Current Topics in Medicinal Chemistry - Volume 22, Issue 25, 2022

Background: Diabetes mellitus (DM) is a critical health issue prevailing in nearly half a billion people worldwide. It is one of the most threatening metabolic diseases. Type 2 DM is caused due to insulin resistance and accounts for 90% of diabetes cases. If it remains untreated, it can lead to major frightening complications and can cause death, which ultimately threatens humankind. Discussion: Various oral hypoglycaemic drugs are available today, acting on different targets by adopting different pathways. However, the α-glucosidase inhibitors proved to be a novel and effective strategy to manage T2DM. These inhibitors alleviate postprandial glycemia by aiming to inhibit intestinal α-glucosidase competitively and reversibly, thus delaying carbohydrate digestion and turning down the rate of glucose absorption. Plenty of α-glucosidase inhibitors have been discovered from synthetic routes as well as from natural sources, including plants, fungi, and bacteria. Conclusion: This article comprises the natural and synthetic α-glucosidase discovered from 2016 to 2021 and can be utilized to discover novel α-glucosidase inhibitors. This review is an endeavor to highlight the progress in the discovery and development of α-glucosidase inhibitors, which could provide an overview to the medicinal chemists for the development of clinically viable drugs using this information.

Naphthoquinone is a heterocyclic moiety whose natural derivatives are present as bioactive compounds in many plants and have stimulated a resurgence of interest in the past decades due to their wide range of pharmacological activities. Naphthoquinone agents have dynamic pharmacophores and privileged sub-structures in the chemistry of medicine. They have received much interest in drug discovery as trypanocidal because naphthoquinone and their derivatives revealed massive significance potential against the trypanosomes. Among natural naphthoquinones, lapachol, β-lapachone and its α-isomer exhibited useful trypanocidal activities. Some naphthoquinones have already been used commercially as an antiparasitic agent. Several naphthoquinones with diverse structural motifs have been synthesized and evaluated mainly against Trypanosoma cruzi and some studies have also been reported against Trypanosoma brucei and Trypanosoma evansi. This review summarized various mechanisms of action of naphthoquinone like reductive activation of quinone by the production of the semiquinone, generation of reactive oxygen species and free radicals such as superoxide anion radical and H2O2, and oxidative stress in the parasite. The information assembled in this review will help to understand the mechanism behind the activity and may also be useful to find the bio-efficacy of naphthoquinone compounds upon substitution against trypanosomatids.

Background: Indoleamine 2,3-dioxygenase (IDO) activity is induced by cellular immune activation and therefore associated with inflammatory diseases, among others psychiatric disorders. This review aims to elucidate IDO activity reflected by kynurenine (KYN) to tryptophan (TRP) ratio in severe mental disorders. Methods: A systematic literature search in MEDLINE and EMBASE was conducted targeting clinical trials in English language measuring KYN/TRP in individuals with a diagnosis of depression, bipolar disorder, or schizophrenia. Results: Five out of 15 studies found higher levels of KYN/TRP in depression compared to a control group while the same amount found no difference. Moreover, three studies showed lower levels. In bipolar disorder, four out of six, and in psychotic disorders, three out of four trials found higher levels in patients compared to controls. There are only two studies comparing KYN/TRP in major depression and bipolar disorder, showing conflicting results. Eight studies focused on associations between KYN/TRP and clinical parameters, whereas two studies found positive correlations between KYN/TRP and severity of depressive symptoms. In contrast, four studies did not show an association. IDO activity during specific psychiatric treatment was analyzed by eight studies. Conclusion: In summary, this review demonstrates an inconsistency in the findings of studies investigating KYN/TRP in severe mental disorders. Although there are hints that inflammation associated with TRP catabolism towards the KYN pathway via elevated IDO activity seems likely, no conclusive statements can be drawn. Presumably, the consideration of influencing factors such as inflammatory processes, metabolic activities and psychological/neuropsychiatric symptoms are pivotal for a deeper understanding of the underlying mechanisms.

Background: The increased degradation of tryptophan (Trp) along the kynurenine (Kyn) pathway due to inflammation and/or activation of the hypothalamic-pituitary–adrenal (HPA) axis has been reported among the biological factors involved in the pathophysiology of major depressive disorder (MDD) and suicide. However, the interaction among these multiple factors is not yet completely clarified. Methods: We studied plasma levels of Trp, Kyn, cortisol and proinflammatory cytokines (IL-1, IL- 6, IL-12, IL-20) and calculated the ratio Kyn/Trp as an index of the breakdown of Trp into Kyn in 31 suicidal MDD patients and 67 non-suicidal MDD patients. Result: We confirmed that suicidal MDD patients have reduced plasma Trp, higher Kyn and Kyn/Trp ratio, and no difference in cortisol levels than non-suicidal MDD patients. IL-1 and IL-12 levels were significantly higher in suicidal MDD than in non-suicidal MDD (p=0.034 and p=0.023, respectively), whereas Il-6 and IL-20 levels were equal in the two groups. The Kyn/Trp ratio was positively correlated with a pro-inflammatory cytokines index (r=0.309, p=0.002) and cortisol (r=0.368, p=0.001). Notably, the variance in the Kyn/Trp ratio explained by the model including both cortisol and inflammatory parameters as dependent variables, substantially improved compared with the models in which the two parameters were considered separately. Conclusion: These findings show that both cortisol and proinflammatory cytokines are involved in the enhanced breakdown of Trp into Kyn occurring in suicidal MDD patients, thus adding new knowledge on the biological mechanisms leading to the activation of the Kyn pathway in MDD and suicide.

Background: Immune activation or high levels of stress may lead to increased metabolism of tryptophan during pregnancy. Porphyromonas gingivalis (Pg), the “keystone” periodontal pathogen, induces immune and indoleamine 2,3-dioxygenase (IDO) activation. Thus, we hypothesized that larger gestational decreases in tryptophan and elevations in neopterin and kynurenine would occur in pregnant women with elevated IgG antibodies to Pg capsular (K) serotypes. Methods: Venous blood of 52 Hispanic pregnant women with a mean age (SD) of 31.8 (5.9) years was sampled once per trimester of pregnancy (V1, V2, V3), and plasma was obtained and stored. ELISAs were used to measure Pg capsular (K) serotype IgG serointensity (V1 only) and neopterin levels (V1-V3). Tryptophan and kynurenine (V1-V3) were measured with high-performance liquid chromatography. The participants having IgG serointensity for any of the seven Pg K serotypes in the highest quartile were defined as the “High PgK_IgG” group and those having IgG serointensity for all K serotypes in the lowest three quartiles were defined as the “Low PgK_IgG” group. Statistics included multivariable linear and nonparametric methods. Results: Significant decreases in plasma tryptophan levels and increases in neopterin during gestation were found in “High PgK_IgG” women but not in “Low PgK_IgG” women. Kynurenine changes were not significantly different between the two groups. Conclusion: If replicated in larger studies and further characterized clinically, radiologically, and microbiologically, our results may potentially lead to novel interventional targets, as well as the development of more complete prognostic and predictive interactive biomarkers for adverse obstetrical outcomes and peripartum depression, and their prevention.