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.

Most of the FDA approved histone deacetylase inhibitors (HDACi) contain hydroxamate as the zinc binding group (ZBG). Hydroxamates form strong electrostatic metal chelation with divalent zinc present in HDAC. This strong zinc chelation leads to unwanted metabolic abnormalities. Therefore, the design of a non-hydroxamate moiety as a ZBG encourages medicinal chemistry researchers. Here, a series of nicotinamide derivatives have been designed and synthesized as HDACi. All compounds were tested for their inhibitory activities against pan HDACs (containing predominantly HDAC1 and HDAC2 isozymes) and against the HDAC3 isoform. Among these, compounds 6b and 6n showed comparable pan HDAC inhibitory activity (IC₅₀ = 4.648 μM and IC₅₀ = 5.481 μM, respectively) compared with BG45 (IC₅₀ = 5.506 μM). Compound 6b exhibited the best potency against HDAC3 with IC₅₀ = 0.694 μM. In addition, the anti-proliferative activity of the synthesized compounds 6a–s was evaluated against three different cancer cell lines including B16F10, MCF-7, and A549. Compound 6b displayed the highest anti-proliferative potency (IC₅₀ = 4.66 μM in B16F10 cell lines) and compounds 6b, 6c, 6h, 6i, 6l, 6m, and 6n exhibited higher cytotoxicity against all cell lines compared with the reference BG45. The selected potent compounds also displayed significant selectivity against cancer cell lines over normal human embryonic kidney (HEK-293) cell lines. The molecular modelling study displayed possible interactions between the most potent inhibitor 6b and HDAC3 active sites. Furthermore, the predicted in silico studies of all target compounds revealed acceptable physicochemical properties and pharmacokinetic parameters.

A series of diaryl imidazole derivatives (5a-h) was designed as novel selective COX-2 anti-inflammatory drug candidates. The designed compounds were synthesised, and their structures were characterized by spectroscopic analysis. The anticipated anti-inflammatory activity for the synthesized compounds was assessed by in-vitro cyclooxygenases (COX-1/COX-2) inhibition assay. Most of tested compounds demonstrated moderate COX-2 inhibitory activity and selectivity (IC50 = 0.068 – 0.80 µm, SI = 7.5 - 175) in comparison to indomethacin (IC50 = 0.079 µm, SI = 12.5) and celecoxib (IC50 = 0.046 µm, SI = 315.22). Molecular modelling study of the synthesized compounds into the active site of COX-2 enzyme was performed to rationalize their preferred binding affinity; except for compound 5f, all compounds showed binding with amino acids at the selectivity pocket Additionally, In-silico simulation studies explored the drug drug-likeness parameters of the synthesized compounds, all synthesized compounds exhibited promising physicochemical parameters and pharmacokinetics according to the in-silico simulation results.