One-pot synthesis of tetrahydropyrimidinecarboxamides enabling in vitro anticancer activity: 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.

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.

1,2,4-Triazole and benzimidazole fused dihydropyrimidine derivatives: Design, green synthesis, antibacterial, antitubercular, and antimalarial activities.

This study reports the design and synthesis of novel 1,2,4-triazolo/benzimidazolo-pyrimidine linked 1-benzyl-4-[(p-tolyloxy)methyl]-1,2,3-triazole derivatives as potent antimicrobial agents according to their in vitro antibacterial, antifungal, antitubercular as well as antimalarial activities. An efficient, ecologically benign, and facile multicomponent synthesis was employed to synthesize these derivatives. The synthesis is accelerated with the mild and eco-friendly organocatalyst tetrabutylammonium bromide, providing a yield of 82%-96% within the short reaction time of 0.5-1.5 h. Compared with the MIC values of ciprofloxacin and ampicillin on the respective strains, compound d2 showed better activity against Escherichia coli and Streptococcus pyogenes and compound d8 showed better MIC against Staphylococcus aureus. Additionally, compounds d3, d4, and d5 showed potent MIC values against Pseudomonas aeruginosa. All triazolo-pyrimidine derivatives d1-d8 showed potent inhibitory action against Gram-positive strains. Compound e3 showed good potency against Mycobacterium tuberculosis H37Rv. The IC50 values of d3 and e2 indicated better activity against Plasmodium falciparum. Collectively, these derivatives depict potent multifaceted activity and provide promising access for further antimicrobial and antimalarial investigations.

Simultaneous ultrasound- and microwave-assisted one-pot 'click' synthesis of 3-formyl-indole clubbed 1,2,3-triazole derivatives and their biological evaluation.

An environment friendly, high yielding, promising one-pot protocol for the click reaction of N-propargyl-3-formylindole 2(a-b), chloroacetic acid/ester 3(a-b) and sodium azide, leading to the formation of 3-formyl-indole clubbed 1,4-disubstituted-1,2,3-triazole derivatives 4(a-b), 5(a-b) and 6(a-f) aided by CuI catalyst accomplished under acceleration of simultaneous ultrasound and microwave irradiation in a very short reaction time has been described. Further, acid derivative 4(a-b) is subjected to acid-amine coupling reaction with secondary amine (p-t) in the presence of HATU to afford 6(p-t) and 7(p-t). The perspective of this protocol is to get rid of the hectic preparation and handling of organic azide which are generated in situ. Consequently, this protocol blossoms the click process by making it environment benign, user-friendly, safe and clean technique. All the synthesized compounds have been preliminarily screen for their in vitro antimicrobial activity against a panel of pathogenic strains. The majority of compounds possess noticeably inhibitory action against E. Coli, S. Typhi, P. Aeruginosa, C. tetani, S. aureus and B. subtillis. Among all compounds, 6p and 7q exhibit excellent inhibitory action against E.Coli and P. Aeruginosa strain, respectively, as compared to standard drug. One compound 5b shows remarkable potency against fungal strain. Molecular docking study was carried out to understand binding of compound with protein. In silico ADME prediction was carried out to check physicochemical properties of synthesized compound.