One-pot two-step catalytic synthesis of 6-amino-2-pyridone-3,5-dicarbonitriles enabling anti-cancer bioactivity

We report a one-pot two-step synthesis of a bioactive 6-amino-2-pyridone-3,5-dicarbonitrile derivative using natural product catalysts betaine and guanidine carbonate. Anti-cancer bioactivity was observed in specific molecules within the library of 16 derivatives. Out of the compounds, 5o had the most potent anti-cancer activity against glioblastoma cells and was selected for further study. Compound 5o showed anti-cancer properties against liver, breast, lung cancers as well as primary patient-derived glioblastoma cell lines. Furthermore, 5o in combination with specific clinically relevant small molecule inhibitors induced enhanced cytotoxicity in glioblastoma cells. Through our current work, we establish a promising 6-amino-2-pyridone-3,5-dicarbonitrile based lead compound with anti-cancer activity either on its own or in combination with specific clinically relevant small molecule kinase and proteasome inhibitors

One-pot synthesis of tetrahydropyrimidinecarboxamides enabling <i>in vitro</i> anticancer activities:a combinative study with clinically relevant brain-penetrant drugs

In this study, we describe a one-pot three-component synthesis of bioactive tetrahydopyrimidinecarboxamide derivatives employing lanthanum triflate as a catalyst. Out of the synthesized compounds, 4f had the most potent anti-cancer activity and impeded cell cycle progression effectively. Anti-cancer bioactivity was observed in 4f against liver, breast, and lung cancers as well as primary patient-derived glioblastoma cell lines. Compound 4f effectively inhibited the 3D neurosphere formation in primary patient-derived glioma stem cells. Specifically, 4f exhibited synergistic cytotoxicity with the EGFR inhibitor that is the clinical epidermal growth factor receptor inhibitor osimertinib. 4f does not exhibit anti-kinase activity and is cytostatic in nature, and further work is needed to understand the true molecular target of 4f and its derivatives. Through our current work, we establish a promising tetrahydopyrimidinecarboxamide-based lead compound with anti-cancer activity, which may exhibit potent anti-cancer activity in combination with specific clinically relevant small molecule kinase inhibitors

Click-chemistry mediated synthesis of OTBN-1,2,3-Triazole derivatives exhibiting STK33 inhibition with diverse anti-cancer activities

There is a continuous and pressing need to establish new brain-penetrant bioactive compounds with anti-cancer properties. To this end, a new series of 4′-((4-substituted-4,5-dihydro-1H-1,2,3-triazol-1-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile (OTBN-1,2,3-triazole) derivatives were synthesized by click chemistry. The series of bioactive compounds were designed and synthesized from diverse alkynes and N3-OTBN, using copper (II) acetate monohydrate in aqueous dimethylformamide at room temperature. Besides being highly cost-effective and significantly reducing synthesis, the reaction yielded 91–98 % of the target products without the need of any additional steps or chromatographic techniques. Two analogues exhibit promising anti-cancer biological activities. Analogue 4l shows highly specific cytostatic activity against lung cancer cells, while analogue 4k exhibits pan-cancer anti-growth activity. A kinase screen suggests compound 4k has single-digit micromolar activity against kinase STK33. High STK33 RNA expression correlates strongly with poorer patient outcomes in both adult and pediatric glioma. Compound 4k potently inhibits cell proliferation, invasion, and 3D neurosphere formation in primary patient-derived glioma cell lines. The observed anti-cancer activity is enhanced in combination with specific clinically relevant small molecule inhibitors. Herein we establish a novel biochemical kinase inhibitory function for click-chemistry-derived OTBN-1,2,3-triazole analogues and further report their anti-cancer activity in vitro for the first time

Click-chemistry mediated synthesis of OTBN-1,2,3-Triazole derivatives exhibiting STK33 inhibition with diverse anti-cancer activities

There is a continuous and pressing need to establish new brain-penetrant bioactive compounds with anti-cancer properties. To this end, a new series of 4′-((4-substituted-4,5-dihydro-1H-1,2,3-triazol-1-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile (OTBN-1,2,3-triazole) derivatives were synthesized by click chemistry. The series of bioactive compounds were designed and synthesized from diverse alkynes and N3-OTBN, using copper (II) acetate monohydrate in aqueous dimethylformamide at room temperature. Besides being highly cost-effective and significantly reducing synthesis, the reaction yielded 91–98 % of the target products without the need of any additional steps or chromatographic techniques. Two analogues exhibit promising anti-cancer biological activities. Analogue 4l shows highly specific cytostatic activity against lung cancer cells, while analogue 4k exhibits pan-cancer anti-growth activity. A kinase screen suggests compound 4k has single-digit micromolar activity against kinase STK33. High STK33 RNA expression correlates strongly with poorer patient outcomes in both adult and pediatric glioma. Compound 4k potently inhibits cell proliferation, invasion, and 3D neurosphere formation in primary patient-derived glioma cell lines. The observed anti-cancer activity is enhanced in combination with specific clinically relevant small molecule inhibitors. Herein we establish a novel biochemical kinase inhibitory function for click-chemistry-derived OTBN-1,2,3-triazole analogues and further report their anti-cancer activity in vitro for the first time

A green bio-organic catalyst (taurine) promoted one-pot synthesis of (R/S)-2-thioxo-3,4-dihydropyrimidine(TDHPM)-5-carboxanilides: chiral investigations using circular dichroism and validation by computational approaches

Owing to the massive importance of dihydropyrimidine (DHPMs) scaffolds in the pharmaceutical industry and other areas, we developed an effective and sustainable one-pot reaction protocol for the synthesis of (R/S)-2-thioxo-DHPM-5-carboxanilides via the Biginelli-type cyclo-condensation reaction of aryl aldehydes, thiourea and various acetoacetanilide derivatives in ethanol at 100 °C. In this protocol, taurine was used as a green and reusable bio-organic catalyst. Twenty-three novel derivatives of (R/S)-TDHPM-5-carboxanilides and their structures were confirmed by various spectroscopy techniques. The aforementioned compounds were synthesized via the formation of one asymmetric centre, one new C–C bond, and two new C–N bonds in the final product. All the newly synthesized compounds were obtained in their racemic form with up to 99% yield. In addition, the separation of the racemic mixture of all the newly synthesized compounds was carried out by chiral HPLC (Prep LC), which provided up to 99.99% purity. The absolute configuration of all the enantiomerically pure isomers was determined using a circular dichroism study and validated by a computational approach. With up to 99% yield of 4d, this one-pot synthetic approach can also be useful for large-scale industrial production. One of the separated isomers (4R)-(+)-4S developed as a single crystal, and it was found that this crystal structure was orthorhombic

A green bio-organic catalyst (taurine) promoted one-pot synthesis of (R/S)-2-thioxo-3,4-dihydropyrimidine(TDHPM)-5-carboxanilides: chiral investigations using circular dichroism and validation by computational approaches

Owing to the massive importance of dihydropyrimidine (DHPMs) scaffolds in the pharmaceutical industry and other areas, we developed an effective and sustainable one-pot reaction protocol for the synthesis of (R/S)-2-thioxo-DHPM-5-carboxanilides via the Biginelli-type cyclo-condensation reaction of aryl aldehydes, thiourea and various acetoacetanilide derivatives in ethanol at 100 °C. In this protocol, taurine was used as a green and reusable bio-organic catalyst. Twenty-three novel derivatives of (R/S)-TDHPM-5-carboxanilides and their structures were confirmed by various spectroscopy techniques. The aforementioned compounds were synthesized via the formation of one asymmetric centre, one new C–C bond, and two new C–N bonds in the final product. All the newly synthesized compounds were obtained in their racemic form with up to 99% yield. In addition, the separation of the racemic mixture of all the newly synthesized compounds was carried out by chiral HPLC (Prep LC), which provided up to 99.99% purity. The absolute configuration of all the enantiomerically pure isomers was determined using a circular dichroism study and validated by a computational approach. With up to 99% yield of 4d, this one-pot synthetic approach can also be useful for large-scale industrial production. One of the separated isomers (4R)-(+)-4S developed as a single crystal, and it was found that this crystal structure was orthorhombic

One-Pot Two-Step Catalytic Synthesis of Rationally Designed 6-amino-2-pyridone-3,5-dicarbonitriles Enabling Anti-Cancer Bioactivity

Herein we report a one-pot two-step synthesis of a bioactive 6-amino-2-pyridone-3,5-dicarbonitrile derivative using natural product catalysts betaine and guanidine carbonate. Upon identification of the anticancer bioactivity of the compound, we carried out structure-activity relationship and rationally designed a library of 16 derivatives. Out of the compounds, 5o had the most potent anti-cancer activity against murine glioblastoma cell lines and was selected for further study. Compound 5o showed anti-cancer properties against liver, breast, lung as well as primary patient-derived glioblastoma cell lines. Furthermore, 5o in combination with specific clinically relevant brain-penetrant small molecule inhibitors induces enhanced cytotoxicity in a murine glioblastoma cell line. Through our current work, we establish a promising 6-amino-2-pyridone-3,5-dicarbonitrile based lead compound with anti-cancer activity either on its own or in combination with specific clinically relevant small molecule kinase and proteasome inhibitors

Indole clubbed 2,4-thiazolidinedione linked 1,2,3-triazole as a potent antimalarial and antibacterial agent against drug-resistant strain and molecular modeling studies

In the face of escalating challenges of microbial resistance strains, this study describes the design and synthesis of 5-({1-[(1H-1,2,3-triazol-4-yl)methyl]-1H-indol-3-yl}methylene)thiazolidine-2,4-dione derivatives, which have demonstrated significant antimicrobial properties. Compared with the minimum inhibitory concentrations (MIC) values of ciprofloxacin on the respective strains, compounds 5a, 5d, 5g, 5l, and 5m exhibited potent antibacterial activity with MIC values ranging from 16 to 25 µM. Almost all the synthesized compounds showed lower MIC compared to standards against vancomycin-resistant enterococcus and methicillin-resistant Staphylococcus aureus strains. Additionally, the majority of the synthesized compounds demonstrated remarkable antifungal activity, against Candida albicans and Aspergillus niger, as compared to nystatin, griseofulvin, and fluconazole. Furthermore, the majority of compounds exhibited notable inhibitory effects against the Plasmodium falciparum strain, having IC50 values ranging from 1.31 to 2.79 μM as compared to standard quinine (2.71 μM). Cytotoxicity evaluation of compounds 5a–q on SHSY-5Y cells at up to 100 μg/mL showed no adverse effects. Comparison with control groups highlights their noncytotoxic characteristics. Molecular docking confirmed compound binding to target active sites, with stable protein–ligand complexes displaying drug-like molecules. Molecular dynamics simulations revealed dynamic stability and interactions. Rigorous tests and molecular modeling unveil the effectiveness of the compounds against drug-resistant microbes, providing hope for new antimicrobial compounds with potential safety