A guide for the synthesis of key nucleoside scaffolds in drug discovery
AbstractThis review aims to provide an overview of the synthetic strategies employed for generating modifications within the sugar backbone of nucleoside analogs. We have focused our discussions on the more popular scaffolds seen in medicinal chemistry including modifications to ribose-based nucleosides and 4 ʹ-thionucleosides. Importantly, the syntheses of emerging nucleoside chemotypes from recent patent literature are also discussed. We believe a detailed review centered in this critical area of research may help identify unsolved synthetic challenges and inspire the development of new methods for ex panding the access...
Source: Medicinal Chemistry Research - July 1, 2023 Category: Chemistry Source Type: research
Structure-based optimization of aminothiadiazole inhibitors of AKT
We report here the discovery and structure-guided optimization of a novel series of AKT kinase inhibitors. Based on docking studies for the predicted active bound-conformation of2, a potent series ofN-substituted-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amines was developed. Compounds in the series achieve AKT pathway inhibition in cancer cells, as measured by inhibition of pathway proteins pGSK and pFKHR. Compound12 was further evaluated in a single dose PK/PD in vivo study in tumor-bearing mice and demonstrated inhibition of phosphorylation of the direct substrate GSK and pathway biomarker S6. (Source: Medicinal Chemistry Research)
Source: Medicinal Chemistry Research - July 1, 2023 Category: Chemistry Source Type: research
Successes in antiviral drug discovery: a tribute to Nick Meanwell
AbstractDrug discovery is a difficult task, and is even more challenging when the target evolves during therapy. Antiviral drug therapy is an excellent example, exemplified by the evolution of therapeutic approaches for treatment of hepatitis C and HIV-1. Nick Meanwell and his colleagues made important contributions leading to molecules for treatment of hepatitis C and HIV-1, each with distinct mechanisms of action. This review summarizes the discovery and impact of these drugs, and will highlight, where applicable, the broader contributions of these discoveries to medicinal chemistry and drug discovery. (Source: Medicinal Chemistry Research)
Source: Medicinal Chemistry Research - July 1, 2023 Category: Chemistry Source Type: research
Acyl glucuronides –mediators of drug-induced toxicities?
AbstractThe role of acyl glucuronide (AG) metabolites as mediators of drug-induced toxicities remains controversial, in part due to difficulties in studying this group of reactive drug conjugates. Confounding factors include the bioactivation of carboxylic acid drugs by alternative pathways, AG-mediated inhibition of key enzymes and transporters, and unanticipated interactions with several biological systems. These issues, together with the inherent instability of AGs under physiological conditions, have led to significant challenges in assessing the human safety of AGs according to current regulatory guidances. Despite im...
Source: Medicinal Chemistry Research - July 1, 2023 Category: Chemistry Source Type: research
Discovery of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of adaptor protein 2-associated kinase 1 for the treatment of pain
AbstractAdaptor protein 2-associated kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases and plays a role in modulating receptor endocytosis. AAK1 was identified as a potential therapeutic target for the treatment of neuropathic pain when it was shown that AAK1 knock out (KO) mice had a normal response to the acute pain phase of the mouse formalin model, but a reduced response to the persistent pain phase. Herein we report our early work investigating a series of pyrrolo[2,1-f][1,2,4]triazines as part of our efforts to recapitulate this KO phenotype with a potent, small molecule inhibitor of AAK...
Source: Medicinal Chemistry Research - July 1, 2023 Category: Chemistry Source Type: research
Future challenges and opportunities with fluorine in drugs?
(Source: Medicinal Chemistry Research)
Source: Medicinal Chemistry Research - July 1, 2023 Category: Chemistry Source Type: research
Special issue of Medicinal Chemistry Research in honor of Dr. Nicholas A. Meanwell
(Source: Medicinal Chemistry Research)
Source: Medicinal Chemistry Research - July 1, 2023 Category: Chemistry Source Type: research
Carboxylated chalcones and related flavonoids as inhibitors of xanthine oxidase
AbstractCarboxylated chalcones and other related flavonoids were synthesized and evaluated as inhibitors of xanthine oxidase, which is a known target for synthetic and herbal drugs used against hyperuricemia, gout, and other diseases. The 4-carboxylated chalcones with hydroxy, methoxy, and ethoxy groups at ring A were found to exhibit in vitro inhibitory activities with IC50 values in the range of 0.057 to 0.26 μM, being 10–60-fold more potent than allopurinol. Structurally related carboxylic acids with Δ3,9-homoisoflavonoid and flavone scaffolds also showed micromolar activity towards xanthine oxidase. At the same ...
Source: Medicinal Chemistry Research - June 28, 2023 Category: Chemistry Source Type: research
Pharmacophore variants of the macrocyclic peptide triazole inactivator of HIV-1 Env
AbstractPreviously we established a family of macrocyclic peptide triazoles (cPTs) that inactivate the Env protein complex of HIV-1, and identified the pharmacophore that engages Env ’s receptor binding pocket. Here, we examined the hypothesis that the side chains of both components of the triazole Pro - Trp segment of cPT pharmacophore work in tandem to make intimate contacts with two proximal subsites of the overall CD4 binding site of gp120 to stabilize binding and function . Variations of the triazole Pro R group, which previously had been significantly optimized, led to identification of a derivative, MG-II-20, cont...
Source: Medicinal Chemistry Research - June 27, 2023 Category: Chemistry Source Type: research
Targeting MDM2 for the development of a new cancer therapy: progress and challenges
AbstractFor much of the past 20 years, MDM2 has been pursued as a cancer therapeutic target. Small molecule inhibitors that block the MDM2-p53 protein-protein interaction (MDM2 inhibitors) have been developed and a number of them have been evaluated in clinical trials for cancer treatment. Notwithstanding various setbacks, several MDM2 inhibitors have now progressed into late-stage clinical development. New strategies have also been developed to enhance the efficacy of MDM2 inhibitors and to mitigate their on-target toxicity. In this review, we summarize the progress and challenges in the development of a MDM2 targeted the...
Source: Medicinal Chemistry Research - June 23, 2023 Category: Chemistry Source Type: research
From the ethnomedicinal plants in northern Indochina to the development of novel anti-cancer therapeutic agents
This article summarizes and exemplifies the plants used in ethnopharmacology for complementary cancer treatment based on the historical wisdom of 10 ethnic groups residing in northern Indochina. Additionally, the major active components with anti-cancer mechanisms are also elucidated and discussed.Graphical Abstract (Source: Medicinal Chemistry Research)
Source: Medicinal Chemistry Research - June 23, 2023 Category: Chemistry Source Type: research
Synthesis, antiviral evaluation, molecular docking study and cytotoxicity of 5 ′-phosphorylated 1,2,3-triazolyl nucleoside analogues with thymine and 6-methyl uracil moieties
AbstractA comparative analysis of in vitro antiviral activity (in terms of the concentration of semi-maximal inhibition, IC50) against influenza virus A/PR/8/34 (H1N1) of a large series of parent 1,2,3-triazolyl nucleoside analogues (with uracil, thymine, 6-methyluracil, quinazoline-2,4-dione moieties as nucleic bases) and their prodrug forms with masked 5 ʹ-phosphate groups (diethyl phosphate, diphenyl phosphate, phosphoramidate) and negatively chargedH-phosphonate and monophosphate groups was carried out. Obtained structure-activity relationships were interpreted based on the assumption that the synthesized parent 1,2,3...
Source: Medicinal Chemistry Research - June 23, 2023 Category: Chemistry Source Type: research
Design, synthesis and biological evaluation of novel hybrids of quinazoline derivatives and phenylsulfonylfuroxan as potential anti-tumor agents
In this study, a series of novel quinazoline/phenylsulfonylfuroxan hybrids were designed, synthesized, and biologically evaluated against five human cancer cell lines (H1975, MCF-7, Eca-109, MGC-803 and A549). The most of hybrids displayed considerable antiproliferative activities against the tested five cancer cells, while compound25q exhibited the most potent antiproliferative activity with the IC50 values of 1.67 and 1.88 μM against H1975 cells and MGC-803 cells, respectively. Further in vitro mechanistic studies showed that25q had the remarkable capacity to suppress the migration of H1975 cells. Besides,25q also ar...
Source: Medicinal Chemistry Research - June 20, 2023 Category: Chemistry Source Type: research
A guide for the synthesis of key nucleoside scaffolds in drug discovery
AbstractThis review aims to provide an overview of the synthetic strategies employed for generating modifications within the sugar backbone of nucleoside analogs. We have focused our discussions on the more popular scaffolds seen in medicinal chemistry including modifications to ribose-based nucleosides and 4 ʹ-thionucleosides. Importantly, the syntheses of emerging nucleoside chemotypes from recent patent literature are also discussed. We believe a detailed review centered in this critical area of research may help identify unsolved synthetic challenges and inspire the development of new methods for ex panding the access...
Source: Medicinal Chemistry Research - June 20, 2023 Category: Chemistry Source Type: research
The rise of targeting chimeras (TACs): next-generation medicines that preempt cellular events
AbstractTraditional targets and modalities that have provided rich substrates for medicine design and decades of productive industrial and academic research are not the primary drug discovery engines of the future. There is a steady shift in the target and modality landscape. Novel modalities such as protein degradation are an intense and hot area of research. The explosion of proximity induced ubiquitination of targets and proteasome or lysosome mediated degradation by expropriating E3 ligases (PROTACS, LYTACS) has inspired a number of other proximity induced post-translational modifications such as de-ubiquitination (DUB...
Source: Medicinal Chemistry Research - June 19, 2023 Category: Chemistry Source Type: research
