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Ahmad G, Sohail M, Bilal M, Rasool N, Qamar MU, Ciurea C, Marceanu LG, Misarca C. N-Heterocycles as Promising Antiviral Agents: A Comprehensive Overview. Molecules 2024; 29:2232. [PMID: 38792094 PMCID: PMC11123935 DOI: 10.3390/molecules29102232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/22/2024] [Accepted: 05/03/2024] [Indexed: 05/26/2024] Open
Abstract
Viruses are a real threat to every organism at any stage of life leading to extensive infections and casualties. N-heterocycles can affect the viral life cycle at many points, including viral entrance into host cells, viral genome replication, and the production of novel viral species. Certain N-heterocycles can also stimulate the host's immune system, producing antiviral cytokines and chemokines that can stop the reproduction of viruses. This review focused on recent five- or six-membered synthetic N-heterocyclic molecules showing antiviral activity through SAR analyses. The review will assist in identifying robust scaffolds that might be utilized to create effective antiviral drugs with either no or few side effects.
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Affiliation(s)
- Gulraiz Ahmad
- Department of Chemistry, Government College University, Faisalabad 38000, Pakistan; (G.A.); (M.S.)
| | - Maria Sohail
- Department of Chemistry, Government College University, Faisalabad 38000, Pakistan; (G.A.); (M.S.)
| | - Muhammad Bilal
- School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China;
| | - Nasir Rasool
- Department of Chemistry, Government College University, Faisalabad 38000, Pakistan; (G.A.); (M.S.)
| | - Muhammad Usman Qamar
- Institute of Microbiology, Faculty of Life Sciences, Government College University, Faisalabad 38000, Pakistan;
- Division of Infectious Diseases, Geneva University Hospitals, 1205 Geneva, Switzerland
- Department of Microbiology and Molecular Medicine, University of Geneva, 1205 Geneva, Switzerland
| | - Codrut Ciurea
- Faculty of Medicine, Transilvania University of Brasov, 500036 Brasov, Romania; (L.G.M.)
| | - Luigi Geo Marceanu
- Faculty of Medicine, Transilvania University of Brasov, 500036 Brasov, Romania; (L.G.M.)
| | - Catalin Misarca
- Faculty of Medicine, Transilvania University of Brasov, 500036 Brasov, Romania; (L.G.M.)
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2
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Pattanayak P, Mishra GP. Docking and PASS-Assisted Evaluation of Furaldehyde Substituted Benzimidazoles as Anthelmintic Agents. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2023. [DOI: 10.1134/s106816202302019x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/24/2023]
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3
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T MK, K R, James N, V S, K R. Discovery of potent Covid-19 main protease inhibitors using integrated drug-repurposing strategy. Biotechnol Appl Biochem 2021; 68:712-725. [PMID: 33797130 PMCID: PMC8250478 DOI: 10.1002/bab.2159] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Accepted: 03/23/2021] [Indexed: 01/06/2023]
Abstract
The emergence and rapid spreading of novel SARS-CoV-2 across the globe represent an imminent threat to public health. Novel antiviral therapies are urgently needed to overcome this pandemic. Given the significant role of the main protease of Covid-19 for virus replication, we performed a drug-repurposing study using the recently deposited main protease structure, 6LU7. For instance, pharmacophore- and e-pharmacophore-based hypotheses such as AARRH and AARR, respectively, were developed using available small molecule inhibitors and utilized in the screening of the DrugBank repository. Further, a hierarchical docking protocol was implemented with the support of the Glide algorithm. The resultant compounds were then examined for their binding free energy against the main protease of Covid-19 by means of the Prime-MM/GBSA algorithm. Most importantly, the machine learning-based AutoQSAR algorithm was used to predict the antiviral activities of resultant compounds. The hit molecules were also examined for their drug-likeness and toxicity parameters through the QikProp algorithm. Finally, the hit compounds activity against the main protease was validated using molecular dynamics simulation studies. Overall, the present analysis yielded two potential inhibitors (DB02986 and DB08573) that are predicted to bind with the main protease of Covid-19 better than currently used drug molecules such as N3 (cocrystallized native ligand), lopinavir, and ritonavir.
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Affiliation(s)
- Muthu Kumar T
- Department of Biotechnology, School of Bio‐Sciences and TechnologyVellore Institute of TechnologyVelloreIndia
| | - Rohini K
- Department of Biotechnology, School of Bio‐Sciences and TechnologyVellore Institute of TechnologyVelloreIndia
| | - Nivya James
- Department of Biotechnology, School of Bio‐Sciences and TechnologyVellore Institute of TechnologyVelloreIndia
| | - Shanthi V
- Department of Biotechnology, School of Bio‐Sciences and TechnologyVellore Institute of TechnologyVelloreIndia
| | - Ramanathan K
- Department of Biotechnology, School of Bio‐Sciences and TechnologyVellore Institute of TechnologyVelloreIndia
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Horishny VY, Matiychuk VS. Synthesis, Antimicrobial and Antitumor Properties of 5-Thiophen-2-ylmethylen-2-Thioxothiazolidin-4-one Derivatives. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2021. [DOI: 10.1134/s1068162021030079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
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5
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Al-Behery AS, Elberembally KM, Eldawy MA. Synthesis, docking, and biological evaluation of thiazolidinone derivatives against hepatitis C virus genotype 4a. Med Chem Res 2021. [DOI: 10.1007/s00044-021-02721-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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6
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Azzam RA, Osman RR, Elgemeie GH. Efficient Synthesis and Docking Studies of Novel Benzothiazole-Based Pyrimidinesulfonamide Scaffolds as New Antiviral Agents and Hsp90α Inhibitors. ACS OMEGA 2020; 5:1640-1655. [PMID: 32010839 PMCID: PMC6990646 DOI: 10.1021/acsomega.9b03706] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 12/20/2019] [Indexed: 05/04/2023]
Abstract
A series of novel substituted 2-pyrimidylbenzothiazoles incorporating either sulfonamide moieties or the amino group at C2 of the pyrimidine ring were synthesized and evaluated for its antiviral potency. The novel synthesis of the ring system was carried out by reacting guanidine or N-arylsulfonated guanidine with different derivatives of ylidene benzothiazole based on Michael addition pathways. The antiviral activity of the newly synthesized compounds was examined by a plaque reduction assay against HSV-1, CBV4, HAV HM 175, HCVcc genotype 4 viruses, and HAdV7. In the case of HSV-1, it was determined that 5 out of the 21 synthesized compounds exhibited superior viral reduction in the range of 70-90% with significant IC50, CC50, and SI values as compared with acyclovir. In the case of CBV4, nine compounds have shown more than 50% reduction. Comparable results were obtained for seven of these synthesized compounds when evaluated against HAV with only a couple of them showing 50% reduction or more against HCVcc genotype 4. Remarkably, one compound, 9a, has shown broad action against all five examined viruses, rendering it as potentially an effective antiviral agent. The five potent compounds 9a, 9b, 14b, 14g, and 14h against HSV-1 have also presented inhibitory activity against the Hsp90α protein with IC50 in the range of 4.87-10.47 μg/mL. Interestingly, a combination of the potent synthesized compounds with acyclovir led to IC50 values lower than that of acyclovir alone. The potent compounds 9a, 9b, 14b, 14g, and 14h were also docked inside the active site of Hsp90α to assess the interaction pattern between the tested compounds and the active site of the protein.
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7
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Ramazani A, Sadighian H, Gouranlou F, Joo SW. Syntheses and Biological Activities of triazole-based Sulfonamides. CURR ORG CHEM 2020. [DOI: 10.2174/1385272823666191021115023] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
:The triazole and sulfonamide compounds are known as biologically active agents that were employed for medicinal applications. These compounds were obtained in different forms by a variety of techniques to vast ranges of applications. The broad biological properties of these compounds have encouraged researchers to design and synthesize triazole-based sulfonamide derivatives as compounds with potential biological activity. In this review, we summarized the synthetic procedures of triazole-based sulfonamide compounds together with their biological activities during the last two decades.
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Affiliation(s)
- Ali Ramazani
- Department of Chemistry, University of Zanjan, P.O. Box 45195-313, Zanjan, Iran
| | - Hamed Sadighian
- Department of Chemistry, University of Zanjan, P.O. Box 45195-313, Zanjan, Iran
| | - Farideh Gouranlou
- Department of Bioscience and Biotechnology, Malek Ashtar University of Technology, Tehran, Iran
| | - Sang W. Joo
- School of Mechanical Engineering, Yeungnam University, Gyeongsan 712-749, Korea
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Hassan GS, Georgey HH, Mohammed EZ, Omar FA. Anti-hepatitis-C virus activity and QSAR study of certain thiazolidinone and thiazolotriazine derivatives as potential NS5B polymerase inhibitors. Eur J Med Chem 2019; 184:111747. [PMID: 31604164 DOI: 10.1016/j.ejmech.2019.111747] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 09/02/2019] [Accepted: 09/27/2019] [Indexed: 02/07/2023]
Abstract
The present study reports on evaluation of anti-HCV activity and QSAR of certain arylidenethiazolidinone derivatives as potential inhibitors of HCV-NS5B polymerase. The pursued compounds involving, 5-aryliden-3-arylacetamidothiazolidin-2,4-diones 4-6(a-f), 5-arylidine-2-(N-arylacetamido)-iminothiazolidin-4-one (10) and their rigid counterparts 5-arylidinethiazolotriazines 13-15(a-f), were synthesized and their structures confirmed by spectral and elemental analyses. The results of NS5B polymerase inhibition assay revealed compound 4e, as the most active inhibitor (IC50 = 0.035 μM), which is four folds greater than that of the reference agent, VCH-759, (IC50 = 0.14 μM). Meanwhile, compounds 4b, 4c, 5a, and 5c, and 13b, 14e and 15c displayed equipotency to 2 folds higher activity than VCH-759 (IC50 values: 0.085, 0.14, 0.14, 0.10, 0.12, 0.09 and 0.07 μM, respectively). Assessment of the anti-HCV activity (GT1a) using human hepatoma cell line (Huh-7.5) illustrates superior activity of 4e (EC50 = 3.80 μM) relative to VCH-759 (EC50 = 5.29 μM). Cytotoxicity evaluation on, Transformed normal cell lines (Human Liver Epithelial-2, THLE-2 and Proximal Tubular Epithelial, RPTEC/TERT1), demonstrate enhanced safety profile of 4e (CC50 = 102.77, 161.37 μM, respectively) compared to VCH-759 (CC50 = 61.83, 81.28 μM, respectively). Molecular docking of the synthesized derivatives to NS5B polymerase allosteric site (PDB: 2HWH) showed similar binding modes to that of the co-crystallized ligand. Moreover, QSAR models were established for the studied thiazolidinones and thiazolotriazines to investigate the molecular characteristics contributing to the observed NS5B polymerase inhibition activity. The obtained results inspire further investigations of thiazolidinones and thiazolotriazine aiming at affording more potent, safe and orally active non-nucleoside NS5B polymerase inhibitors as anti-HCV drug candidates.
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Affiliation(s)
- Ghaneya S Hassan
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Badr University, Cairo, 11829, Egypt
| | - Hanan H Georgey
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
| | - Esraa Z Mohammed
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, October 6 University, Giza, 12585, Egypt
| | - Farghaly A Omar
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, October 6 University, Giza, 12585, Egypt
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9
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Bhosle MR, Kharote SA, Bondle GM, Mali JR. Tromethamine organocatalyzed efficient tandem-multicomponent synthesis of new thiazolyl-4-thiazolidinones in aqueous medium. SYNTHETIC COMMUN 2019. [DOI: 10.1080/00397911.2019.1597124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Manisha R. Bhosle
- Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, Maharashtra, 431004, India
| | - Sayali A. Kharote
- Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, Maharashtra, 431004, India
| | - Giribala M. Bondle
- Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, Maharashtra, 431004, India
| | - Jyotirling R. Mali
- College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea
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10
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Kasralikar HM, Jadhavar SC, Goswami SV, Kaminwar NS, Bhusare SR. Design, synthesis and molecular docking of pyrazolo [3,4d] thiazole hybrids as potential anti-HIV-1 NNRT inhibitors. Bioorg Chem 2019; 86:437-444. [PMID: 30771690 DOI: 10.1016/j.bioorg.2019.02.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 01/28/2019] [Accepted: 02/03/2019] [Indexed: 12/14/2022]
Abstract
A series of pyrazolo[3.4,d]thiazole hybrids 6 were synthesized from 5-arylidene-2-imino-3-(4-arylthiazol-2-yl)-thiazolidin-4-ones 5. The 5-arylidene-2-imino-3-(4-arylthiazol-2-yl)-thiazolidin-4-ones 5 were synthesized from 2-amino-4-arylthiazoles 1 and 2-chloro-acetamido-4-arylthiazoles 2 via the formation of 2-imino-3-(4-substituted-arylthiazol-2-yl)-thiazolidin-4-ones 3 using substituted aldehydes 4. The 5-acrylidene derivative 5 on cyclisation with phenyl hydrazine give the pyrazolo [3, 4, d] thiazole derivatives 6. The obtained pyrazolo [3.4, d]thiazole derivatives were studied as anti-HIV-1 NNRT inhibitors. It was found that these compounds might have potent RT inhibition activity.
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Affiliation(s)
- H M Kasralikar
- Department of Chemistry, Dnyanopasak College, Parbhani 431 401, MS, India
| | - S C Jadhavar
- Department of Chemistry, Dnyanopasak College, Parbhani 431 401, MS, India
| | - S V Goswami
- Department of Chemistry, Dnyanopasak College, Parbhani 431 401, MS, India
| | - N S Kaminwar
- Department of Chemistry, L. B. S. Mahavidyalaya, Dharmabad, Dist. Nanded, MS, India
| | - S R Bhusare
- Department of Chemistry, Dnyanopasak College, Parbhani 431 401, MS, India.
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11
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Kaminskyy D, Kryshchyshyn A, Lesyk R. 5-Ene-4-thiazolidinones - An efficient tool in medicinal chemistry. Eur J Med Chem 2017; 140:542-594. [PMID: 28987611 PMCID: PMC7111298 DOI: 10.1016/j.ejmech.2017.09.031] [Citation(s) in RCA: 110] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Revised: 07/14/2017] [Accepted: 09/17/2017] [Indexed: 02/02/2023]
Abstract
The presented review is an attempt to summarize a huge volume of data on 5-ene-4-thiazolidinones being a widely studied class of small molecules used in modern organic and medicinal chemistry. The manuscript covers approaches to the synthesis of 5-ene-4-thiazolidinone derivatives: modification of the C5 position of the basic core; synthesis of the target compounds in the one-pot or multistage reactions or transformation of other related heterocycles. The most prominent pharmacological profiles of 5-ene derivatives of different 4-thiazolidinone subtypes belonging to hit-, lead-compounds, drug-candidates and drugs as well as the most studied targets have been discussed. Currently target compounds (especially 5-en-rhodanines) are assigned as frequent hitters or pan-assay interference compounds (PAINS) within high-throughput screening campaigns. Nevertheless, the crucial impact of the presence/nature of C5 substituent (namely 5-ene) on the pharmacological effects of 5-ene-4-thiazolidinones was confirmed by the numerous listed findings from the original articles. The main directions for active 5-ene-4-thiazolidinones optimization have been shown: i) complication of the fragment in the C5 position; ii) introduction of the substituents in the N3 position (especially fragments with carboxylic group or its derivatives); iii) annealing in complex heterocyclic systems; iv) combination with other pharmacologically attractive fragments within hybrid pharmacophore approach. Moreover, the utilization of 5-ene-4-thiazolidinones in the synthesis of complex compounds with potent pharmacological application is described. The chemical transformations cover mainly the reactions which involve the exocyclic double bond in C5 position of the main core and correspond to the abovementioned direction of the 5-ene-4-thiazolidinone modification.
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Affiliation(s)
- Danylo Kaminskyy
- Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv-10, 79010, Ukraine
| | - Anna Kryshchyshyn
- Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv-10, 79010, Ukraine
| | - Roman Lesyk
- Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv-10, 79010, Ukraine.
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12
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Havrylyuk D, Roman O, Lesyk R. Synthetic approaches, structure activity relationship and biological applications for pharmacologically attractive pyrazole/pyrazoline-thiazolidine-based hybrids. Eur J Med Chem 2016; 113:145-66. [PMID: 26922234 PMCID: PMC7115613 DOI: 10.1016/j.ejmech.2016.02.030] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Revised: 02/10/2016] [Accepted: 02/11/2016] [Indexed: 11/28/2022]
Abstract
The features of the chemistry of 4-thiazolidinone and pyrazole/pyrazolines as pharmacologically attractive scaffolds were described in a number of reviews in which the main approaches to the synthesis of mentioned heterocycles and their biological activity were analyzed. However, the pyrazole/pyrazoline–thiazolidine-based hybrids as biologically active compounds is poorly discussed in the context of pharmacophore hybrid approach. Therefore, the purpose of this review is to summarize the data about the synthesis and modification of heterocyclic systems with thiazolidine and pyrazoline or pyrazole fragments in molecules as promising objects of modern bioorganic and medicinal chemistry. The description of biological activity was focused on SAR analysis and mechanistic insights of mentioned hybrids.
Synthesis and chemistry of pyrazole/pyrazoline–thiazolidine-based hybrids. A diverse spectrum of pyrazole/pyrazoline–thiazolidine-based hybrids biological activities has been presented. Structure activity relationship of pyrazole/pyrazoline–thiazolidine-based hybrids for different activities has been discussed.
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Affiliation(s)
- Dmytro Havrylyuk
- Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, 69 Pekarska Street, Lviv, 79010, Ukraine; Department of Chemistry, University of Kentucky, 505 Rose Street, Lexington, KY 40506, United States
| | - Olexandra Roman
- Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, 69 Pekarska Street, Lviv, 79010, Ukraine
| | - Roman Lesyk
- Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, 69 Pekarska Street, Lviv, 79010, Ukraine.
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13
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Shahavar Sulthana S, Arul Antony S, Balachandran C, Syed Shafi S. Thiophene and benzodioxole appended thiazolyl-pyrazoline compounds: Microwave assisted synthesis, antimicrobial and molecular docking studies. Bioorg Med Chem Lett 2015; 25:2753-7. [PMID: 26028159 DOI: 10.1016/j.bmcl.2015.05.033] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 04/29/2015] [Accepted: 05/14/2015] [Indexed: 12/29/2022]
Abstract
A novel series of thiophene and benzodioxole appended thiazolyl-pyrazoline derivatives have been designed, synthesized and evaluated against different bacteria and fungi. The antimicrobial activity of the synthesized compounds were screened using MIC method and were proved synthesized compounds 7o, 7r and 7t to show good antimicrobial activity against bacteria and fungi. In silico molecular docking studies revealed that all the synthesized molecules showed good binding energy toward the target receptor DNA topoisomerase IV, ranging from -10.42 to -11.66 kcal/mol.
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Affiliation(s)
- S Shahavar Sulthana
- PG & Research Department of Chemistry, Presidency College, Chennai 600 005, India
| | - S Arul Antony
- PG & Research Department of Chemistry, Presidency College, Chennai 600 005, India.
| | - C Balachandran
- Division of Microbiology and Cancer Biology, Entomology Research Institute, Loyola College, Chennai 600034, India
| | - S Syed Shafi
- Department of Chemistry, Thiruvalluvar University, Serkadu, Vellore 632 115, India.
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14
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Harikishore A, Li E, Lee JJ, Cho NJ, Yoon HS. Combination of pharmacophore hypothesis and molecular docking to identify novel inhibitors of HCV NS5B polymerase. Mol Divers 2015; 19:529-39. [PMID: 25862642 DOI: 10.1007/s11030-015-9591-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2014] [Accepted: 03/25/2015] [Indexed: 01/03/2023]
Abstract
Hepatitis C virus (HCV) infection or HCV-related liver diseases are now shown to cause more than 350,000 deaths every year. Adaptability of HCV genome to vary its composition and the existence of multiple strains makes it more difficult to combat the emergence of drug-resistant HCV infections. Among the HCV polyprotein which has both the structural and non-structural regions, the non-structural protein NS5B RNA-dependent RNA polymerase (RdRP) mainly mediates the catalytic role of RNA replication in conjunction with its viral protein machinery as well as host chaperone proteins. Lack of such RNA-dependent RNA polymerase enzyme in host had made it an attractive and hotly pursued target for drug discovery efforts. Recent drug discovery efforts targeting HCV RdRP have seen success with FDA approval for sofosbuvir as a direct-acting antiviral against HCV infection. However, variations in drug-binding sites induce drug resistance, and therefore targeting allosteric sites could delay the emergence of drug resistance. In this study, we focussed on allosteric thumb site II of the non-structural protein NS5B RNA-dependent RNA polymerase and developed a five-feature pharmacophore hypothesis/model which estimated the experimental activity with a strong correlation of 0.971 & 0.944 for training and test sets, respectively. Further, the Güner-Henry score of 0.6 suggests that the model was able to discern the active and inactive compounds and enrich the true positives during a database search. In this study, database search and molecular docking results supported by experimental HCV viral replication inhibition assays suggested ligands with best fitness to the pharmacophore model dock to the key residues involved in thumbs site II, which inhibited the HCV 1b viral replication in sub-micro-molar range.
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Affiliation(s)
- Amaravadhi Harikishore
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore,
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15
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Al-Ansary GH, Ismail MA, Abou El Ella DA, Eid S, Abouzid KA. Molecular design and synthesis of HCV inhibitors based on thiazolone scaffold. Eur J Med Chem 2013; 68:19-32. [DOI: 10.1016/j.ejmech.2013.07.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2013] [Revised: 07/08/2013] [Accepted: 07/15/2013] [Indexed: 01/25/2023]
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16
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Küçükgüzel I, Satılmış G, Gurukumar KR, Basu A, Tatar E, Nichols DB, Talele TT, Kaushik-Basu N. 2-Heteroarylimino-5-arylidene-4-thiazolidinones as a new class of non-nucleoside inhibitors of HCV NS5B polymerase. Eur J Med Chem 2013; 69:931-41. [PMID: 24161679 DOI: 10.1016/j.ejmech.2013.08.043] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Revised: 08/27/2013] [Accepted: 08/31/2013] [Indexed: 12/09/2022]
Abstract
Hepatitis C virus (HCV) NS5B polymerase is an important and attractive target for the development of anti-HCV drugs. Here we report on the design, synthesis and evaluation of twenty-four novel allosteric inhibitors bearing the 4-thiazolidinone scaffold as inhibitors of HCV NS5B polymerase. Eleven compounds tested were found to inhibit HCV NS5B with IC₅₀ values ranging between 19.8 and 64.9 μM. Compound 24 was the most active of this series with an IC₅₀ of 5.6 μM. A number of these derivatives further exhibited strong inhibition against HCV 1b and 2a genotypes in cell based antiviral assays. Molecular docking analysis predicted that the thiazolidinone derivatives bind to the NS5B thumb pocket-II (TP-II). Our results suggest that further optimization of the thiazolidinone scaffold may be possible to yield new derivatives with improved enzyme- and cell-based activity.
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Affiliation(s)
- Ilkay Küçükgüzel
- Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Haydarpaşa, 34668 İstanbul, Turkey.
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17
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Haudecoeur R, Peuchmaur M, Ahmed-Belkacem A, Pawlotsky JM, Boumendjel A. Structure-Activity Relationships in the Development of Allosteric Hepatitis C Virus RNA-Dependent RNA Polymerase Inhibitors: Ten Years of Research. Med Res Rev 2012; 33:934-84. [DOI: 10.1002/med.21271] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- Romain Haudecoeur
- Département de Pharmacochimie Moléculaire; Université de Grenoble/CNRS; UMR 5063, BP 53; 38041; Grenoble Cedex 9; France
| | - Marine Peuchmaur
- Département de Pharmacochimie Moléculaire; Université de Grenoble/CNRS; UMR 5063, BP 53; 38041; Grenoble Cedex 9; France
| | | | | | - Ahcène Boumendjel
- Département de Pharmacochimie Moléculaire; Université de Grenoble/CNRS; UMR 5063, BP 53; 38041; Grenoble Cedex 9; France
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el-Sabbagh OI, Baraka MM, Ibrahim SM, Pannecouque C, Andrei G, Snoeck R, Balzarini J, Rashad AA. Synthesis and antiviral activity of new pyrazole and thiazole derivatives. Eur J Med Chem 2009; 44:3746-53. [PMID: 19419804 DOI: 10.1016/j.ejmech.2009.03.038] [Citation(s) in RCA: 233] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2008] [Revised: 02/27/2009] [Accepted: 03/26/2009] [Indexed: 11/26/2022]
Abstract
New N-acetyl (5-8) and N-thiocarbamoyl (9-12) derivatives of 4,5-dihydropyrazole were synthesized starting from alpha,beta-unsaturated ketones under the effect of hydrazine hydrate and thiosemicarbazide, respectively. N-Thiocarbamoylpyrazole derivatives (9-12) were cyclized using either ethyl bromoacetate or phenacyl bromides to afford the novel pyrazolothiazol-4(5H)-ones (13-16) or pyrazolothiazoles (17-24). The antiviral activity for such novel compounds against a broad panel of viruses in different cell cultures revealed that N-acetyl 4,5-dihydropyrazole 7 was the only active one at subtoxic concentrations against vaccinia virus (Lederle strain) in HEL cell cultures with a 50% effective concentration (EC(50)) value of 7 microg/ml.
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Affiliation(s)
- Osama I el-Sabbagh
- Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
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19
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Dolle RE, Bourdonnec BL, Goodman AJ, Morales GA, Thomas CJ, Zhang W. Comprehensive Survey of Chemical Libraries for Drug Discovery and Chemical Biology: 2007. ACTA ACUST UNITED AC 2008; 10:753-802. [PMID: 18991466 DOI: 10.1021/cc800119z] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Roland E. Dolle
- Adolor Corporation, 700 Pennsylvania Drive, Exton, Pennsylvania 19341, Semafore Pharmaceuticals Inc., 8496 Georgetown Road, Indianapolis, Indiana 46268, NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, and Department of Chemistry, University of Massachusetts, 100 Morrissey Boulevard, Boston, Massachusetts 02125
| | - Bertrand Le Bourdonnec
- Adolor Corporation, 700 Pennsylvania Drive, Exton, Pennsylvania 19341, Semafore Pharmaceuticals Inc., 8496 Georgetown Road, Indianapolis, Indiana 46268, NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, and Department of Chemistry, University of Massachusetts, 100 Morrissey Boulevard, Boston, Massachusetts 02125
| | - Allan J. Goodman
- Adolor Corporation, 700 Pennsylvania Drive, Exton, Pennsylvania 19341, Semafore Pharmaceuticals Inc., 8496 Georgetown Road, Indianapolis, Indiana 46268, NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, and Department of Chemistry, University of Massachusetts, 100 Morrissey Boulevard, Boston, Massachusetts 02125
| | - Guillermo A. Morales
- Adolor Corporation, 700 Pennsylvania Drive, Exton, Pennsylvania 19341, Semafore Pharmaceuticals Inc., 8496 Georgetown Road, Indianapolis, Indiana 46268, NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, and Department of Chemistry, University of Massachusetts, 100 Morrissey Boulevard, Boston, Massachusetts 02125
| | - Craig J. Thomas
- Adolor Corporation, 700 Pennsylvania Drive, Exton, Pennsylvania 19341, Semafore Pharmaceuticals Inc., 8496 Georgetown Road, Indianapolis, Indiana 46268, NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, and Department of Chemistry, University of Massachusetts, 100 Morrissey Boulevard, Boston, Massachusetts 02125
| | - Wei Zhang
- Adolor Corporation, 700 Pennsylvania Drive, Exton, Pennsylvania 19341, Semafore Pharmaceuticals Inc., 8496 Georgetown Road, Indianapolis, Indiana 46268, NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, and Department of Chemistry, University of Massachusetts, 100 Morrissey Boulevard, Boston, Massachusetts 02125
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Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of thiazolone derivatives as hepatitis C virus NS5B polymerase allosteric inhibitors. J Comput Aided Mol Des 2008; 22:711-25. [DOI: 10.1007/s10822-008-9230-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2008] [Accepted: 07/13/2008] [Indexed: 01/27/2023]
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21
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Concerted solvent processes for common sulfonyl chloride precursors used in the synthesis of sulfonamide-based drugs. Int J Mol Sci 2008; 9:914-925. [PMID: 19325793 PMCID: PMC2635714 DOI: 10.3390/ijms9050914] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2008] [Revised: 05/19/2008] [Accepted: 05/19/2008] [Indexed: 11/26/2022] Open
Abstract
Specific rates of solvolysis in hydroxylic solvents available for the solvolysis of 2-thiophenesulfonyl chloride and phenylmethanesulfonyl chloride are supplemented by determining the values in fluoroalcohol-containing solvents. The data sets are then correlated using the extended Grunwald-Winstein equation. For both substrates, it is found that a single correlation controls the influence of solvent over the full range of solvent composition. The sensitivities to solvent nucleophilicity and solvent ionizing power are compared to values available for other substrates. Three of these previous studies are upgraded by the incorporation of additional specific rate values from the recent literature. With a methyl, isopropyl, benzyl, aromatic or heteroaromatic group as the R group of RSO2Cl, a concerted SN2 mechanism is proposed for the solvolysis.
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Batey RG. Controversies in and challenges to our understanding of hepatitis C. World J Gastroenterol 2007; 13:4168-76. [PMID: 17696244 PMCID: PMC4250614 DOI: 10.3748/wjg.v13.i31.4168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Discovered in 1989, the hepatitis C virus (HCV) continues to cause significant morbidity and mortality world-wide despite a huge research commitment to defining and understanding the virus and the disease it causes. This paper discusses a number of areas where progress in the management of the HCV have not kept pace with the scientific understanding of the HCV. It is suggested that in the fields of HCV prevention and providing access to treatment, practice falls short of what could be achieved. The role of alcohol in the pathogenesis of HCV liver injury is discussed. Discrimination against those with HCV infection and particularly those in prison settings fails to match good clinical practice. The complicated processes of sharing information between specialty groups is also discussed in an attempt to optimise knowledge dissemination in this field.
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Affiliation(s)
- Robert G Batey
- Drug and Alcohol Clinical Services, Hunter New England Area Health Services, Newcastle, New South Wales, Australia.
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Chapter 18 Recent Progress on Novel HCV Inhibitors. ANNUAL REPORTS IN MEDICINAL CHEMISTRY 2007. [DOI: 10.1016/s0065-7743(07)42018-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register]
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