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1.
J Med Chem ; 65(14): 9580-9606, 2022 07 28.
Article in English | MEDLINE | ID: covidwho-2185473

ABSTRACT

Sirtiun 5 (SIRT5) is a NAD+-dependent protein lysine deacylase primarily located in mitochondria. SIRT5 displays an affinity for negatively charged acyl groups and mainly catalyzes lysine deglutarylation, desuccinylation, and demalonylation while possessing weak deacetylase activity. SIRT5 substrates play crucial roles in metabolism and reactive oxygen species (ROS) detoxification, and SIRT5 activity is protective in neuronal and cardiac physiology. Moreover, SIRT5 exhibits a dichotomous role in cancer, acting as context-dependent tumor promoter or suppressor. Given its multifaceted activity, SIRT5 is a promising target in the design of activators or inhibitors that might act as therapeutics in many pathologies, including cancer, cardiovascular disorders, and neurodegeneration. To date, few cellular-active peptide-based SIRT5 inhibitors (SIRT5i) have been described, and potent and selective small-molecule SIRT5i have yet to be discovered. In this perspective, we provide an outline of SIRT5's roles in different biological settings and describe SIRT5 modulators in terms of their mode of action, pharmacological activity, and structure-activity relationships.


Subject(s)
Neoplasms , Sirtuins , Humans , Lysine/metabolism , Peptides , Structure-Activity Relationship
2.
Int J Mol Sci ; 23(22)2022 Nov 13.
Article in English | MEDLINE | ID: covidwho-2143225

ABSTRACT

Target-based drug design, a high-efficiency strategy used to guide the development of novel pesticide candidates, has attracted widespread attention. Herein, various natural-derived ferulic acid derivatives incorporating substituted isopropanolamine moieties were designed to target the tobacco mosaic virus (TMV) helicase. Bioassays demonstrating the optimized A19, A20, A29, and A31 displayed excellent in vivo antiviral curative abilities, affording corresponding EC50 values of 251.1, 336.2, 347.1, and 385.5 µg/mL, which visibly surpassed those of commercial ribavirin (655.0 µg/mL). Moreover, configurational analysis shows that the R-forms of target compounds were more beneficial to aggrandize antiviral profiles. Mechanism studies indicate that R-A19 had a strong affinity (Kd = 5.4 µM) to the TMV helicase and inhibited its ability to hydrolyze ATP (50.61% at 200 µM). Meanwhile, A19 could down-regulate the expression of the TMV helicase gene in the host to attenuate viral replication. These results illustrate the excellent inhibitory activity of A19 towards the TMV helicase. Additionally, docking simulations uncovered that R-A19 formed more hydrogen bonds with the TMV helicase in the binding pocket. Recent studies have unambiguously manifested that these designed derivatives could be considered as promising potential helicase-based inhibitors for plant disease control.


Subject(s)
Tobacco Mosaic Virus , Structure-Activity Relationship , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , DNA Helicases
3.
J Med Chem ; 64(24): 17601-17626, 2021 12 23.
Article in English | MEDLINE | ID: covidwho-2084518

ABSTRACT

Nucleic acid aptamers are single-stranded DNA or RNA molecules selected in vitro that can bind to a broad range of targets with high affinity and specificity. As promising alternatives to conventional anti-infective agents, aptamers have gradually revealed their potential in the combat against infectious diseases. This article provides an overview on the state-of-art of aptamer-based antibacterial and antiviral therapeutic strategies. Diverse aptamers targeting pathogen-related components or whole pathogenic cells are summarized according to the species of microorganisms. These aptamers exhibited remarkable in vitro and/or in vivo inhibitory effect for pathogenic invasion, enzymatic activities, or viral replication, even for some highly drug-resistant strains and biofilms. Aptamer-mediated drug delivery and controlled drug release strategies are also included herein. Critical technical barriers of therapeutic aptamers are briefly discussed, followed by some future perspectives for their implementation into clinical utility.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Antiviral Agents/therapeutic use , Aptamers, Nucleotide/therapeutic use , Communicable Diseases/drug therapy , Animals , Anti-Bacterial Agents/chemistry , Antiviral Agents/chemistry , Aptamers, Nucleotide/chemistry , Biofilms , Humans , Structure-Activity Relationship
4.
Int J Mol Sci ; 23(20)2022 Oct 19.
Article in English | MEDLINE | ID: covidwho-2081861

ABSTRACT

d-Arabinofuranosyl-pyrimidine and -purine nucleoside analogues containing alkylthio-, acetylthio- or 1-thiosugar substituents at the C2' position were prepared from the corresponding 3',5'-O-silylene acetal-protected nucleoside 2'-exomethylenes by photoinitiated, radical-mediated hydrothiolation reactions. Although the stereochemical outcome of the hydrothiolation depended on the structure of both the thiol and the furanoside aglycone, in general, high d-arabino selectivity was obtained. The cytotoxic effect of the arabinonucleosides was studied on tumorous SCC (mouse squamous cell) and immortalized control HaCaT (human keratinocyte) cell lines by MTT assay. Three pyrimidine nucleosides containing C2'-butylsulfanylmethyl or -acetylthiomethyl groups showed promising cytotoxicity at low micromolar concentrations with good selectivity towards tumor cells. SAR analysis using a methyl ß-d-arabinofuranoside reference compound showed that the silyl-protecting group, the nucleobase and the corresponding C2' substituent are crucial for the cell growth inhibitory activity. The effects of the three most active nucleoside analogues on parameters indicative of cytotoxicity, such as cell size, division time and cell generation time, were investigated by near-infrared live cell imaging, which showed that the 2'-acetylthiomethyluridine derivative induced the most significant functional and morphological changes. Some nucleoside analogues also exerted anti-SARS-CoV-2 and/or anti-HCoV-229E activity with low micromolar EC50 values; however, the antiviral activity was always accompanied by significant cytotoxicity.


Subject(s)
COVID-19 , Pyrimidine Nucleosides , Thiosugars , Humans , Mice , Animals , Arabinonucleosides/chemistry , Arabinonucleosides/pharmacology , Nucleosides/pharmacology , Nucleosides/chemistry , Antiviral Agents/pharmacology , Acetals , Sulfhydryl Compounds/chemistry , Purines , Structure-Activity Relationship
5.
Bioorg Chem ; 129: 106195, 2022 12.
Article in English | MEDLINE | ID: covidwho-2068728

ABSTRACT

The importance of the quinoxaline framework is exemplified by its presence in the well-known drugs such as varenicline, brimonidine, quinacillin, etc. In the past few years, preparation of a variety of organic compounds containing the quinoxaline framework has been reported by several research groups. The chloroquinoxalines were successfully used as substrates in many of these synthetic approaches due to their easy availability along with the reactivity especially towards a diverse range of metal and transition metal-catalyzed transformations including Sonogashira, Suzuki, Heck type of cross-coupling reactions. The transition metals e.g., Pd, Cu, Fe and Nb catalysts played a key role in these transformations for the construction of various CX (e.g., CC, CN, CO, CS, CP, CSe, etc) bonds. These approaches can be classified based on the catalyst employed, type of the reaction performed and nature of CX bond formation during the reaction. Several of these resultant quinoxaline derivatives have shown diverse biological activities which include apoptosis inducing activities, SIRT1 inhibition, inhibition of luciferace enzyme, antibacterial and antifungal activities, cytotoxicity towards cancer cells, inhibition of PDE4 (phosphodiesterase 4), potential uses against COVID-19, etc. Notably, a review article covering the literature based on transition metal-catalyzed reactions of chloroquinoxalines at the same time summarizing the relevant biological activities of resultant products is rather uncommon. Therefore, an attempt is made in the current review article to summarize (i) the recent advances noted in the transition metal-catalyzed reactions of chloroquinoxalines (ii) with the relevant mechanistic discussions (iii) along with the in vitro, and in silico biological studies (wherever reported) (iv) including Structure-Activity Relationship (SAR) within the particular series of the products reported between 2010 and 2022.


Subject(s)
Pharmaceutical Preparations , Quinoxalines , Transition Elements , Humans , Catalysis , Quinoxalines/chemical synthesis , Quinoxalines/chemistry , Quinoxalines/pharmacology , Transition Elements/chemical synthesis , Transition Elements/pharmacology , Structure-Activity Relationship , Pharmaceutical Preparations/chemical synthesis , Pharmaceutical Preparations/chemistry
6.
J Med Chem ; 65(19): 12500-12534, 2022 10 13.
Article in English | MEDLINE | ID: covidwho-2050246

ABSTRACT

The viral main protease is one of the most attractive targets among all key enzymes involved in the SARS-CoV-2 life cycle. Covalent inhibition of the cysteine145 of SARS-CoV-2 MPRO with selective antiviral drugs will arrest the replication process of the virus without affecting human catalytic pathways. In this Perspective, we analyzed the in silico, in vitro, and in vivo data of the most representative examples of covalent SARS-CoV-2 MPRO inhibitors reported in the literature to date. In particular, the studied molecules were classified into eight different categories according to their reactive electrophilic warheads, highlighting the differences between their reversible/irreversible mechanism of inhibition. Furthermore, the analyses of the most recurrent pharmacophoric moieties and stereochemistry of chiral carbons were reported. The analyses of noncovalent and covalent in silico protocols, provided in this Perspective, would be useful for the scientific community to discover new and more efficient covalent SARS-CoV-2 MPRO inhibitors.


Subject(s)
COVID-19 , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Coronavirus 3C Proteases , Cysteine , Cysteine Endopeptidases/metabolism , Humans , Molecular Docking Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , SARS-CoV-2 , Structure-Activity Relationship , Viral Nonstructural Proteins
7.
Methods Enzymol ; 675: 299-321, 2022.
Article in English | MEDLINE | ID: covidwho-1995924

ABSTRACT

Mutations on the spike (S) protein of SARS-CoV-2 could induce structural changes that help increase viral transmissibility and enhance resistance to antibody neutralization. Here, we report a robust workflow to prepare recombinant S protein variants and its host receptor angiotensin-convert enzyme 2 (ACE2) by using a mammalian cell expression system. The functional states of the S protein variants are investigated by cryo-electron microscopy (cryo-EM) and negative staining electron microscopy (NSEM) to visualize their molecular structures in response to mutations, receptor binding, antibody binding, and environmental changes. The folding stabilities of the S protein variants can be deduced from morphological changes based on NSEM imaging analysis. Differential scanning calorimetry provides thermodynamic information to complement NSEM. Impacts of the mutations on host receptor binding and antibody neutralization are in vitro by kinetic binding analyses in addition to atomic insights gleaned from cryo-electron microscopy (cryo-EM). This experimental strategy is generally applicable to studying the molecular basis of host-pathogen interactions.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2/genetics , Angiotensins/genetics , Angiotensins/metabolism , Animals , COVID-19/genetics , Cryoelectron Microscopy , Humans , Mammals/metabolism , Models, Molecular , Mutation , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Protein Binding , Receptors, Virus/chemistry , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship
8.
Molecules ; 27(15)2022 Jul 25.
Article in English | MEDLINE | ID: covidwho-1994112

ABSTRACT

A set of heterocyclic products was synthesized from natural (+)-camphor and semi-synthetic (-)-camphor. Then, 2-Imino-4-thiazolidinones and 2,3-dihydrothiazoles were obtained using a three-step procedure. For the synthesized compounds, their antiviral activity against the vaccinia virus and Marburg virus was studied. New promising agents active against both viruses were found among the tested compounds.


Subject(s)
Antiviral Agents , Camphor , Antiviral Agents/pharmacology , Camphor/pharmacology , Structure-Activity Relationship , Thiazoles/pharmacology
9.
Int J Mol Sci ; 23(16)2022 Aug 14.
Article in English | MEDLINE | ID: covidwho-1981428

ABSTRACT

The emergence of phytopathogenic bacteria resistant to antibacterial agents has rendered previously manageable plant diseases intractable, highlighting the need for safe and environmentally responsible agrochemicals. Inhibition of bacterial cell division by targeting bacterial cell division protein FtsZ has been proposed as a promising strategy for developing novel antibacterial agents. We previously identified 4'-demethylepipodophyllotoxin (DMEP), a naturally occurring substance isolated from the barberry species Dysosma versipellis, as a novel chemical scaffold for the development of inhibitors of FtsZ from the rice blight pathogen Xanthomonas oryzae pv. oryzae (Xoo). Therefore, constructing structure-activity relationship (SAR) studies of DMEP is indispensable for new agrochemical discovery. In this study, we performed a structure-activity relationship (SAR) study of DMEP derivatives as potential XooFtsZ inhibitors through introducing the structure-based virtual screening (SBVS) approach and various biochemical methods. Notably, prepared compound B2, a 4'-acyloxy DMEP analog, had a 50% inhibitory concentration of 159.4 µM for inhibition of recombinant XooFtsZ GTPase, which was lower than that of the parent DMEP (278.0 µM). Compound B2 potently inhibited Xoo growth in vitro (minimum inhibitory concentration 153 mg L-1) and had 54.9% and 48.4% curative and protective control efficiencies against rice blight in vivo. Moreover, compound B2 also showed low toxicity for non-target organisms, including rice plant and mammalian cell. Given these interesting results, we provide a novel strategy to discover and optimize promising bactericidal compounds for the management of plant bacterial diseases.


Subject(s)
Oryza , Xanthomonas , Anti-Bacterial Agents/chemistry , Bacterial Proteins/metabolism , Cell Division , Plant Diseases/microbiology , Plant Diseases/prevention & control , Podophyllotoxin/metabolism , Podophyllotoxin/pharmacology , Structure-Activity Relationship
11.
Int J Mol Sci ; 23(14)2022 Jul 12.
Article in English | MEDLINE | ID: covidwho-1964004

ABSTRACT

It is well-known that thiazole derivatives are usually found in lead structures, which demonstrate a wide range of pharmacological effects. The aim of this research was to explore the antiviral, antioxidant, and antibacterial activities of novel, substituted thiazole compounds and to find potential agents that could have biological activities in one single biomolecule. A series of novel aminothiazoles were synthesized, and their biological activity was characterized. The obtained results were compared with those of the standard antiviral, antioxidant, antibacterial and anticancer agents. The compound bearing 4-cianophenyl substituent in the thiazole ring demonstrated the highest cytotoxic properties by decreasing the A549 viability to 87.2%. The compound bearing 4-trifluoromethylphenyl substituent in the thiazole ring showed significant antiviral activity against the PR8 influenza A strain, which was comparable to the oseltamivir and amantadine. Novel compounds with 4-chlorophenyl, 4-trifluoromethylphenyl, phenyl, 4-fluorophenyl, and 4-cianophenyl substituents in the thiazole ring demonstrated antioxidant activity by DPPH, reducing power, FRAP methods, and antibacterial activity against Escherichia coli and Bacillus subtilis bacteria. These data demonstrate that substituted aminothiazole derivatives are promising scaffolds for further optimization and development of new compounds with potential influenza A-targeted antiviral activity. Study results could demonstrate that structure optimization of novel aminothiazole compounds may be useful in the prevention of reactive oxygen species and developing new specifically targeted antioxidant and antibacterial agents.


Subject(s)
Antioxidants , Influenza, Human , Anti-Bacterial Agents/chemistry , Antioxidants/chemistry , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Escherichia coli , Humans , Microbial Sensitivity Tests , Structure-Activity Relationship , Thiazoles/chemistry
12.
Arch Pharm (Weinheim) ; 355(11): e2200214, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-1940703

ABSTRACT

The prevalence of tuberculosis (TB) remains the leading cause of death from a single infectious agent, ranking it above all other contagious diseases. The problem to tackle this disease seems to become even worse due to the outbreak of SARS-CoV-2. Further, the complications related to drug-resistant TB, prolonged treatment regimens, and synergy between TB and HIV are significant drawbacks. There are several drugs to treat TB, but there is still no rapid and accurate treatment available. Intensive research is, therefore, necessary to discover newer molecular analogs that can probably eliminate this disease within a short span. An increase in efficacy can be achieved through re-engineering old TB-drug families and repurposing known drugs. These two approaches have led to the production of newer classes of compounds with novel mechanisms to treat multidrug-resistant strains. With respect to this context, we discuss structural aspects of developing new anti-TB drugs as well as examine advances in TB drug discovery. It was found that the fluoroquinolone, oxazolidinone, and nitroimidazole classes of compounds have greater potential to be further explored for TB drug development. Most of the TB drug candidates in the clinical phase are modified versions of these classes of compounds. Therefore, here we anticipate that modification or repurposing of these classes of compounds has a higher probability to reach the clinical phase of drug development. The information provided will pave the way for researchers to design and identify newer molecular analogs for TB drug development and also broaden the scope of exploring future-generation potent, yet safer anti-TB drugs.


Subject(s)
COVID-19 , Mycobacterium tuberculosis , Tuberculosis , Humans , Drug Repositioning , SARS-CoV-2 , Structure-Activity Relationship , Tuberculosis/drug therapy , Antitubercular Agents/pharmacology , Antitubercular Agents/chemistry , Drug Discovery
13.
Bioorg Chem ; 127: 105985, 2022 10.
Article in English | MEDLINE | ID: covidwho-1906793

ABSTRACT

We previously discovered that triterpenoid saponin platycodin D inhibits the SARS-CoV-2 entry to the host cell. Herein, we synthesized various saponin derivatives and established a structure-activity relationship of saponin-based antiviral agents against SARS-CoV-2. We discovered that the C3-glucose, the C28-oligosaccharide moiety that consist of (→3)-ß-d-Xyl-(1 â†’ 4)-α-l-Rham-(1 â†’ 2)-ß-d-Ara-(1 â†’ ) as the last three sugar units, and the C16-hydroxyl group were critical components of saponin-based coronavirus cell entry inhibitors. These findings enabled us to develop minimal saponin-based antiviral agents that are equipotent to the originally discovered platycodin D. We found that our saponin-based antiviral agents inhibited both the endosomal and transmembrane protease serine 2-mediated cell surface viral entries. Cell fusion assay experiment revealed that our newly developed compounds inhibit the SARS-CoV-2 entry by blocking the fusion between the viral and host cell membranes. The effectiveness of the newly developed antiviral agents over various SARS-CoV-2 variants hints at the broad-spectrum antiviral efficacy of saponin-based therapeutics against future coronavirus variants.


Subject(s)
COVID-19 , Saponins , Antiviral Agents/pharmacology , Humans , Membrane Fusion , SARS-CoV-2 , Saponins/pharmacology , Structure-Activity Relationship
14.
J Med Chem ; 65(13): 9376-9395, 2022 07 14.
Article in English | MEDLINE | ID: covidwho-1900408

ABSTRACT

The main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target in coronaviruses because of its crucial involvement in viral replication and transcription. Here, we report on the design, synthesis, and structure-activity relationships of novel small-molecule thioesters as SARS-CoV-2 Mpro inhibitors. Compounds 3w and 3x exhibited excellent SARS-CoV-2 Mpro inhibition with kinac/Ki of 58,700 M-1 s-1 (Ki = 0.0141 µM) and 27,200 M-1 s-1 (Ki = 0.0332 µM), respectively. In Calu-3 and Vero76 cells, compounds 3h, 3i, 3l, 3r, 3v, 3w, and 3x displayed antiviral activity in the nanomolar range without host cell toxicity. Co-crystallization of 3w and 3af with SARS-CoV-2 Mpro was accomplished, and the X-ray structures showed covalent binding with the catalytic Cys145 residue of the protease. The potent SARS-CoV-2 Mpro inhibitors also inhibited the Mpro of other beta-coronaviruses, including SARS-CoV-1 and MERS-CoV, indicating that they might be useful to treat a broader range of coronaviral infections.


Subject(s)
Antiviral Agents , COVID-19 , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Coronavirus 3C Proteases , Cysteine Endopeptidases/metabolism , Humans , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2 , Structure-Activity Relationship , Viral Nonstructural Proteins , X-Rays
15.
Comput Biol Med ; 147: 105738, 2022 08.
Article in English | MEDLINE | ID: covidwho-1894906

ABSTRACT

Over a span of two years ago, since the emergence of the first case of the novel coronavirus (SARS-CoV-2) in China, the pandemic has crossed borders causing serious health emergencies, immense economic crisis and impacting the daily life worldwide. Despite the discovery of numerous forms of precautionary vaccines along with other recently approved orally available drugs, yet effective antiviral therapeutics are necessarily needed to hunt this virus and its variants. Historically, naturally occurring chemicals have always been considered the primary source of beneficial medications. Considering the SARS-CoV-2 main protease (Mpro) as the duplicate key element of the viral cycle and its main target, in this paper, an extensive virtual screening for a focused chemical library of 15 batzelladine marine alkaloids, was virtually examined against SARS-CoV-2 main protease (Mpro) using an integrated set of modern computational tools including molecular docking (MDock), molecule dynamic (MD) simulations and structure-activity relationships (SARs) as well. The molecular docking predictions had disclosed four promising compounds including batzelladines H-I (8-9) and batzelladines F-G (6-7), respectively according to their prominent ligand-protein energy scores and relevant binding affinities with the (Mpro) pocket residues. The best two chemical hits, batzelladines H-I (8-9) were further investigated thermodynamically though studying their MD simulations at 100 ns, where they showed excellent stability within the accommodated (Mpro) pocket. Moreover, SARs studies imply the crucial roles of the fused tricyclic guanidinic moieties, its degree of unsaturation, position of the N-OH functionality and the length of the side chain as a spacer linking between two active sites, which disclosed fundamental structural and pharmacophoric features for efficient protein-ligand interaction. Such interesting findings are greatly highlighting further in vitro/vivo examinations regarding those marine natural products (MNPs) and their synthetic equivalents as promising antivirals.


Subject(s)
Alkaloids , COVID-19 , Alkaloids/pharmacology , Antiviral Agents/chemistry , COVID-19/drug therapy , Coronavirus 3C Proteases , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2 , Structure-Activity Relationship , Viral Nonstructural Proteins/chemistry
16.
Molecules ; 27(11)2022 May 29.
Article in English | MEDLINE | ID: covidwho-1892925

ABSTRACT

Chemical modification of sugars and nucleosides has a long history of producing compounds with improved selectivity and efficacy. In this study, several modified sugars (2-3) and ribonucleoside analogs (4-8) have been synthesized from α-d-glucose in a total of 21 steps. The compounds were tested for peripheral anti-nociceptive characteristics in the acetic acid-induced writhing assay in mice, where compounds 2, 7, and 8 showed a significant reduction in the number of writhes by 56%, 62%, and 63%, respectively. The compounds were also tested for their cytotoxic potential against human HeLa cell line via trypan blue dye exclusion test followed by cell counting kit-8 (CCK-8) assay. Compound 6 demonstrated significant cytotoxic activity with an IC50 value of 54 µg/mL. Molecular docking simulations revealed that compounds 2, 7, and 8 had a comparable binding affinity to cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes. Additionally, the bridged nucleoside analogs 7 and 8 potently inhibited adenosine kinase enzyme as well, which indicates an alternate mechanistic pathway behind their anti-nociceptive action. Cytotoxic compound 6 demonstrated strong docking with cancer drug targets human cytidine deaminase, proto-oncogene tyrosine-protein kinase Src, human thymidine kinase 1, human thymidylate synthase, and human adenosine deaminase 2. This is the first ever reporting of the synthesis and analgesic property of compound 8 and the cytotoxic potential of compound 6.


Subject(s)
Antineoplastic Agents , Nucleosides , Analgesics/chemistry , Animals , Antineoplastic Agents/chemistry , Cyclooxygenase 2/metabolism , Dose-Response Relationship, Drug , HeLa Cells , Humans , Mice , Molecular Docking Simulation , Molecular Structure , Nucleosides/pharmacology , Structure-Activity Relationship , Sugars
17.
Molecules ; 27(11)2022 May 24.
Article in English | MEDLINE | ID: covidwho-1892922

ABSTRACT

BACKGROUND: Heterocyclic compounds and their fused analogs, which contain pharmacophore fragments such as pyridine, thiophene and pyrimidine rings, are of great interest due to their broad spectrum of biological activity. Chemical compounds containing two or more pharmacophore groups due to additional interactions with active receptor centers usually enhance biological activity and can even lead to a new type of activity. The search for new effective neurotropic drugs in the series of derivatives of heterocycles containing pharmacophore groups in organic, bioorganic and medical chemistry is a serious problem. METHODS: Modern methodology of drugs involves synthesis, physicochemical study, molecular modeling and selection of active compounds through virtual screening and experimental evaluation of the biological activity of new chimeric compounds with pharmacophore fragments. For the synthesis of new compounds, classical organic methods were used and developed. For the evaluation of neurotropic activity of new synthesized compounds, some biological methods were used according to indicators characterizing anticonvulsant, sedative and antianxiety activity as well as side effects. For docking analysis, various soft ware packages and methods were used. RESULTS: As a result of multistep reactions, 11 new, tri- and tetracyclic heterocyclic systems were obtained. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures as well as some psychotropic effects. The biological assays evidenced that nine of the eleven studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of the compounds is low, and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity, it was found that the selected compounds have an activating behavior and anxiolytic effects on the "open field" and "elevated plus maze" (EPM) models. The data obtained indicate the anxiolytic (antianxiety) activity of the derivatives of tricyclic thieno[2,3-b]pyridines and tetracyclic pyridothieno[3,2-d]pyrimidin-8-ones, especially pronounced in compounds 3b-f and 4e. The studied compounds increase the latent time of first immobilization on the "forced swimming" (FS) model and exhibit antidepressant effects; compounds 3e and 3f especially exhibit these effects, similarly to diazepam. Docking studies revealed that compounds 3c and 4b bound tightly in the active site of γ-aminobutyric acid type A (GABAA) receptors with a value of the scoring function that estimates free energy of binding (∆G) at -10.0 ± 5 kcal/mol. Compound 4e showed the best affinity ((∆G) at -11.0 ± 0.54 kcal/mol) and seems to be an inhibitor of serotonin (SERT) transporter. Compounds 3c-f and 4e practically bound with the groove of T4L of 5HT_1A and blocked it completely, while the best affinity observed was in compound 3f ((∆G) at -9.3 ± 0.46 kcal/mol). CONCLUSIONS: The selected compounds have an anticonvulsant, activating behavior and anxiolytic effects and at the same time exhibit antidepressant effects.


Subject(s)
Anti-Anxiety Agents , Pentylenetetrazole , Anti-Anxiety Agents/pharmacology , Anticonvulsants/chemistry , Antidepressive Agents/pharmacology , Molecular Docking Simulation , Pentylenetetrazole/adverse effects , Pyridines/chemistry , Pyrimidines/chemistry , Receptors, GABA-A , Structure-Activity Relationship
18.
Chem Biol Drug Des ; 100(6): 1086-1121, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1891512

ABSTRACT

Due to the emergence of drug-resistant microbial strains, different research groups are continuously developing novel drug molecules against already exploited and unexploited targets. 1,3,4-Oxadiazole derivatives exhibited noteworthy antimicrobial activities. The presence of 1,3,4-oxadiazole moiety in antimicrobial agents can modify their polarity and flexibility, which significantly improves biological activities due to various bonded and non-bonded interactions viz. hydrogen bond, steric, electrostatic, and hydrophobic with target sites. The present review elaborates the therapeutic targets and mode of interaction of 1,3,4-oxadiazoles as antimicrobial agents. 1,3,4-oxadiazole derivatives target enoyl reductase (InhA), 14α-demethylase in the mycobacterial cell; GlcN-6-P synthase, thymidylate synthase, peptide deformylase, RNA polymerase, dehydrosqualene synthase in bacterial strains; ergosterol biosynthesis pathway, P450-14α demethylase, protein-N-myristoyltransferase in fungal strains; FtsZ protein, interfere with purine and functional protein synthesis in plant bacteria. The present review also summarizes the effect of different moieties and functional groups on the antimicrobial activity of 1,3,4-oxadiazole derivatives.


Subject(s)
Anti-Infective Agents , Oxadiazoles , Microbial Sensitivity Tests , Oxadiazoles/pharmacology , Oxadiazoles/chemistry , Anti-Infective Agents/pharmacology , Anti-Infective Agents/chemistry , Bacteria , Structure-Activity Relationship , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry
19.
Molecules ; 27(11)2022 Jun 04.
Article in English | MEDLINE | ID: covidwho-1884285

ABSTRACT

Novel 1,3,4-thiadiazole derivatives were synthesized through the reaction of methyl 2-(4-hydroxy-3-methoxybenzylidene) hydrazine-1-carbodithioate and the appropriate hydrazonoyl halides in the presence of a few drops of diisopropylethylamine. The chemical structure of the newly fabricated compounds was inferred from their microanalytical and spectral data. With the increase in microbial diseases, fungi remain a devastating threat to human health because of the resistance of microorganisms to antifungal drugs. COVID-19-associated pulmonary aspergillosis (CAPA) and COVID-19-associated mucormycosis (CAM) have higher mortality rates in many populations. The present study aimed to find new antifungal agents using the disc diffusion method, and minimal inhibitory concentration (MIC) values were estimated by the microdilution assay. An in vitro experiment of six synthesized chemical compounds exhibited antifungal activity against Rhizopus oryzae; compounds with an imidazole moiety, such as the compound 7, were documented to have energetic antibacterial, antifungal properties. As a result of these findings, this research suggests that the synthesized compounds could be an excellent choice for controlling black fungus diseases. Furthermore, a molecular docking study was achieved on the synthesized compounds, of which compounds 2, 6, and 7 showed the best interactions with the selected protein targets.


Subject(s)
Anti-Infective Agents , COVID-19 , Thiadiazoles , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Bacteria , Fungi , Humans , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship , Thiadiazoles/chemistry , Thiadiazoles/pharmacology
20.
Molecules ; 27(11)2022 May 26.
Article in English | MEDLINE | ID: covidwho-1866459

ABSTRACT

Dipyridamole, apart from its well-known antiplatelet and phosphodiesterase inhibitory activities, is a promising old drug for the treatment of pulmonary fibrosis. However, dipyridamole shows poor pharmacokinetic properties with a half-life (T1/2) of 7 min in rat liver microsomes (RLM). To improve the metabolic stability of dipyridamole, a series of pyrimidopyrimidine derivatives have been designed with the assistance of molecular docking. Among all the twenty-four synthesized compounds, compound (S)-4h showed outstanding metabolic stability (T1/2 = 67 min) in RLM, with an IC50 of 332 nM against PDE5. Furthermore, some interesting structure-activity relationships (SAR) were explained with the assistance of molecular docking.


Subject(s)
Dipyridamole , Idiopathic Pulmonary Fibrosis , Animals , Dipyridamole/pharmacology , Dipyridamole/therapeutic use , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/metabolism , Microsomes, Liver/metabolism , Molecular Docking Simulation , Molecular Structure , Rats , Structure-Activity Relationship
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