11a

Particulate matter with diameter ≤2.5 μm particles (PM2.5) can trigger pulmonary inflammation and lung injury. However, there is still no specific and effective treatment. Lansiumamide B (LB) is a natural cis-enamide compound isolated from wampee seeds, and has potential anti-inflammatory effect. Herein, two series of pyrazole enamide analogues were designed and synthesized based on the scaffold hopping strategy. The inhibition rates of inflammatory cytokines on compound 11a were superior to other compounds and exhibited good dose-dependent manner and safety. Mechanism studies shown that 11a activated the Keap1/Nrf2/HO-1 signaling pathway and promoted Nrf2 entering into nucleus. Further, 11a alleviated pulmonary inflammation, collagen formation and mucus secretion in PM2.5 induced lung injury mice. Besides, 11a administration inhibited M1 macrophage polarization and neutrophil infiltration. Overall, 11a is an effective anti-inflammatory agent which might be a potent candidate to treat lung injury.

New Biginelli adducts were rationalised, via the introduction of selected anti-tubercular (TB) pharmacophores into the dihydropyrimidine (DHPM) ring of deoxythymidine monophosphate (dTMP), the natural substrate of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt). Repurposing was one of the design rationale strategies for some selected mimics of the designed compounds. The anti-TB activity was screened against the Mtb H₃₇Rv strain where 11a was superior to ethambutol (EMB), and was 9-fold more potent than pyrazinamide (PZA). Additionally, compounds 11b, 4a, 4b, 13a, 13b and 14a elicited higher anti-TB activity than PZA, showing better safety profiles than EMB against RAW 264.7 cells' growth. The in vitro TMPKmt inhibition assay released compounds 11a, 11b and 13b as the most potent inhibitors. Docking studies presumed the binding modes and molecular dynamics (MD) simulation revealed the dynamic stability of 11a-TMPKmt complex over 100 ns. In silico prediction of the chemo-informatics properties of the most active compounds was conducted.