A racemic mixture results from classical chemical synthesis, barring the implementation of stereospecific methods. For single-enantiomeric drug development, asymmetric synthesis has risen to prominence in the realm of drug discovery. The hallmark of asymmetric synthesis is the conversion of an achiral initial material to a chiral final product. This review explores the various methods of synthesizing FDA-approved chiral drugs between 2016 and 2020. Particular attention is given to asymmetric syntheses employing chiral induction, resolution, or the chiral pool approach.
In chronic kidney disease (CKD), renin-angiotensin system (RAS) inhibitors and calcium channel blockers (CCBs) are frequently combined therapeutically. By examining the PubMed, EMBASE, and Cochrane Library databases, randomized controlled trials (RCTs) were located to investigate the potential of improved CCB subtypes for treating CKD. A comprehensive meta-analysis of 12 randomized controlled trials (RCTs) involving 967 CKD patients treated with RAS inhibitors reveals a significant advantage of N-/T-type CCBs over L-type CCBs in reducing urine albumin/protein excretion (SMD, -0.41; 95% CI, -0.64 to -0.18; p < 0.0001) and aldosterone, without affecting serum creatinine (WMD, -0.364; 95% CI, -1.163 to 0.435; p = 0.037). Notably, glomerular filtration rate (SMD, 0.006; 95% CI, -0.013 to 0.025; p = 0.053) and adverse effects (RR, 0.95; 95% CI, 0.35 to 2.58; p = 0.093) remained unchanged. The study found no difference in systolic blood pressure (BP) (weighted mean difference, 0.17; 95% confidence interval, -10.5 to 13.9; p = 0.79) or diastolic BP (weighted mean difference, 0.64; 95% confidence interval, -0.55 to 1.83; p = 0.29) between N-/T-type and L-type calcium channel blockers (CCBs). In chronic kidney disease patients receiving renin-angiotensin system inhibitors, the use of non-dihydropyridine calcium channel blockers leads to a greater reduction in urine albumin/protein excretion compared to dihydropyridine calcium channel blockers without concomitant rises in serum creatinine, decreases in glomerular filtration rate, or increases in adverse effects. Separately from blood pressure, this added advantage could be correlated with decreased aldosterone, evidenced by the PROSPERO study (CRD42020197560).
Due to its dose-limiting nephrotoxicity, cisplatin, an antineoplastic agent, is carefully administered. Cp-induced kidney damage is recognized by the synergistic interplay of oxidative stress, inflammation, and apoptosis. Acute kidney injuries are significantly associated with the inflammatory response triggered by the pattern recognition receptors toll-like receptor 4 (TLR4) and NLRP3 inflammasome, alongside gasdermin (GSDMD). N-acetylcysteine (NAC) and chlorogenic acid (CGA) demonstrate kidney-protective effects through the suppression of oxidative and inflammatory mechanisms. see more Consequently, this study sought to examine the role of elevated TLR4/inflammasome/gasdermin signaling in Cp-induced kidney damage, along with the potential impact of NAC or CGA on modulating this pathway.
One Wistar rat received a single injection of Cp, dosed at 7 mg/kg, through the intraperitoneal route. Prior to and subsequent to the Cp injection, rats received either NAC (250 mg/kg, per os) or CGA (20 mg/kg, per os), or both, administered one week apart.
Cp-induced acute kidney damage was characterized by a rise in blood urea nitrogen and serum creatinine, coupled with discernible histopathological injury. Kidney tissue inflammation, evidenced by increased lipid peroxidation, reduced antioxidant levels, and elevated inflammatory mediators (NF-κB and TNF-), was associated with nephrotoxicity. Subsequently, Cp upregulated the TLR4/NLPR3/interleukin-1 beta (IL-1) and caspase-1/GSDMD pathways, presenting a concomitant rise in the Bax/BCL-2 ratio, suggesting an inflammatory basis for apoptosis. see more Significant correction of these changes was observed with both NAC and/or CGA.
Inhibition of TLR4/NLPR3/IL-1/GSDMD signaling may represent a novel mechanism through which NAC or CGA provide nephroprotection against Cp-induced toxicity in rats, as indicated by this study.
A potential novel pathway for the nephroprotective effects of NAC or CGA in rats against Cp-induced nephrotoxicity is the inhibition of the TLR4/NLPR3/IL-1/GSDMD inflammatory response, as this study demonstrates.
Although 2022 witnessed a low count of 37 newly approved drug entities, marking the lowest since 2016, the TIDES category still held a firm position, achieving five authorizations. This included four peptide drugs and one oligonucleotide drug. Remarkably, 23 of the 37 medications were novel, earning expedited FDA designations like breakthrough therapy, priority review voucher, orphan drug, accelerated approval, and more. see more The 2022 TIDES approvals are examined here, with a consideration of their chemical structures, the diseases they target, how they work, how they are administered, and their usual negative side effects.
Mycobacterium tuberculosis, the bacterium responsible for tuberculosis, leads to 15 million deaths annually, with a parallel increase in the number of bacteria exhibiting resistance to standard treatments. This fact emphasizes the requirement for discovering molecules that intervene in new molecular pathways of M. tuberculosis. Mycolic acids, exceptionally long-chain fatty acids vital for the survival of Mycobacterium tuberculosis, are produced by two types of fatty acid synthase systems. The FAS-II pathway is profoundly reliant on MabA (FabG1), a fundamental enzyme. The recent report from our team details the discovery of anthranilic acids, which act as inhibitors for MabA. This work addressed the structure-activity relationships based on the anthranilic acid core, focusing on the fluorinated analog's binding to MabA using NMR, alongside an investigation of their physico-chemical properties and antimycobacterial activity. In further examining the mechanisms through which these bacterio compounds act, we found that they target other mycobacterial components besides MabA, and their efficacy against tuberculosis is attributable to their carboxylic acid functionality which produces an intrabacterial acidification.
Parasitic infections, causing considerable morbidity and suffering worldwide, have faced significant hurdles in vaccine development in comparison to the comparatively quicker advancement of vaccines for viral and bacterial diseases. The development of a parasite vaccine has been hampered by a lack of strategies that can induce the sophisticated and multifaceted immune responses required to overcome the persistent nature of parasitic infections. Complex disease targets, such as HIV, tuberculosis, and parasitic ailments, are finding potential solutions in the form of adenovirus vectors and similar viral vectors. AdVs are exceptionally immunogenic and specifically stimulate CD8+ T cell responses, which are characteristic markers of immunity during infections caused by most protozoan parasites and a number of helminthic species. This paper provides an overview of current advancements in AdV-vectored vaccine strategies, focusing on their use against five prominent parasitic diseases affecting humans: malaria, Chagas disease, schistosomiasis, leishmaniasis, and toxoplasmosis. Multiple vaccines, reliant on AdV vectors and employing a wide assortment of antigens and delivery approaches, have been created to combat these diseases. Human parasitic diseases, a historically difficult challenge, may find a promising solution in vector-vectored vaccines.
Derivatives of chromene, attached to indole, were synthesized in a single vessel reaction incorporating N-alkyl-1H-indole-3-carbaldehydes, 55-dimethylcyclohexane-13-dione, and malononitrile, facilitated by DBU at 60-65°C, within a brief reaction period. Non-toxicity, a simple setup, rapid reaction speeds, and high yields are among the methodology's strengths. Additionally, the synthesized compounds' capacity to combat cancer was assessed using a selection of cancer cell lines. 4c and 4d derivatives exhibited superior cytotoxic properties, with IC50 values ranging between 79 and 91 µM. Molecular docking demonstrated their enhanced affinity for tubulin protein compared to the control, and molecular dynamics simulations validated the stability of these ligand-receptor complexes. Ultimately, the derivatives, correspondingly, conformed to all the drug-likeness filters.
The fatal and devastating outcome of Ebola virus disease (EVD) compels the search for potent biotherapeutic molecules. This review aims to offer insights into enhancing existing Ebola virus (EBOV) research by exploring the application of machine learning (ML) techniques in predicting small molecule inhibitors of EBOV. Anti-EBOV compound prediction has leveraged a variety of machine learning techniques, encompassing Bayesian approaches, support vector machines, and random forest models, resulting in strong predictive models with reliable outcomes. Deep learning models' application to predicting anti-EBOV molecules is insufficiently exploited; hence, this paper explores their capability to build efficient, robust, novel, and rapid algorithms to support the identification of anti-EBOV drugs. The use of deep neural networks as a likely machine learning model for the prediction of anti-EBOV compounds is examined more closely. We additionally synthesize the abundance of data sources instrumental in machine learning predictions, formulated as a systematic and comprehensive high-dimensional dataset. The persistent commitment to eradicating EVD is bolstered by the integration of artificial intelligence-powered machine learning in EBOV drug discovery research, leading to data-informed decision-making and potentially reducing the high attrition rate of drug compounds.
Alprazolam (ALP), a benzodiazepine (BDZ) frequently prescribed for the alleviation of anxiety, panic, and sleep disturbances, stands as a globally prominent psychotropic medication. ALP's long-term (mis)use has led to substantial side effects posing a serious challenge to pharmacotherapy, driving the imperative to delve deeper into their underlying molecular processes.