Baev, Dmitry S

Sokolova A.S., Baev D.S., Mordvinova E.D., Yarovaya O.I., Volkova N.V., Shcherbakov D.N., Okhina A.A., Rogachev A.D., Shnaider T.A., Chvileva A.S., Nikitina T.V., Tolstikova T.G., Salakhutdinov N.F.

The increasing frequency of filovirus outbreaks in African countries has led to a pressing need for the development of effective antifilovirus agents. In continuation of our previous research on the antifilovirus activity of monoterpenoid derivatives, we synthesized a series of (+)-fenchol and (-)-isopinocampheol derivatives by varying the type of heterocycle and linker length. Derivatives with an N-alkylpiperazine cycle proved to be the most potent antiviral compounds, with half-maximal inhibitory concentration (IC

Cheremnykh K.P., Baev D.S., Nacharova E.A., Pokrovskii M.A., Savelyev V.A., Meshkova Y.V., Marenina M.K., Tolstikova T.G., Pokrovskii A.G., Shults E.E.

The aminocarbonylation of ethyl 2-substituted 5-iodobenzoate has been investigated in the presence of a series of amine nucleophiles, providing an efficient synthetic route for producing various 5-carboxamide and 5-glyoxylamide derivatives of 2-(N-substituted) ethylbenzoates. It was shown, after detailed optimization study, that the formation of amides and α-ketoamides is strongly influenced by the reaction conditions. Performing the reactions of ethyl 2-substituted 5-iodobenzoate with nitrogen nucleophiles at 1 atm of carbon monoxide pressure in the presence of [Pd(η3-C3H5)(μ-Cl)]2 as a palladium source and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) as the base, the corresponding 2-ketocarboxamides were formed as major products (up to 60%). We have characterized the cytotoxicity (MTT test) and SAR of a new class of 2-(N-substituted) ethylbenzoate 5-amides and 5-(α-keto)amides. 5-Glyoxylamido derivatives 9a,b, 14a,d exhibited remarkably good cytotoxic potential on MCF-7 and T98G cancer cell lines. In addition, all the synthesized compounds were found to be non-toxic against normal cells (DF-2). The readily available nitrogen substituted 5-glyoxylamido-2-(N-acetylamino)ethylbenzoates 14a,d may serve as lead molecules for the future research regarding the identification of new anticancer agents. These novel compounds were confirmed to be cyclin-dependent kinase 6 and 9 (CDK6 and 9) inhibitors through in silico molecular modeling studies for the mode of action.

Yarovaya O.I., Filimonov A.S., Baev D.S., Borisevich S.S., Zaykovskaya A.V., Chirkova V.Y., Marenina M.K., Meshkova Y.V., Belenkaya S.V., Shcherbakov D.N., Gureev M.A., Luzina O.A., Pyankov O.V., Salakhutdinov N.F., Khvostov M.V.

Although the COVID-19 pandemic caused by SARS-CoV-2 viruses is officially over, the search for new effective agents with activity against a wide range of coronaviruses is still an important task for medical chemists and virologists. We synthesized a series of thiazolo-thiophenes based on (+)- and (−)-usnic acid and studied their ability to inhibit the main protease of SARS-CoV-2. Substances containing unsubstituted thiophene groups or methyl- or bromo-substituted thiophene moieties showed moderate activity. Derivatives containing nitro substituents in the thiophene heterocycle—just as pure (+)- and (−)-usnic acids—showed no anti-3CLpro activity. Kinetic parameters of the most active compound, (+)-3e, were investigated, and molecular modeling of the possible interaction of the new thiazolo-thiophenes with the active site of the main protease was carried out. We evaluated the binding energies of the ligand and protein in a ligand–protein complex. Active compound (+)-3e was found to bind with minimum free energy; the binding of inactive compound (+)-3g is characterized by higher values of minimum free energy; the positioning of pure (+)-usnic acid proved to be unstable and is accompanied by the formation of intermolecular contacts with many amino acids of the catalytic binding site. Thus, the molecular dynamics results were consistent with the experimental data. In an in vitro antiviral assay against six strains (Wuhan, Delta, and four Omicron sublineages) of SARS-CoV-2, (+)-3e demonstrated pronounced antiviral activity against all the strains.

Yarovaya O.I., Baev D.S., Kovaleva K.S., Gatilov Y.V., Meshkova Y.V., Marinina M.K., Oreshko V.V., Tolstikova T.G., Salakhutdinov N.F.

Conjugates of isatin and hydrazones based on (+)-camphor and (–)-fenchone were synthesized for the first time. The physicochemical properties of the synthesized compounds have been studied, and for the hydrazone product of fenchone and isatin X-ray diffraction data have been obtained. Molecular modeling of the possible interaction of new compounds with the active site of the basic protease 3CLpro of the SARS-CoV-2 virus was carried out, and the properties of isatin-terpene compounds as inhibitors of the 3CLpro protease were studied. It was found that the new conjugates do not exhibit inhibitory properties against 3CLpro, which makes it possible to clarify the direction of further chemical modifications of monoterpenoid derivatives in order to obtain molecules with antiviral properties.

Sokolova A.S., Yarovaya O.I., Artyushin O.I., Sharova E.V., Baev D.S., Mordvinova E.D., Shcherbakov D.N., Shnaider T.A., Nikitina T.V., Esaulkova I.L., Ilyina P.A., Zarubaev V.V., Brel V.K., Tolstikova T.G., Salakhutdinov N.F.

AbstractA new series of heterocyclic derivatives with a 1,7,7‐trimethylbicyclo[2.2.1]heptane fragment was designed, synthesised and biologically evaluated. Synthesis of the target compounds was performed using the Cu(I) catalysed cycloaddition reaction. The key starting substances in the click reaction were an alkyne containing a 1,7,7‐trimethylbicyclo[2.2.1]heptane fragment and a series of azides with saturated nitrogen‐containing heterocycles. Some of the derivatives were found to exhibit strong antiviral activity against Marburg and Ebola pseudotype viruses. Lysosomal trapping assays revealed the derivatives to possess lysosomotropic properties. The molecular modelling study demonstrated the binding affinity between the compounds investigated and the possible active site to be mainly due to hydrophobic interactions. Thus, combining a natural hydrophobic structural fragment and a lysosome‐targetable heterocycle may be an effective strategy for designing antiviral agents.

Yarovaya O., Filimonov A., Baev D., Borisevich S.S., Chirkova V., Zaykovskaya A., Mordvinova E., Belenkaya S., Shcherbakov D.N., Luzina O., Pyankov O., Salakhutdinov N.

Although the Covid-19 pandemic is officially over and the spread of coronavirus infection is no longer considered an international emergency, the virus continues to persist in the population, supporting the...

Sokolova A.S., Baranova D.V., Yarovaya O.I., Zybkina A.V., Mordvinova E.D., Zaykovskaya A.V., Baev D.S., Tolstikova T.G., Shcherbakov D.N., Pyankov O.V., Maksyutov R.A., Salakhutdinov N.F.

A series of new (1S)-(+)-camphor-10-sulfonamides containing various substituents at the nitrogen atom were synthesized, and their antiviral properties against Ebola virus were evaluated using a vesicular stomatitis virus-based pseudovirus system. The reduction of the carbonyl group at the C(2) atom leads to a significant improvement in the antiviral efficacy, whereas the transformation into oxime results in the almost complete disappearance of antiviral activity. According to the evaluation of antiviral activity against natural Ebola virus, the lead compounds exhibit moderate inhibitory activity. Interactions of the lead compounds with the binding site of Ebola virus glycoprotein were studied by molecular modeling. A comparative analysis of the changes due to possible interactions of the synthesized ligands and known inhibitors with Ebola virus surface glycoprotein was carried out.

Cheremnykh K.P., Bryzgalov A.O., Baev D.S., Borisov S.A., Sotnikova Y.S., Savelyev V.A., Tolstikova T.G., Sagdullaev S.S., Shults E.E.

Diterpenoid alkaloids, originating from the amination of natural tetracyclic diterpenes, have long interested scientists due to their medicinal uses and infamous toxicity which has limited the clinical application of the native compound. Alkaloid lappaconitine extracted from various Aconitum and Delphinium species has displayed extensive bioactivities and active ongoing research to reduce its adverse effects. A convenient route to construct hybrid molecules containing diterpenoid alkaloid lappaconitine and 3H-1,5-benzodiazepine fragments was proposed. The key stage involved the formation of 5′-alkynone-lappaconitines in situ by acyl Sonogashira coupling of 5′-ethynyllappaconitine, followed by cyclocondensation with o-phenylenediamine. New hybrid compounds showed low toxicity and outstanding analgesic activity in experimental pain models, which depended on the nature of the substituent in the benzodiazepine nucleus. An analogous dependence was also shown for the antiarrhythmic activity in the epinephrine arrhythmia test in vivo. Studies on the isolated atrium have shown that the mechanism of action of the new compounds is included the blockade of beta-adrenergic receptors and potassium channels. Molecular docking analysis was conducted to determine the binding potential of target molecules with the voltage-gated sodium channel NaV1.5. All obtained results provide a basis for future rational modifications of lappaconitine, reducing side effects, while retaining its therapeutic effects.

Meshkova Y.V., Baev D.S., Sorokina I.V., Popadyuk I.I., Salomatina O.V., Zhukova N.A., Tolstikova T.G., Salakhutdinov N.F.

Dalinger A.I., Baev D.S., Yarovaya O.I., Chirkova V.Y., Sharlaeva E.A., Belenkaya S.V., Shcherbakov D.N., Salakhutdinov N.F., Vatsadze S.Z.

Based on the data obtained by molecular modeling of the non-covalent interaction of non-symmetric N-benzylbispidin-9-ol amides with the active site of the main protease 3CLpro of the SARS-CoV-2 virus, a series of compounds was synthesized, and their inhibitory activity against 3CLpro was studied and compared with that of the known inhibitor ML188 (IC50 = 1.56±0.55 µmol L−1). It was found that only compound 1g containing the 1,4-dihydroindeno[1,2-c]pyrazole fragment showed moderate activity (IC50 = 100±5.7µmol L−1) and was characterized by the highest calculated binding energy among the studied bispidine derivatives according to molecular docking data.

Shchegravina E.S., Usova S.D., Baev D.S., Mozhaitsev E.S., Shcherbakov D.N., Belenkaya S.V., Volosnikova E.A., Chirkova V.Y., Sharlaeva E.A., Svirshchevskaya E.V., Fonareva I.P., Sitdikova A.R., Salakhutdinov N.F., Yarovaya O.I., Fedorov A.Y.

Conjugates of the natural alkaloid (aR,7S)-colchicine with bicyclic monoterpenoids and their derivatives were synthesized for the first time. Molecular docking of the synthesized agents in the active site of the main viral protease of the SARS-CoV-2 virus was carried out. The cytotoxic properties of the agents against different cell lines and the ability to inhibit the main viral protease 3CLPro were studied.

Baev D.S., Blokhin M.E., Chirkova V.Y., Belenkaya S.V., Luzina O.A., Yarovaya O.I., Salakhutdinov N.F., Shcherbakov D.N.

Although the incidence and mortality of SARS-CoV-2 infection has been declining during the pandemic, the problem related to designing novel antiviral drugs that could effectively resist viruses in the future remains relevant. As part of our continued search for chemical compounds that are capable of exerting an antiviral effect against the SARS-CoV-2 virus, we studied the ability of triterpenic acid amides to inhibit the SARS-CoV-2 main protease. Molecular modeling suggested that the compounds are able to bind to the active site of the main protease via non-covalent interactions. The FRET-based enzyme assay was used to reveal that compounds 1e and 1b can inhibit the SARS-CoV-2 main protease at micromolar concentrations.

Reshetnikov D.V., Ivanov I.D., Baev D.S., Rybalova T.V., Mozhaitsev E.S., Patrushev S.S., Vavilin V.A., Tolstikova T.G., Shults E.E.

Xanthine derivatives have been a great area of interest for the development of potent bioactive agents. Thirty-eight methylxanthine derivatives as acetylcholinesterase inhibitors (AChE) were designed and synthesized. Suzuki–Miyaura cross-coupling reactions of 8-chlorocaffeine with aryl(hetaryl)boronic acids, the CuAAC reaction of 8-ethynylcaffeine with several azides, and the copper(I) catalyzed one-pot three-component reaction (A3-coupling) of 8-ethynylcaffeine, 1-(prop-2-ynyl)-, or 7-(prop-2-ynyl)-dimethylxanthines with formaldehyde and secondary amines were the main approaches for the synthesis of substituted methylxanthine derivatives (yield 53–96%). The bioactivity of all new compounds was evaluated by Ellman’s method, and the results showed that most of the synthesized compounds displayed good and moderate acetylcholinesterase (AChE) inhibitory activities in vitro. The structure-activity relationships were also discussed. The data revealed that cоmpounds 53, 59, 65, 66, and 69 exhibited the most potent inhibitory activity against AChE with IC50 of 0.25, 0.552, 0.089, 0.746, and 0.121 μM, respectively. The binding conformation and simultaneous interaction modes were further clarified by molecular docking studies.

Filimonov A.S., Yarovaya O.I., Zaykovskaya A.V., Rudometova N.B., Shcherbakov D.N., Chirkova V.Y., Baev D.S., Borisevich S.S., Luzina O.A., Pyankov O.V., Maksyutov R.A., Salakhutdinov N.F.

In order to test the antiviral activity, a series of usnic acid derivatives were synthesized, including new, previously undescribed compounds. The activity of the derivatives against three strains of SARS-CoV-2 virus was studied. To understand the mechanism of antiviral action, the inhibitory activity of the main protease of SARS-CoV-2 virus was studied using the developed model as well as the antiviral activity against the pseudoviral system with glycoprotein S of SARS-CoV-2 virus on its surface. It was shown that usnic acid exhibits activity against three strains of SARS-CoV-2 virus: Wuhan, Delta, and Omicron. Compounds 10 and 13 also showed high activity against the three strains. The performed biological studies and molecular modeling allowed us to assume that the derivatives of usnic acid bind in the N-terminal domain of the surface glycoprotein S at the binding site of the hemoglobin decay metabolite.

Sorokina I.V., Zhukova N.A., Meshkova Y.V., Baev D.S., Tolstikova T.G., Bakarev M.A., Lushnikova E.L.

In order to optimize the testosterone model of benign prostatic hyperplasia, we studied the effect of castration and different doses of testosterone on the induction of the proliferative process in the prostate of Wistar rats. It was shown that 4-week subcutaneous administration of testosterone propionate in a dose of 20 mg/kg causes pronounced proliferative and hemodynamic disorders in the dorsolateral gland morphologically similar in castrated and non-castrated males. Administration of testosterone in a dose of 3 mg/kg had no significant effect on the dynamics of the pathological process in non-operated rats and normalized the structure of the gland in castrated animals. Morphological study showed that castration of males provides no visible advantages in reproducing the testosterone model of benign prostatic hyperplasia. The proposed non-traumatic modification of the model with a high dose of testosterone has good reproducibility and sensitivity to therapeutic agents, as shown by the example of finasteride.

Patel R.C., Rajput C.V., Patel M.P.

Jiang T., Zuo S., Liu C., Xing W., Wang P.

Methylxanthines are ubiquitous purine alkaloids in nature and have rich biological activities and functions. Today, the demand for methylxanthine is increasing but its production is low. This issue prevents its widespread use in many industrial fields, such as pharmaceuticals, food manufacturing, and chemical engineering. To address these issues, this review provides a comprehensive and systematic exploration of methylxanthines, delving into their biological structures, detailed biosynthetic pathways, and the latest research trends. These findings serve as valuable references for researchers, fostering advancements in the optimization of synthesis processes for methylxanthines and their derivatives and promoting their application across diverse industrial fields, such as medicine, food, and chemical engineering. By bridging fundamental research and practical applications, this work aims to advance the understanding of methylxanthine compounds, enhance their production efficiency, and contribute to healthcare and technological progress.

Chalouati W., Taamally W., Hraoui M., Ammari F., Abdelhedi O., Singh D.P., Delattre F., Ouerghui A.

A coupled reaction between 1H-1,2,4-triazole-3,5-diamine and carboxylic acids was studied to synthesize new amido-1H-1,2,4-triazoles derivatives (1–5), under various optimization conditions, leading to the higher yield of this coupling obtained with N,N′-diisopropylcarbodiimide (DIC) as a catalyst at 0 °C for 48 h. The produced compounds were subsequently identified by analytical techniques (1H NMR, 13C NMR and IR) and evaluated for various biological activities, including antibacterial, anti-inflammatory, and antioxidant effects. The findings demonstrated that all compounds exhibited powerful antibacterial effect against the tested strains, as found by the promising activities with minimum inhibitory concentration (MIC), ranging from 0.07 to 3.24 µmol mL−1 when compared to amoxicillin as a positive control (0.171 ≤ MIC ≤ 0.684 µmol mL−1). Of particular, compound 5 showed the highest antibacterial activity among other compounds. The in vitro investigation was conducted on the synthesized compounds to estimate their anti-inflammatory effects, as assessed by bovine serum albumin denaturation approach. Compounds 4 and 5 showed excellent anti-denaturation activities with IC50 values of 0.11 and 0.10 µmol mL−1, respectively, compared to diclofenac sodium (standard drug) and other compounds (IC50 from 0.19 to 0.27 µmol mL−1). Synthesized compounds were also tested for their antioxidant power, as assessed by DPPH radical-scavenging activity, and the maximum inhibition was found to be 33.17% at 100 µg mL−1. Furthermore, analysis with molecular docking against bacterial enzymes revealed that the compounds 2 and 5 showed a strong interaction with high docking scores of 1RO5 (− 8.160 kcal mol−1) and 2XCT (− 7.994 kcal mol−1) proteins, respectively. Therefore, these compounds can be considered as a promising candidate for antibacterial agents.

Bishnoi P., Saroha B., Kumar S., Kumar G., Bhardwaj A., Kumari M., Kumar N.

Recently, it has been seen that there is a rapid surge in Click Chemistry (CC) research owing to its fast, reliable, and biocompatible nature, making it an ideal tool for drug discovery. CC approach allows facile and sustainable development of complex molecules with minimal off-target products. With the rapid advancement of the CC field, its applications have significantly expanded across various domains, including biomedical, pharmaceutical, radiochemistry, nanochemistry, polymer chemistry, and microscopy. However, its applications remain most prominent in medicinal chemistry. This review initially covers the introduction and distinct types of click reactions such as copper-catalyzed azide-alkyne cycloaddition (CuAAC), strain-promoted azide-alkyne cycloaddition (SPAAC), and Diels–Alder Cycloaddition (DA), followed by the different techniques facilitating the click reactions. Among these, the CuAAC reaction is most effective and extensive CC approach widely explored for creating huge number of molecular libraries of medicinal significance due to its excellent biocompatibility, reliability, and specificity. In this review, we mainly included the synthesis and medicinal attributes of click reaction (CuAAC & SPAAC)-derived organic heterocycles from 2012–2023, particularly anticancer, antiviral, antidiabetic, and antimicrobial that will help the readers to understand the concept of CC, medicinal significance of CC-derived heterocycles, unexplored areas, challenges, and future prospects. This review will also provide a roadmap for new research directions and applications of click-derived heterocycles in medicinal chemistry.

Atatreh N., Mahgoub R.E., Ghattas M.A.

LIN J., LIU W., LI X., LIN J., FANG X., LIANG Y., ZHANG W., Jianwei R.E., WANG F., ZOU L., LIU Y.

Feng Z., Han C., Zhang N., Wang Y., Luo G., Gao X.

Patrushev S.S., Kichkina D.O., Moralev A.D., Rybalova T.V., Krasnov V.I., Chernyak E.I., Zenkova M.A., Markov A.V., Shults E.E.

Patrushev S.S., Vasil'eva D.O., Krasnov V.I., Rybalova T.V., Nefedov A.A., Shults E.E.

Poyil M.M., Alsharif M.H., El-Bidawy M.H., Alqahtani M.S., Alarabi T.G., Albadrani A.A., Hamid A.A., Arafah A.M., Abdel Tawab A., Alqasem S., Al-Gonaim A.

AbstractCatheter-associated urinary tract infection (CAUTI) is one of the most important nosocomial infections among hospitalized patients and causes serious complications due to the development of drug-resistant, biofilms forming strains of microorganisms resulting in treatment challenges. As the chemical catheter-coating agents often fail to prevent biofilm formation, the researchers are looking for compounds of natural origin, and the phytocompounds with multiple modes of action pose as a promising option. Thus, the present study investigated the antibacterial anti-biofilm potentials of the phytocompounds in one of the least explored medicinal plants -Tamarix ericoidesRottl. and its leaf methanolic extract was analyzed againstEscherichia coli– one of the most notorious multidrug-resistant, biofilm- forming uropathogens in CAUTIs. The well-diffusion method showed the antibacterial activity of methanolic leaf extract againstE. coliand using the microdilution method, the minimal inhibitory concentration (MIC) of the extract againstE. coliwas calculated as 1 mg/ml. GC-MS profiling of methanolic fractions ofT. ericoidesshowed the presence of eight important phytochemicals such as diethyl phthalate, ethanol, 2-[2-[(2-ethylhexyl)oxy]ethoxy]-, n-hexadecanoic acid, 9-octadecenoic acid, (E)-, 9,12-octadecadien-1-ol, (Z,Z)-octadecanoic acid, -hydroxy-3-(1,1-dimethylprop-2-enyl) coumarin and Cholestan-3,22,26-triol 16-[2- [formylthio]ethyl]- that are responsible for antibacterial activities. The killing kinetics ofT. ericoidesleaf extract againstE. colishowed at 1 h. Further, the antibiofilm activity ofT. ericoidesleaf extract againstE. colion nonliving surfaces was analyzed and quantified by crystal violet assay.T. ericoidesleaf extract reduced mature biofilms ofE. coliby 81%, 85%, and 89 % after treatment with 1X MIC (1 mg/ml), 2X MIC (2 mg/ml), and 3X MIC (3mg/ml) concentrations of the extract respectively. This was further confirmed using SEM analysis wherein biofilm reduction was observed when compared to untreated. The catheter coating withT. ericoidesleaf extract showed antibacterial activity in thein vitrobladder model and was quantified based on colony count. The CLSM reveals the anti-adhesive property ofT. ericoidesleaf extract on the catheter surface which reduced the biofilm formation and biofilm thickness when contacted withE. colicells. Also, 82% of dead cells were observed in the FDA and PI combination. Further, SEM showed the impact ofT. ericoidesleaf extract onE. colicell morphology as the cells displayed damage including cell shrinkage. Furthermore, the leaf extract was found to be non-toxic to normal cells. Based on the findings, the authors recommend further investigation to developT. ericoidesleaf extract as a potential catheter coating agent to manage CAUTIs.

Frankenberger S., Wendinger D., Scherer A., Sonogashira K., Tykwinski R.R.

Conjugated alkynes are valuable intermediates in the synthesis of natural products, agrochemicals, pharmaceuticals, fine chemicals, and organic molecular materials. Since its introduction in 1975, the palladium‐catalyzed Sonogashira reaction has become the primary choice for the construction of sp–sp 2 carbon–carbon bonds in aryl‐, heteroaryl‐, and alkenyl‐substituted alkynes. A vast range of reaction conditions have been explored to expand and optimize the scope of the Sonogashira reaction, including sustainable variants, microwave‐assisted cross couplings, and cross couplings performed in water. Research efforts also target the development of improved catalytic systems for the Sonogashira reaction, such as solid‐supported palladium catalysts and nanoparticles, the use of N ‐heterocyclic carbenes (NHCs) as ligands, as well as copper‐free variants of the reaction. This Chapter reviews the application of the palladium‐catalyzed Sonogashira cross coupling of terminal alkynes with aryl or alkenyl halides and triflates. Coupling reactions that form conjugated alkynes via alternative methods, or use different electrophiles, catalysts, or alkynes, are also briefly described.

Shaaban A.E., Ali A.R., Ayyad S.N., Badria F.A.

López-Méndez L.J., Martínez-Cásares R.M., López-Luna A., Luna H., Guadarrama P., Estrada-Reyes R., Enríquez R.G., Cassani J.

Lokole P.B., Byamungu G.G., Mutwale P.K., Ngombe N.K., Mpuza M.K., Mudogo V., Krause R.W., Nkanga C.I.

Zhao Z., Zou Q., Ma Y., Morris‐Natschke S.L., Li X., Shi L., Ma G., Xu X., Yang M., Zhao Z., Li Y., Xue J., Chen C., Wu H.

Cancer poses a significant global public health challenge, with commonly used adjuvant or neoadjuvant chemotherapy often leading to adverse side effects and drug resistance. Therefore, advancing cancer treatment necessitates the ongoing development of novel anticancer agents with diverse structures and mechanisms of action. Natural products remain crucial in the process of drug discovery, serving as a primary source for pharmaceutical leads and therapeutic advancements. Triterpenoids are particularly compelling due to their complex structures and wide array of biological activities. Recent research has demonstrated that naturally occurring triterpenes and their derivatives have the potential to serve as promising candidates for new drug development. This review aims to comprehensively explore the anticancer properties of triterpenoids and their synthetic analogs, with a focus on recent advancements. Various aspects, such as synthesis, phytochemistry, and molecular simulation for structure-activity relationship analyses, are summarized. It is anticipated that triterpenoid derivatives will emerge as notable anticancer agents following further investigation into their mechanisms of action and in vivo studies.

da Rocha J.M., Campos D.M., Esmaile S.C., Menezes G.D., Bezerra K.S., da Silva R.A., Junior E.D., Tayyeb J.Z., Akash S., Fulco U.L., Alqahtani T., Oliveira J.I.

Jadhav P., Huang B., Osipiuk J., Zhang X., Tan H., Tesar C., Endres M., Jedrzejczak R., Tan B., Deng X., Joachimiak A., Cai J., Wang J.

The COVID-19 pandemic is caused by SARS-CoV-2, an RNA virus with high transmissibility and mutation rate. Given the paucity of orally bioavailable antiviral drugs to combat SARS-CoV-2 infection, there is a critical need for additional antivirals with alternative mechanisms of action. Papain-like protease (PLpro) is one of the two SARS-CoV-2 encoded viral cysteine proteases essential for viral replication. PLpro cleaves at three sites of the viral polyproteins. In addition, PLpro antagonizes the host immune response upon viral infection by cleaving ISG15 and ubiquitin from host proteins. Therefore, PLpro is a validated antiviral drug target. In this study, we report the X-ray crystal structures of papain-like protease (PLpro) with two potent inhibitors, Jun9722 and Jun9843. Subsequently, we designed and synthesized several series of analogs to explore the structure-activity relationship, which led to the discovery of PLpro inhibitors with potent enzymatic inhibitory activity and antiviral activity against SARS-CoV-2. Together, the lead compounds are promising drug candidates for further development.

Sokolova A.S., Yarovaya O.I., Artyushin O.I., Sharova E.V., Baev D.S., Mordvinova E.D., Shcherbakov D.N., Shnaider T.A., Nikitina T.V., Esaulkova I.L., Ilyina P.A., Zarubaev V.V., Brel V.K., Tolstikova T.G., Salakhutdinov N.F.

AbstractA new series of heterocyclic derivatives with a 1,7,7‐trimethylbicyclo[2.2.1]heptane fragment was designed, synthesised and biologically evaluated. Synthesis of the target compounds was performed using the Cu(I) catalysed cycloaddition reaction. The key starting substances in the click reaction were an alkyne containing a 1,7,7‐trimethylbicyclo[2.2.1]heptane fragment and a series of azides with saturated nitrogen‐containing heterocycles. Some of the derivatives were found to exhibit strong antiviral activity against Marburg and Ebola pseudotype viruses. Lysosomal trapping assays revealed the derivatives to possess lysosomotropic properties. The molecular modelling study demonstrated the binding affinity between the compounds investigated and the possible active site to be mainly due to hydrophobic interactions. Thus, combining a natural hydrophobic structural fragment and a lysosome‐targetable heterocycle may be an effective strategy for designing antiviral agents.

Belenkaya S.V., Merkuleva I.A., Yarovaya O.I., Chirkova V.Y., Sharlaeva E.A., Shanshin D.V., Volosnikova E.A., Vatsadze S.Z., Khvostov M.V., Salakhutdinov N.F., Shcherbakov D.

Yarovaya O., Filimonov A., Baev D., Borisevich S.S., Chirkova V., Zaykovskaya A., Mordvinova E., Belenkaya S., Shcherbakov D.N., Luzina O., Pyankov O., Salakhutdinov N.

Although the Covid-19 pandemic is officially over and the spread of coronavirus infection is no longer considered an international emergency, the virus continues to persist in the population, supporting the...

Kovaleva K.S., Abdrakhmanova V.S., Yarovaya O.I., Gatilov Y.V., Rybalova T.V., Salakhutdinov N.F.

AbstractFor the first time, an effective method for the synthesis of spirocyclic camphor‐ and fenchone‐based 1,3,4‐oxadiazolines has been developed. The influence of the molecular structure of the terpene substrate on the reaction stereoselectivity was studied. The structural features of the target products were studied using NMR spectroscopy and X‐ray diffraction analysis. The proposed method allows obtaining of spirocyclic products with a wide structural diversity, stereoselectively and in good yields.

Sokolova A.S., Baranova D.V., Yarovaya O.I., Zybkina A.V., Mordvinova E.D., Zaykovskaya A.V., Baev D.S., Tolstikova T.G., Shcherbakov D.N., Pyankov O.V., Maksyutov R.A., Salakhutdinov N.F.

A series of new (1S)-(+)-camphor-10-sulfonamides containing various substituents at the nitrogen atom were synthesized, and their antiviral properties against Ebola virus were evaluated using a vesicular stomatitis virus-based pseudovirus system. The reduction of the carbonyl group at the C(2) atom leads to a significant improvement in the antiviral efficacy, whereas the transformation into oxime results in the almost complete disappearance of antiviral activity. According to the evaluation of antiviral activity against natural Ebola virus, the lead compounds exhibit moderate inhibitory activity. Interactions of the lead compounds with the binding site of Ebola virus glycoprotein were studied by molecular modeling. A comparative analysis of the changes due to possible interactions of the synthesized ligands and known inhibitors with Ebola virus surface glycoprotein was carried out.

Pang X., Xu W., Liu Y., Li H., Chen L.

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication and transcription and represents an attractive drug target for fighting COVID-19. Many SARS-CoV-2 Mpro inhibitors have been reported, including covalent and noncovalent inhibitors. The SARS-CoV-2 Mpro inhibitor PF-07321332 (Nirmatrelvir) designed by Pfizer has been put on the market. This paper briefly introduces the structural characteristics of SARS-CoV-2 Mpro and summarizes the research progress of SARS-CoV-2 Mpro inhibitors from the aspects of drug repurposing and drug design. These information will provide a basis for the drug development of treating the infection of SARS-CoV-2 and even other coronaviruses in the future.

Bao H., Tu G., Yue Q., Liu P., Zheng H., Yao X.

AbstractSARS‐CoV‐2 chymotrypsin‐like cysteine protease (3CLpro) is one of the most widely developed drug targets for COVID‐19. This study aimed to design and synthesize isatin derivatives to target SARS‐CoV‐2 3CLpro in a covalent binding manner. Through the process, a potent 3CLpro inhibitor (5g) was discovered with an IC50 value of 0.43 ± 0.17 μM. To understand the binding affinity and specificity of 5g as a candidate inhibitor of SARS‐CoV‐2 3CLpro, several assays were conducted, including FRET enzyme activity assays, thermodynamic‐based and kinetic‐based validation of inhibitor‐target interactions, and cell‐based FlipGFP assays. The interaction mechanism between 3CLpro‐5g was characterized by docking. Overall, these findings suggest that 5g is a new potent SARS‐CoV‐2 3CLpro inhibitor for the treatment of COVID‐19.

Letafati A., Salahi Ardekani O., Karami H., Soleimani M.

Ebola virus disease (EVD), which is also referred to as Ebola hemorrhagic fever, is a highly contagious and frequently lethal sickness caused by the Ebola virus. In 1976, the disease emerged in two simultaneous outbreaks in Sudan and the Democratic Republic of Congo. Subsequently, it has caused intermittent outbreaks in several African nations. The virus is primarily spread via direct contact with the bodily fluids of an infected individual or animal. EVD is distinguished by symptoms such as fever, fatigue, muscle pain, headache, and hemorrhage. The outbreak of EVD in West Africa in 2014–2016 emphasized the need for effective control and prevention measures. Despite advancements and the identification of new treatments for EVD, the primary approach to treatment continues to be centered around providing supportive care. Early detection and supportive care can enhance the likelihood of survival. This includes intravenous fluids, electrolyte replacement, and treatment of secondary infections. Experimental therapies, for instance, monoclonal antibodies and antiviral drugs, have shown promising results in animal studies and some clinical trials. Some African countries have implemented the use of vaccines developed for EVD, but their effectiveness and long-term safety are still being studied. This article provides an overview of the history, transmission, symptoms, diagnosis, treatment, epidemiology, and Ebola coinfection, as well as highlights the ongoing research efforts to develop effective treatments and vaccines to combat this deadly virus.

Hu Y., Lewandowski E.M., Tan H., Zhang X., Morgan R.T., Zhang X., Jacobs L.M., Butler S.G., Gongora M.V., Choy J., Deng X., Chen Y., Wang J.

Rosa L., Cutone A., Galla R., Uberti F., Valenti P.

ElNaggar M.H., Elgazar A.A., Gamal G., Hamed S.M., Elsayed Z.M., El-Ashrey M.K., Abood A., El Hassab M.A., Soliman A.M., El-Domany R.A., Badria F.A., Supuran C.T., Eldehna W.M.

Harris E.

Cheremnykh K.P., Bryzgalov A.O., Baev D.S., Borisov S.A., Sotnikova Y.S., Savelyev V.A., Tolstikova T.G., Sagdullaev S.S., Shults E.E.

Diterpenoid alkaloids, originating from the amination of natural tetracyclic diterpenes, have long interested scientists due to their medicinal uses and infamous toxicity which has limited the clinical application of the native compound. Alkaloid lappaconitine extracted from various Aconitum and Delphinium species has displayed extensive bioactivities and active ongoing research to reduce its adverse effects. A convenient route to construct hybrid molecules containing diterpenoid alkaloid lappaconitine and 3H-1,5-benzodiazepine fragments was proposed. The key stage involved the formation of 5′-alkynone-lappaconitines in situ by acyl Sonogashira coupling of 5′-ethynyllappaconitine, followed by cyclocondensation with o-phenylenediamine. New hybrid compounds showed low toxicity and outstanding analgesic activity in experimental pain models, which depended on the nature of the substituent in the benzodiazepine nucleus. An analogous dependence was also shown for the antiarrhythmic activity in the epinephrine arrhythmia test in vivo. Studies on the isolated atrium have shown that the mechanism of action of the new compounds is included the blockade of beta-adrenergic receptors and potassium channels. Molecular docking analysis was conducted to determine the binding potential of target molecules with the voltage-gated sodium channel NaV1.5. All obtained results provide a basis for future rational modifications of lappaconitine, reducing side effects, while retaining its therapeutic effects.