Vladimir V. Chernyshov

Four series of 5-alkyl-6-benzyl-2-[(methylthio/phenylthio)alkyl]thiopyrimidin-4(3H)-ones were systematically diversified at C2, C5, and C6 and evaluated as anti-HIV-1 agents. In MT-4 cells, these compounds displayed low-to-moderate cytotoxicity and subnanomolar-to-submicromolar inhibition of WT HIV-1, with potency governed by a balanced SAR. Ortho-dihalogenated C6-benzyl groups, particularly 2,6-F2 and 2,6-Cl2, were generally favored. In the 2,6-dihalobenzyl series, optimal activity required C5 methyl combined with para-substituted phenylthiomethyl groups at C2, whereas 3,5-Me2-benzyl analogues benefited from C5 isopropyl paired with methylthioethyl (24l) or unsubstituted phenylthiomethyl (24m) C2 side chains. The p-methoxyphenylthiomethyl thiothymine derivatives 21e (2,6-F2) and 23e (2,6-Cl2) emerged as lead inhibitors, showing high selectivity, potent activity against WT and clinically relevant HIV-1 variants, superior efficacy compared with nevirapine and efavirenz, dapivirine-like potency, and improved resistance tolerance relative to phenethyl-S-DABO bioisosteres. Together, biological and QSAR and docking data contribute to defining optimization strategies aimed at achieving durable anti-HIV-1 activity within the investigated chemotype and support further development of next-generation NNRTIs with improved efficacy against clinically relevant HIV-1 strains.

A new domino transformation during the high-temperature reaction of 2-amino-4-aryloxazoles with methyl 6-(1,2,4-triazin-3-yl)pyridine-2-carboxylates has been discovered. The transformation afforts methyl 3'-hydroxy-[2,4'-bipyridine]-6-carboxylates, which are scarcely accessible by other methods. A plausible mechanism of this process has been proposed. The structure of one of the products was confirmed by X-ray diffraction analysis.

The current research focuses on studying the interaction of 2-amino-4-aryloxazoles with 5-unsubstituted 3,6-di(hetero)aryl-1,2,4-triazines capable of undergoing nucleophilic substitution of hydrogen. Previously, our research group has demonstrated that 2-amino-4-aryloxazoles act as dienophiles in [4+2] cycloaddition reactions with 1,2,4-triazines. In the present study, it has been found that, under high-temperature conditions, reactions with 5-unsubstituted 1,2,4-triazines proceed in a fundamentally different manner: 2-amino-4-aryloxazoles act as C-nucleophiles. These reactions afford two types of products: (Z)-2-(1,2,4-triazin-5-yl)ethen-1-amines, formed via elimination of isocyanic acid from intermediate σ^H-adducts, and 5-(1,2,4-triazin-5-yl)-1,3-oxazol-2-amines resulting from direct C–H/C–H functionalization. When 2-amino-4-arylthiazoles are employed, no thiazole ring opening occurs and exclusively C–H/C–H coupling products are obtained. The σ^H-adducts have been synthesized and fully characterized, and for some of them, their oxidative aromatization has been demonstrated. However, when the dihydrotriazine core simultaneously bears an aminooxazole moiety at the C⁵ position and a 2-pyridyl substituent at the C³ position, such aromatization does not take place. Overall, the results show that the presence of a free electron-deficient C⁵ position in the 1,2,4-triazine ring switches the reaction pathway with 2-aminooxazoles from inverse electron-demand Diels–Alder cycloaddition to nucleophilic substitution of hydrogen.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal endocrine L cells that activates the GLP-1 receptor (GLP-1R), leading to glucose-dependent insulin secretion and suppression of glucagon release. In recent years, GLP-1R agonists (GLP-1RAs) have become one of the leading therapeutic options for the treatment of type 2 diabetes mellitus; however, for a long time clinically approved GLP-1RAs were limited to peptide drugs unsuitable for oral administration. The discovery of the “first-in-class” small molecule agonist danuglipron in 2018 demonstrated the feasibility of orally available GLP-1RAs and stimulated the development of numerous danuglipron-like compounds, some of which showed increased efficacy over the prototype. In this study, we report the design and synthesis of novel GLP-1RAs based on a regioisomeric danuglipron scaffold, 1H-benzo[d]imidazole-5-carboxylic acid. A series of 35 compounds was synthesized and evaluated in vitro for cytotoxicity and GLP-1R agonistic activity using a cAMP accumulation assay. A potent lead compound 12r (pEC₅₀ = 7.72, pCC₅₀ < 3.60) was found which is a close structural analog of danuglipron with reduced cytotoxicity and excellent selectivity over two other class B GPCRs, including GCGR and GIPR. Despite decreased potency compared to danuglipron, the obtained results hold promise for further optimization and provide valuable structure–activity relationship insights.

The KRAS protein is one of the key targets in cancer therapy. The clinical application of covalent KRAS inhibitors (sotorasib, adagrasib) is limited to the treatment of only certain KRASG12C-mediated types of cancer. In addition, using covalent inhibitors has several drawbacks, the main ones being limited to specific mutations (e.g., G12C) and the potential development of mutagenic resistance in tumors. Recently, the first representatives of a new class of allosteric inhibitors, termed pan-KRAS, have been discovered and studied due to their activity against multiple mutant forms of the KRAS protein. The development of pan-KRAS inhibitors represents a promising new direction in the therapeutic approach to treating KRAS-mediated cancers. The possibility to target multiple mutant forms of KRAS will significantly enlarge the number of patients that benefit from the therapy and reduce the likelihood of mutagenic resistance in tumors. This study reviews patents published between 2022 and 2024 that present new pan-specific KRAS inhibitors. The consideration of 28 patents included descriptions of the structures of the presented molecules, identification of the most active and selective examples of compounds, as well as results from structure-activity relationship (SAR) analyses for each sample. As a result of this work, some structural features of the most active examples of pan-KRAS inhibitors were identified.

Background: GLP-1 receptor peptide agonists have revolutionized type 2 di-abetes mellitus and obesity treatment, primarily through injection-based therapies. Small-molecule GLP-1 receptor agonists allow oral administration, but none are clini-cally established. Pfizer's danuglipron and lotiglipron, presented in 2018-2019, were "first-in-class" drug candidates, becoming prototypes for "next-in-class" drug develop-ment. Objective: This review summarizes "next-in-class" GLP-1 receptor agonists developed, identifying different relationships between the molecular structure and functional activi-ty of agonists. Methods: Patents containing danuglipron- and lotiglipron-like agonists from January 2021 to July 2024 were browsed in databases, such as Espacenet and Google Patents, using specified keywords. Over 5,000 compounds from 67 patent publications were an-alyzed. Results: Our analysis identified some key general SAR trends. The presence of a car-boxyl group leads to highly active agonists, but replacing it with bioisosteric analogs may improve the ADME profile of the target compounds. The introduction of specific privileged fragments, as well as the replacement of 1H-benzo[d]imidazole nucleus or (S)-oxetan-2-ylmethyl substituent in the prototype structure with bioisosteric heterocy-cles, may be viable approaches. The replacement of 1,4-disubstituted piperidine linked with its (S)-2-methyl-substituted homologue or O, N-disubstituted piperidin-4-ol may also result in highly potent agonists. Additionally, the classic 2,4-EWG-disubstituted benzyl alcohol residue allows significant variability. Conclusion: Despite the limited clinical success of danuglipron and lotiglipron, as well as the inherent problems associated with the complex nature of GLP-1R signaling, the current state of research and the abundance of novel, promising chemotypes of highly potent compounds suggest that approved GLP-1R agonists may emerge in the coming years.

Several approaches to the synthesis of risdiplam, a pharmacologically relevant pyridopyrimidinone derivative, have been recently reported. However, most of these routes rely exclusively on palladium-catalyzed, cross-coupling reactions and involve low-yielding intermediates, which limit their scalability and complicate impurity control. In this work, we present a five-step, straightforward route to risdiplam, utilizing ethyl 2,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylate—an accessible and cost-effective building block previously developed by our research group—as a starting material. The key step involves construction of the 4H-pyrido[1,2-a]pyrimidin-4-one scaffold via a copper(I)-catalyzed heterocyclization reaction. This represents a novel and convenient protocol for the synthesis of 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one, which serves as a crucial intermediate in the final stages of risdiplam synthesis. The overall process allows us to obtain the target compound with a 20% total yield (from abovementioned starting material) and high purity (99.86%, by HPLC-UV), with a maximum level of unidentified impurities not exceeding 0.046%. The developed approach eliminates the use of palladium catalysis and chromatographic purification, offering a practical and scalable alternative for risdiplam production.

In this study, we report for the first time a brand-new protocol for the multigram-scale synthesis of 5-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic and 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylic acids, without the utilization of metal-complex catalysts. The developed technology for the production of the aforementioned acids is of great importance for two reasons. Firstly, these acids serve as intermediates in the synthesis of risdiplam, the first small-molecule drug approved for the treatment of spinal muscular atrophy. Secondly, they themselves are valuable building blocks right from a broader medicinal chemistry perspective. The synthesis of risdiplam was carried out using a modified synthetic protocol, utilizing the acids indicated above as the key intermediates. The protocols presented in this study enable the production of target compounds with high purity and an acceptable yield.