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WO2021126118A1 - Synthèse de dérivés de 2-(phényle substitué)-5-(hétéroaryle substitué)-1h-benzimidazole et recherche de leurs effets biologiques - Google Patents

Synthèse de dérivés de 2-(phényle substitué)-5-(hétéroaryle substitué)-1h-benzimidazole et recherche de leurs effets biologiques Download PDF

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Publication number
WO2021126118A1
WO2021126118A1 PCT/TR2020/051232 TR2020051232W WO2021126118A1 WO 2021126118 A1 WO2021126118 A1 WO 2021126118A1 TR 2020051232 W TR2020051232 W TR 2020051232W WO 2021126118 A1 WO2021126118 A1 WO 2021126118A1
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WO
WIPO (PCT)
Prior art keywords
spectrum
compound
synthesis
benzimidazole
imidazole
Prior art date
Application number
PCT/TR2020/051232
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English (en)
Inventor
Zafer Asim KAPLANCIKLI
Yusuf ÖZKAY
Ulviye ACAR ÇEVİK
Begüm Nurpelin SAĞLIK
Derya OSMANİYE
Serkan LEVENT
Betül KAYA ÇAVUŞOĞLU
Özlem ATLI EKLİOĞLU
Abdullah Burak KARADUMAN
Original Assignee
Anadolu Üni̇versi̇tesi̇
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from TR2020/04660A external-priority patent/TR202004660A2/tr
Application filed by Anadolu Üni̇versi̇tesi̇ filed Critical Anadolu Üni̇versi̇tesi̇
Publication of WO2021126118A1 publication Critical patent/WO2021126118A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention is related to the synthesis of 2-((5-(2-(4-Substitutedphenyl)-1H- benzo[d]imidazole-6-yl)-1,3,4-oxadiazole-2-yl)thio)-1-(4substitutedpiperazine-1-yl)-ethane- 1-one derivative compounds and the determination of anticancer activity effects of these compounds.
  • chemotherapy which is the most commonly used method among these, the apoptosis of cancer cells is targeted with chemical agents, while the cancer is stopped and its spreading is prevented.
  • chemotherapeutic drugs inhibit DNA-dependent RNA polymerase by forming DNA-drug complexes. Due to the high synthesis rate of enzymes involved in DNA metabolism in tumor cells, enzymes involved in DNA metabolism are selected as target molecules in antitumor drug design.
  • Topoisom erases are essential enzymes in DNA replication, transcription and recombination processes in both prokaryotes and eukaryotes. The inhibition of topoisomerase enzymes required in cell proliferation and their ability to stop the proliferation of uncontrolled and rapidly dividing cancer cells make these proteins anticancer drug targets.
  • US 2010/0069381 A1 is related to the synthesis of benzimidazole 1,3,4 oxadiazole derived compounds which can be used in the treatment of many diseases including cancer by inhibiting GSK-3 protein.
  • DNA synthesis inhibition of effective compounds was calculated by the BrDU proliferation method.
  • the apoptotic effects of the compounds were investigated by the Annexin V/PI method.
  • their effects on DNA Topoisomerase I enzyme were evaluated.
  • DNA Topoisomerase I enzyme inhibition assay the kit protocol described by the supplier (SKU TG1018-2A, TopoGen, USA) was applied.
  • the crystal structure was first prepared for docking studies by applying the Protein Preparation Wizard protocol included in Schrodinger Suite 2015 Update 2, the bond lengths were arranged using the OPLS 2005 force field, and the possible loads of the atoms on the charged amino acids under the specified environmental conditions were automatically determined.
  • the compounds to be docked were prepared for docking with the LigPrep 3.8 module. Grid was created with Glide 7.1 and docking process was performed with single precision (SP) using the same module.
  • Figure 1 The 24-hour and 48-hour antiproliferative effect of compound 5k on the C6 cell line with the BrdU proliferation method, is shown.
  • FIG. 1 The 24-hour and 48-hour antiproliferative effect of compounds 5b, 51 and 5n on the HeLa cell line with the BrdU proliferation method, is shown.
  • FIG. 3 The 24-hour and 48-hour antiproliferative effect of compound 5n on the A-549 cell line with the BrdU proliferation method, is shown.
  • FIG. 4 The antiproliferative effect of compound 5a on the HepG2 cell line with the BrdU proliferation method, is shown.
  • FIG. 5 With the BrdU proliferation method, the 24-hour and 48-hour antiproliferative effect of compounds 5a, 5d, 5e, 5o on the MCF-7 cell line is shown.
  • Figure 6 The results of apoptotic effects of compound 5n on A-549 cell line by the Annexin V/PI method.
  • Figure 7 The apoptotic effect results of the compound 5k on C6 cell line by the Annexin V/PI method
  • Figure 8 The apoptotic effect results of the compounds 5a, 5d, 5e and 5o on MCF-7 cell line by the Annexin V/PI method
  • Figure 10 The apoptotic effect results of the compounds 5b, 51 and 5n on HeLa cell line by the Annexin V/PI method
  • Figure 11 Electrophoresis imaging of the inhibitory effect of compounds 5a, 5b, 5d, 5e, 5k, 51, 5n, 5o and Hoechst 33342 and camptothecin on the DNA Topoisomerase I
  • Figure 27 1 HNMR spectrum and 13 CNMR spectrum of Compound 5h Figure 28: IR spectrum and mass spectrum of Compound 5i Figure 29: 1 HNMR spectrum and 13 CNMR spectrum of Compound 5i Figure 30: IR spectrum and mass spectrum of Compound 5j Figure 31: 1 HNMR spectrum and 13 CNMR spectrum of Compound 5j Figure 32: IR spectrum and mass spectrum of Compound 5k Figure 33: 1 HNMR spectrum and 13 CNMR spectrum of Compound 5k Figure 34: IR spectrum and mass spectrum of Compound 51 Figure 33: 1 HNMR spectrum and 13 CNMR spectrum of Compound 51 Figure 36: IR spectrum and mass spectrum of Compound 5m Figure 37: 1 HNMR spectrum and 13 CNMR spectrum of Compound 5m Figure 38: IR spectrum and mass spectrum of Compound 5n Figure 39: 1 HNMR spectrum and 13 CNMR spectrum of Compound 5n Figure 40: IR spectrum and mass spectrum of Compound 5o Figure 41: 1 HNMR spectrum and 13 CNMR spectrum of Compound 5o Figure 41: 1 HNMR
  • Figure 44 The van der Waals interaction of compound 5n with the active site of DNA- Topoisomerase I enzyme complex
  • Figure 45 The electrostatic interaction of compound 5n with the active site of DNA- Topoisomerase I enzyme complex
  • the invention relates to the synthesis of compound derivatives carrying the benzimidazole- 1,3,4-oxadiazole structure, evaluation of the anticancer activities and elucidation of the action mechanism on the DNA topoisomerase I enzyme and developing anticancer drugs.
  • 2-((5-(2-(4-substitutedphenyl)-1H-benzo[d]imidazole-6-yl)-1,3,4- oxadiazole-2-yl)thio)- 1 -(4substitutedpiperazine- 1 -yl)-ethane- 1 -one derivative compounds were synthesized and anticancer activity efficiencies of said compounds were investigated in five cancer cell lines, HeLa, MCF7, A549, HepG2 and C6. The activities of the active compounds on the DNA topoisomerase I enzyme have been proven.
  • the present invention is the compound of Formula (I) or pharmaceutically acceptable salt and/or solvate thereof,
  • R 1 substituent: OH, OCH 3 or OC 2 H 5
  • R 2 substituent: CH 3 , C 2 H 5
  • IC 50 values ( ⁇ M) of the compounds for cancer cell lines A549, MCF-7, C6, HepG2, HeLa and NIH3T3 were presented in Table 1. It was determined that the compounds whose anticancer activity was investigated on HeLa, MCF7, A549, HepG2 and C6 cancer cells showed higher activity against HeLa cancer cell lines compared to other cancer cell lines.
  • compounds 51 and 5n are the most active compounds with IC 50 values of 0.224 mM and 0.205 ⁇ M against HeLa cell line and these compounds are more effective compared to the reference drug doxorubicin (14.280 mM) and Hoechst 33342 (0.306 ⁇ M).
  • the pharmaceutical composition containing the compound according to the invention or pharmaceutically acceptable salt and/or solvate thereof has the potential to be used in the preparation of a drug to be used in the treatment of cancer.
  • Table 1 The IC 50 values ( ⁇ M) of the compounds for cell lines A549, MCF-7, C6, HepG2, HeLa and NIH3T3 Dox. 12.420 ⁇ 0.521 10.525 ⁇ 0.472 28.690 ⁇ 1.228 16.482 ⁇ 0.804 14.280 ⁇ 0.704 1110.80 ⁇ 8.254
  • the selectivity of the compounds of the invention against cancer cells A549, MCF-7, C6, HepG2, HeLa and NIH3T3 was evaluated in the NIH3T3 cell line and, as shown in Table 2, it was determined that compounds 51 and 5n have selectivity indices of 506.48 and 919.85 against HeLa cell. This finding increased the chance of the compounds to be anticancer agents against HeLa cell lines and the necessity to clarify the mechanism of action with more comprehensive studies was revealed.
  • the greatest criterion for anticancer drug candidates is that while it has toxic effects on cancer cells at low concentrations, it does not show the same effect on normal healthy cells. The biggest problem with existing drugs is their side effects. Therefore, it is aimed to discover compounds with high selectivity index today.
  • Apoptosis is a regular and programmed cell death that occurs during physiological or pathological processes. Necrosis is irregular and unscheduled cell death. The desired form of death in cells in cancer drugs is apoptosis. The death of the cancer cell by apoptosis indicates that some cellular mechanisms of the cancer cell are impaired and as a result, the cell will die. This shows that the drug affects the cell with a certain mechanism of action.
  • phosphatidylserine on the cytoplasmic surface of the cell membrane passes to the outer lipid layer of the cell membrane. This displacement takes place early in apoptosis.
  • annexin V is a protein that can bind to phosphatidylserine, this protein is labeled with a fluorescent agent (FITC) to make the apoptotic cell visible. This binding rate can also be measured with a flow cytometry device. Since annexin binding can also be seen in necrotic cells, staining with propidium iodide (PI), a vital dye, is also applied. Since the membranes of living cells are intact, they are not stained with PI dye.
  • FITC fluorescent agent
  • Living cells are distinguished as FITC Annexin V (-) / PI (-), early apoptotic cells as FITC Annexin V (+) / PI (-) and late apoptotic or necrotic cells as FITC (+) / PI (+).
  • the apoptotic effects of compounds and positive controls with selective anticancer activities detected by MTT cytotoxicity test were determined by Annexin V/PI method.
  • DNA Topoisomerase I inhibitory effects of compounds 5a, 5b, 5d, 5e, 5k, 51, 5n and 5o derivatives, which are prominent in terms of activity, were evaluated. When the inhibition effects of the tested compounds on the DNA topoisomerase I enzyme were examined, it was found that they had a toxic effect on the topoisomerase I enzyme. It was found that this strong inhibition effect was achieved by stabilizing the covalently linked DNA-topoisomerase I enzyme-cut complex and by preventing the recombination of DNA single strand breaks, thus causing the accumulation of permanent DNA single strand breaks.
  • Benzimidazole ring system has attracted attention in terms of polar and apolar interactions. Similarly, p- p interactions were observed between the purine ring of adenine (DAI 13) in the DNA chain separately in the benzene and imidazole rings of benzimidazole in the compound 5n. Also, in this compound, the benzene of benzimidazole has formed p- p interaction with Arg364. It has been determined that the nitrogen atom in the benzimidazole ring is important in terms of polar interactions. It has been observed that the oxadiazole ring in the structure of the compound 5n contributes to the binding to the DNA-Topoisom erase I enzyme complex active site. Oxadiazole ring formed p- p interaction with the pyrimidine of cytosine (DC112) in the compound 5n.
  • DC112 cytosine
  • the oxygen atom of the ethoxy group in the para position of the phenyl ring in compound 5n has formed a hydrogen bond with the hydroxyl of Thr718.
  • An additional cation-p interaction was observed between para-ethoxyphenyl and the amino group of Lys532 in the compound 5n.
  • the pyridine ring adjacent to the piperazine ring is included in the chemical structure of the compound whose molecular docking studies are carried out.
  • the pyridine ring system located in the position 4 of the piperazine ring is highly effective in binding to the DNA-Topoisom erase I enzyme complex active site. It has been observed that the nitrogen atoms in these ring systems are quite effective and important in binding to the relevant region.
  • Schema 1 The schematic representation of synthesis of 2-(4-Substitutedphenyl)-1H- benzo[d]imidazole-6-carboxylic acid derivatives b) Synthesis of 2-chloro-1-(4-substitutedpiperazine-1-yl)-ethane-1-one derivatives
  • Schema 2 The schematic representation of synthesis of 2-chloro-1-(4-substitutedpiperazine- l-yl)-ethane-1-one derivatives c) Synthesis of methyl 2-(4-substitutedphenyl)-lH-benzo[d]imidazole-6-carboxylate derivatives
  • Schema 3 The schematic representation of synthesis of methyl 2-(4-substitutedphenyl)-1H- benzo[d]imidazole-6-carboxylate derivatives d) Synthesis of 2-(4-substitutedphenyl)-lH-benzo[d]imidazole-6-carbohydrazide derivatives
  • Schema 4 The schematic representation of synthesis of 2-(4-substitutedphenyl)-1H- benzo[d]imidazole-6-carbohydrazide derivatives e) Synthesis of 2-((4-substitutedphenyl)-(6-(5-mercapto-l,3,4-oxadiazole-2-yl)-lH- benzo[d]imidazole derivatives
  • Schema 5 The schematic representation of synthesis of 2-((4-substitutedphenyl)-(6-(5- mercapto-1,3,4-oxadiazole-2-yl)-1H-benzo[d]imidazole derivatives f) Synthesis of 2-((5-(2-(4-substitutedphenyl)-lH-benzo[d]imidazole-6-yl)-l,3,4- oxadiazole-2-yl)thio)-1-(4-substitutedpiperazine-1-yl)-ethane-1-one derivatives
  • Schema 6 The schematic representation of synthesis of 2-((5-(2-(4-substitutedphenyl)-1H- benzo[d]imidazole-6-yl)-1,3,4-oxadiazole-2-yl)thio)- 1 -(4-substitutedpiperazine- 1 -yl)-ethane- 1-one derivatives
  • IR (ATR) vmax (cm -1 ): 3365 (N-H stretch band), 1645 (C 0 stretch band), 840 (1,4- disubstituted benzene out-of-plane deformation band).
  • IR (ATR) vmax (cm -1 ): 3361 (N-H stretch band), 1635 (C 0 stretch band), 840 (1,4- disubstituted benzene out-of-plane deformation band).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne la synthèse de composés dérivés de 2-((5-(2-(4-phényle substitué)-1H-benzo[d]imidazole-6-yle)-1,3,4-oxadiazole-2-yle)thio)-1-(4-pipérazine substitué-1-yle)-éthane-1-one et la recherche de leurs effets biologiques. La cytotoxicité des composés obtenus sur 5 lignées cellulaires cancéreuses différentes a été évaluée et leurs indices de sélectivité ont été calculés.
PCT/TR2020/051232 2019-12-20 2020-12-04 Synthèse de dérivés de 2-(phényle substitué)-5-(hétéroaryle substitué)-1h-benzimidazole et recherche de leurs effets biologiques WO2021126118A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
TR201920909 2019-12-20
TR2019/20909 2019-12-20
TR2020/04660A TR202004660A2 (tr) 2019-12-20 2020-03-25 2-(sübsti̇tüfeni̇l)-5-(sübsti̇tüeheteroari̇l)-1h-benzi̇mi̇dazol türevleri̇ni̇n sentezi̇ ve bi̇yoloji̇k etki̇leri̇ni̇n araştirilmasi
TR2020/04660 2020-03-25

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WO2021126118A1 true WO2021126118A1 (fr) 2021-06-24

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008075196A1 (fr) * 2006-12-15 2008-06-26 Pfizer Products Inc. Dérivés du benzamidazole
RU2333208C2 (ru) * 2002-06-13 2008-09-10 Вертекс Фармасьютикалз Инкорпорейтед Производные 2-уреидо-6-гетероарил-3н-бензимидазол-6-карбоновой кислоты и родственные соединения в качестве ингибиторов гиразы и/или топоизомеразы iv для лечения бактериальных инфекций

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2333208C2 (ru) * 2002-06-13 2008-09-10 Вертекс Фармасьютикалз Инкорпорейтед Производные 2-уреидо-6-гетероарил-3н-бензимидазол-6-карбоновой кислоты и родственные соединения в качестве ингибиторов гиразы и/или топоизомеразы iv для лечения бактериальных инфекций
WO2008075196A1 (fr) * 2006-12-15 2008-06-26 Pfizer Products Inc. Dérivés du benzamidazole

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BARIS ATAKAN ; OZGUR B. AKAN ; SASITHARAN BALASUBRAMANIAM: "Body area nanonetworks with molecular communications in nanomedicine", IEEE COMMUNICATIONS MAGAZINE., IEEE SERVICE CENTER, PISCATAWAY., US, vol. 50, no. 1, 1 January 2012 (2012-01-01), US, pages 28 - 34, XP011396931, ISSN: 0163-6804, DOI: 10.1109/MCOM.2012.6122529 *

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