New sets of ibuprofen and indomethacin conjugates comprising triazolyl heterocycle were synthesized via click chemistry, adopting an optimized protocol through the molecular hybridization approach affording the targeted agents in good yields. The new non-steroidal anti-inflammatory drug (NSAID) conjugates were designed and synthesized and could be considered as potential drug candidates for the treatment of pain and inflammation. The anti-inflammatory properties were investigated for all the synthesized conjugates. Among 14 synthesized conjugates, four (5a, 5b, 5d, and 5e) were found to have significant anti-inflammatory properties potency 117.6%, 116.5%, 93.8%, and 109.1% in comparison to reference drugs ibuprofen (97.2%) and indomethacin (100%) in the rat paw edema carrageenan test without any ulcerogenic liability. The suppression effect of cytokines IL-6, TNF-α, and iNOS in addition to NO in the LPS-induced RAW264.7 cells supports the promising anti-inflammatory properties observed in the ibuprofen conjugates. In addition, several conjugates showed promising peripheral and central analgesic activity. The selectivity index (SI) of compound 5a (23.096) indicates the significant efficacy and selectivity for COX-2 over COX-1. Molecular modeling (docking and QSAR) studies described the observed biological properties.

Background: Benzimidazole, a fused heterocyclic compound, has emerged as a privileged structure in medicinal chemistry due to its broad spectrum of biological activities, particularly in antimicrobial and antitubercular (anti-TB) applications. Its structural ingenuity allows for diverse substitutions at key positions, facilitating interactions with various biological targets such as bacterial enzymes and nucleic acids. Main body. Benzimidazole derivatives have demonstrated potent activity against a wide range of Gram-positive and Gram-negative bacteria, as well as against Mycobacterium tuberculosis, including drug-resistant strains. The pharmacophoric features of benzimidazole contribute to its ability to inhibit vital microbial processes, including cell wall synthesis, DNA replication, and energy metabolism. Structural optimization of benzimidazole scaffold has led to the development of several lead compounds with enhanced efficacy and pharmacokinetic profiles. Conclusion: This review highlights the significance of benzimidazole as a privileged scaffold in the development of novel antimicrobial and anti-TB agents, emphasizing recent advances in structure–activity relationship (SAR) studies, and potential for future drug development.

Background: The increasing prevalence of drug resistance in cancer therapy underscores the urgent need for novel therapeutic approaches. Dual enzyme inhibitors, targeting critical kinases such as CDK2 and TRKA, represent a promising strategy. The goal of this investigation was to design, synthesize, and evaluate a set of pyrazolo[1,5-a]pyrimidine derivatives for their dual inhibition potential toward CDK2 and TRKA kinases, along with their potential antiproliferative against cancer cell lines. Methods: A set of pyrazolo[1,5-a]pyrimidine derivatives (6a–t, 11a–g, and 12) was synthesized and subjected to in vitro enzymatic assays to determine their inhibitory activity against CDK2 and TRKA kinases. Selected compounds were further assessed for antiproliferative effects across the set of 60 cell lines from the NCI, representing various human cancer types. Additionally, simulations of molecular docking were conducted to explore the modes of binding for the whole active compounds and compare them with known inhibitors. Results: Compounds 6t and 6s exhibited potent dual inhibitory activity, showing an IC₅₀ = 0.09 µM and 0.23 µM against CDK2, and 0.45 µM against TRKA, respectively. These results were comparable to reference inhibitors ribociclib (CDK2, IC₅₀ = 0.07 µM) and larotrectinib (TRKA, IC₅₀ = 0.07 µM). Among the studied derivatives, compound 6n displayed a notable broad-spectrum anticancer activity, achieving a mean growth inhibition (GI%) of 43.9% across 56 cell lines. Molecular docking simulations revealed that the synthesized compounds adopt modes of binding similar to those of the lead inhibitors. Conclusions: In this study, prepared pyrazolo[1,5-a]pyrimidine derivatives demonstrated significant potential as dual CDK2/TRKA inhibitors, and showed potent anticancer activity toward diverse cancer cell lines. These findings highlight their potential as key compounds for the design of novel anticancer therapeutics.

Background: In continuation of a previous work concerned with the anticancer activity of some 8-alkyl-2,4-bisarylidene-8-nortropan-3-ones, this work focuses on further modification to the tropane/p... Graphical abstract