Three series of new imidazole‐fused imidazo[2,1‐b][1,3,4]thiadiazole analogues (compounds 20 a–g, 21 a–g, and 22 a–g) have been synthesized, and their antibacterial and antifungal activities have been evaluated. All the target compounds showed strong antifungal activity and high selectivity for the test fungus Candida albicans over Gram‐positive and ‐negative bacteria. N‐((4‐(2‐Cyclopropyl‐6‐(4‐fluorophenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)‐5‐(6‐methyl‐pyridin‐2‐yl)‐1H‐imidazol‐2‐yl)methyl)aniline (21 a) showed the highest activity against C. albicans (MIC50=0.16 μg/mL), 13 and three times that of the positive control compounds gatifloxacin and fluconazole, respectively. Compounds 21 a and 20 e did not show cytotoxicity against human foreskin fibroblast‐1 cells, and compound 21 a was as safe as the positive control compounds in hemolysis tests. These results strongly suggest that some of the compounds produced in this work have value for development as antifungal agents.

Pimpinellin is a coumarin-like compound extracted from the root of Toddalia asiatica. Its effects on platelet function has not been investigated. This study found that pimpinellin pretreatment effectively inhibited collagen-induced platelet aggregation, but did not alter ADP- and thrombin-induced aggregation. Platelets pretreated with pimpinellin showed reduced α granule (CD62) level and secretion of dense granule (ATP release). Pimpinellin-treated platelets also exhibited decreased clot reaction and TxB2 production. Pimpinellin pretreatment suppressed adhesion and spreading of human platelets on the fibrinogen coated surface. Analysis of tail bleeding time of mice administered with pimpinellin (40 mg/kg) revealed that pimpinellin did not change tail bleeding time significantly, number of blood cells, and APTT and PT levels. Pimpinellin inhibited collagen-induced ex vivo aggregation of mice platelets. Immunoblotting results showed that pimpinellin suppressed collagen-induced phosphorylation of PI3K-Akt-Gsk3β and PKC/MAPK in platelets.

Background: TGF-β signaling pathway inhibition is considered an effective way to prevent the development of several diseases. In the design and synthesis of TGF-β inhibitors, a rhodanine compound containing a quinoxalinyl imidazole moiety was found to have strong antimicrobial activity. Objective: The purpose of this work was to investigate the antimicrobial activity of other chiral rhodanine TGF-β inhibitors synthesized. Methods: Two series of 3-substituted-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalinyl-6-yl)- 1H-imidazol-2-yl)methylene)-2-thioxothiazolin-4-ones (12a–h and 13a–e) were synthesized and evaluated for their ALK5 inhibitory and antimicrobial activity. The structures were confirmed by their 1H NMR, 13C NMR, and HRMS spectra. All the synthesized compounds were screened against Gram-positive strains, Gram-negative strains, and fungi. Results: Among the synthesized compounds, compound 12h showed the highest activity (IC50 = 0.416 μM) against ALK5 kinase. Compound 12h exhibited a good selectivity index of > 24 against p38α MAP kinase and was 6.0-fold more selective than the clinical candidate, compound 2 (LY-2157299). Nearly all the compounds displayed high selectivity toward both Gram-positive and Gram-negative bacteria. They also showed similar or 2.0-fold greater antifungal activity (minimum inhibitory concentration [MIC] = 0.5 µg/mL) compared with the positive control compounds Gatifloxacin (MIC = 0.5 µg/mL) and fluconazole (MIC = 1 µg/mL). Conclusion: The findings suggest that the synthesized rhodanine compounds have good ALK5 inhibitory activity and can be used for further research and development as potential antifungal drugs.

Our previous studies using an Induction‐Delay‐Expression (IND‐DEL‐EXP) paradigm to study hypertensive response sensitization (HTRS) demonstrated that various challenges (stressors) including a subpressor dose of angiotensin (ANG) II given during IND, resulted in HTRS to a subsequent treatment with slow‐pressor dose of ANG II during EXP. The induction of HTRS is associated with upregulated expression of proinflammatory cytokines and the macrophage marker CD11b in the brain regions involved in blood pressure (BP) regulation including the lamina terminalis (LT) and paraventricular hypothalamic nucleus (PVN). In this study, we investigated whether brain macrophages are necessary for low‐dose ANG II‐induced HTRS. Depletion of brain macrophages was produced by feeding a colony‐stimulating factor 1 receptor (CSF1‐R) inhibitor, PLX3397 (75 mg/kg/d), beginning 1 week before starting IND and continuing the drug throughout the 1 week IND period. The results showed that in control condition, low‐dose ANG II (10 ng/kg/min) treatment during IND resulted in an enhanced hypertensive response to the subsequent slow‐pressor dose of ANG II (120 ng/kg/min) when compared to control animals with saline pretreatment during IND (Δ39.1±4.2 vs. Δ21.5±4.9 mmHg). Depletion of brain macrophages during IND slightly increased baseline BP, which came back after stopping feeding PLX3397 during DEL. However, the depletion of macrophages blocked HTRS induced by low‐dose ANG II given during IND (Δ25.8±4.3 mmHg). Immunohistochemistry confirmed the depletion of macrophages in the subfornical organ and PVN after feeding PLX3397. The results indicate that brain macrophages are necessary for the induction of HTRS.

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