound 3 being the most active. In the ATPase assay, selected compounds exhibited characteristics of P-gp inhibitors.

Psilocybin analogues have been synthesized comprising a non-hydrolysable P–C bond to evaluate the biological activity and the selectivity towards 5-HT_2AR, 5-HT_2BR and the TNAP receptor. No activity was observed towards the phosphatase, however all compounds showed good binding affinity for 5-HT_2AR and 5-HT_2BR and one compound showed a higher selectivity towards 5-HT_2AR than psilocin.

Based on a multitarget approach implementing rivastigmine-INDY hybrids 1, we identified a set of pseudo-irreversible carbamate-type inhibitors of eqBuChE that, after carbamate transfer at the active site serine residue, released the corresponding INDY analogues 2 endowed with hDYRK1A/hCLK1 kinases inhibitory properties. A SAR study and molecular docking investigation of both series of compounds 1 and 2 revealed that appropriate structural modifications at the carbamate moiety and at the N-appendage of the benzothiazole core led to potent and selective eqBuChE inhibitors with IC₅₀ up to 27 nM and potent hDYRK1A and hCLK1 inhibitors with IC₅₀ up to 106 nM and 17 nM respectively. Pleasingly, identification of the matched pair of compounds 1b/2b with a good balance between inhibition of eqBuChE and hDYRK1A/hCLK1 kinases (IC₅₀ = 68 nM and IC₅₀ = 529/54 nM, respectively) further validated our multitarget approach based on a sequential mechanism of action. In addition, target compound 1b exhibited a suitable ADMET profile, including good brain permeability and high stability in PBS, encouraging further biological investigation as a drug candidate.

A new library of allo-gibberic acid-based aminoalcohol regioisomers was synthesised stereoselectively starting from commercially available gibberellic acid, which yields allo-gibberic acid under mild acidic conditions. The successful formation of hydroxymethyl ketone derivative 5, by acid-mediated rearrangement of previously prepared epoxide, paved the way to obtain the desired 1,3-aminoalcohols through Schiff base formation. To obtain the desired regioisomers, the primary alcohol functionality of 5 was subjected to mesylation, then replaced with either primary amine or sodium azide. The formed azide derivative was subjected to either CuAAC reaction to obtain 1,2,3-triazoles or underwent Pd-catalysed hydrogenolysis to obtain primary aminoalcohol, which was further transformed into 1,3-aminoalcohols by reductive alkylation. All prepared aminoalcohols were identified in a satisfactory manner using modern spectroscopic techniques and assessed for their antiproliferative activity against a panel of human cancer cell lines. The antiproliferative effects of the prepared compounds were assayed by in vitro MTT method against a panel of human cancer cell lines (HeLa, SiHa, A2780, MCF-7 and MDA-MB-231). A significant difference was observed in the antiproliferative activity between the regioisomers. Some compounds exerted outstanding activities against the malignant cells with limited action on fibroblasts, indicating considerable cancer selectivity.

In this paper, we present the design and synthesis of a novel series of pyrido[2,3-d]pyridazine-2,8-dione derivatives via the annulation of the 2-pyridone pattern. The synthesized derivatives were evaluated for in vivo anti-inflammatory activity using an ear edema model. Compound 7c, which showed a greater inhibition of ear edema (82%), was further tested for its in vitro COX-1/COX-2 inhibitory activity. Compound 7c showed similar inhibitory activities against COX-1 and COX-2 isoenzymes. The structural features that ensure the dual inhibition of COX-1 and COX-2 were elucidated using molecular docking studies. Overall, the ring closing of 2-pyridone pattern I transformed this highly selective COX-2 inhibitor into a dual COX inhibitor (7c), which could serve as a model for determining selectivity for COX-2.

Malaria eradication is still a global challenge due to the lack of a broadly effective vaccine and the emergence of drug resistance to most of the currently available drugs as part of the mainline artemisinin-based combination therapy. A variety of experimental approaches are quite successful in identifying and synthesizing new promising pharmacophore hybrids with distinct mechanisms of action. Based on our recent findings, the current study demonstrates the reinvestigation of a series of diphenylmethylpiperazine and pyrazine-derived molecular hybrids. Pyrazine-derived molecular hybrids were screened to investigate the antiplasmodial activity on drug-susceptible Pf3D7 and drug-resistant PfW2 strains. The selected compounds were shown to be potent dual inhibitors of cysteine protease PfFP2 and PfFP3. Time-course parasitic development study demonstrated that compounds were able to arrest the growth of the parasite at the early trophozoite stage. The compounds did not show hemolysis of red blood cells and showed selectivity to the parasite compared with the mammalian Vero and A5489 cell lines. The study underlined HR5 and HR15 as a new class of Plasmodial falcipain inhibitors with an IC₅₀ of 6.2 μM and 5.9 μM for PfFP2 and 6.8 μM and 6.4 μM for PfFP3, respectively. Both compounds have antimalarial efficacy with IC₅₀ values of 3.05 μM and 2.80 μM for the Pf3D7 strain, and 4.35 μM and 3.39 μM for the PfW2 strain, respectively. Further structural optimization may turn them into potential Plasmodial falcipain inhibitors for malaria therapeutics.