Diarylsulfonamides and their bioisosteres as dual inhibitors of alkaline phosphatase and carbonic anhydrase: Structure activity relationship and molecular modelling studies.

The effect of bioisosteric replacement of carboxamide linking group with sulfonamide linking group, on alkaline phosphatase (AP) and carbonic anhydrase (CA) inhibition activity of aromatic benzenesulfonamides was investigated. A series of carboxamide linked aromatic benzenesulfonamides 1a-1c, 2a-2d and their sulfonamide linked bioisosteres 3a-3d, 4a-4d was synthesized and evaluated for inhibitory activity against bovine tissue non-specific alkaline phosphatase (TNAP), intestinal alkaline phosphatase (IAP) and bCA II. A significant increase in CA inhibition activity was observed upon bioisosteric replacement of carboxamide linking group with a sulfonamide group. Some of these compounds were identified as highly potent and selective AP inhibitors. Compounds 1b, 2b, 3d, 4d 5b and 5c were found to be selective bTNAP inhibitors, whereas compounds 1a, 1c, 2a, 2c, 2d, 3a, 3c, 4a, 4b, 4c, 5a were found to be selective bIAP inhibitors. For most active AP inhibitor 3b, detailed kinetic studies indicated a competitive mode of inhibition against tissue non-specific alkaline phosphatase (TNAP) and non-competitive mode of inhibition against intestinal alkaline phosphatase (IAP). Molecular docking studies were carried out to rationalize important binding site interactions.

Leptin and adiponectin levels in major depressive disorder: A systematic review and meta-analysis.

OBJECTIVES: To explore differences in adipokine levels (i.e., leptin and adiponectin levels) between adults with Major Depressive Disorder (MDD) and healthy controls (HC), and to discuss the possible role of adipokine regulation in the development and progression of MDD. METHODS: A systematic review and meta-analysis were conducted based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. A systematic search was conducted for all English and Chinese peer-reviewed articles from inception to November 2017. A random effects model was used to calculate the standardized mean difference (SMD) of leptin and/or adiponectin levels in subjects diagnosed with MDD versus HC within a 95% confidence interval (CI). RESULTS: Thirty-three studies were included in this meta-analysis. In total, 4,372 (52.3%) subjects with MDD and 3,984 (47.7%) HC were compared. We identified significant lower adiponectin levels in MDD compared to HC with a small effect size (ES) (SMD = -0.25; 95% CI: -0.48, -0.02; P < 0.001). However, no significant difference was observed in leptin levels between MDD subjects and HC (SMD = 0.13; 95% CI: -0.06, 0.31; P = 0.170). The heterogeneity in the results of our meta-analysis could not be completely explained by dividing subjects into subgroups. Results from subgroup analyses suggested that studies involving samples with BMI ≥ 25 had lower adiponectin levels in subjects with MDD compared to HC, and older age samples (i.e., age ≥ 40) with BMI ≥ 25 had both higher leptin levels and lower adiponectin levels in MDD subjects as compared to HC. LIMITATIONS: The heterogeneity of included studies, small sample sizes, and potential publication bias were significant limitations. CONCLUSIONS: The current systematic review and meta-analysis indicated that lower adiponectin levels may be associated with MDD. Moreover, the results suggest that males expressing lower adiponectin and leptin levels have an increased likelihood of developing MDD. Future studies should aim to investigate the manifestation of depressive phenotypes in older, obese populations with altered metabolic profiles resulting from adipokine dysregulation. The review has been registered with PROSPERO (registration number CRD42018082733).