DOCSLIB.ORG

Synthesis and Evaluation of Functionalized Imidazole and Triazoles As Novel Anti-Fungal Agents

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Synthesis and Evaluation of Functionalized Imidazole and Triazoles As Novel Anti-Fungal Agents Synthesis and Evaluation of Functionalized Imidazole and Triazoles as Novel Anti-fungal Agents A THESIS PRESENTED TO THE FACULTY OF THE UNIVERSITY OF MINNESOTA BY GRADY L. NELSON IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE DR. VENKATRAM R. MEREDDY SEPTEMBER 2014 © Grady L. Nelson. September 2014 ACKNOWLEDGEMENTS I would like to express my greatest gratitude to Dr. Venkatram Mereddy who has helped and supported me through my graduate career. I am grateful to my teacher for his continuous support, valuable advice, and his colossal amount of patience. I would also like to thank the members of my committee Dr. Erin Sheets and Dr. Steven Berry for their valuable time and help. Department of Chemistry and Biochemistry for its financial support for the past two years. I would also like to thank the faculty in the Department of Chemistry and Biochemistry for the knowledge and skills they have taught me. At last but not least I would like to thank my family Catherine, Gary and Jessica Nelson for their continued support and interest in my research and schooling. i ABSTRACT GRADY L. NELSON, Synthesis and Evaluation of Functionalized Imidazoles as Novel Anti-Fungal Agents, Master of Science (Department of Chemistry and Biochemistry), University of Minnesota. Fungal species are highly prevalent in our environment. Some are relatively harmless but there are others that are pathogenic. A problem arises when dermatophytes enter into the blood system. Commonly associated with immunocompromised patients, fungemia is when a fungal species enters the blood stream. Currently there are many treatments but there is a growing fear of resistance to these drugs and a need for novel therapeutics. The Baylis-Hillman reaction is a flexible template in which an aldehyde and various acrylates form a highly functionalized Baylis-Hillman derivative. In this paper, a small library of Baylis-Hillman reaction-derived imidazole and triazoles are synthesized and characterized. Furthermore, their anti-fungal activities are evaluated against Candida albicans and Cryptococcus neoformans. It was found that some of the derivatives showed moderate to good activity against Candida albicans (MIC 213-46.5 µg/ml) and Cryptococcus neoformans (MIC 5.50-1.68 µg/ml). ii TABLE OF CONTENTS I. ACKNOWLEDGEMENTS i II. ABSTRACT ii III. TABLE OF CONTENTS iii IV. LIST OF SCHEMES iv V. LIST OF FIGURES vi VI. LIST OF TABLES vi VII. LIST OF ABBREVIATIONS vii VIII. CHAPTER 1: INTRODUCTION 1 IX. CHAPTER 2: RESULTS AND DISCUSSION 26 X. CHAPTER 3: SPECTRAL CHARACTERIZATION 49 XI. REFERENCES 71 XI. APPENDIX A 75 iii LIST OF SCHEMES Scheme Title of the scheme Pg.No. Scheme 1.1 Multicomponent coupling for 1,2,4,5 – tetrasubstituted 3 imidazoles Scheme 1.2 Synthesis of naphthalimido imidazoles and triazoles 4 Scheme 1.3 Formation of 1-(3,5-diaryl-4,5-dihydro-1H-pyrazol-4- 5 yl)-1H-imidazole Scheme 1.4 Synthesis of the benzoxazinyl imidazole hybrids 6 Scheme 1.5 Synthesis of berberbine-imidazole hybrids 7 Scheme 1.6 Synthesis of novel 2-acetylnaphthalene derivatives 9 Scheme 1.7 Synthesis of a library of di-substituted imidazole based 10 alcohols Scheme 1.8 Synthesis of triazole clubbed benzothiazoles 11 Scheme 1.9 Synthesis of a series of Schiff base triazoles 14 Scheme 1.10 Synthesis of fluconazole based derivatives 16 Scheme 1.11 Synthesis of coumarin coupled triazole hybrids 18 Scheme 1.12 Hybrid derivatives of fluconazole and clinafloxacin 12 Scheme 1.13 Synthesis of fluconazole based derivatives 18 Scheme 1.14 Synthesis of novel 1,2,4-triazone based triazoles 19 iv Scheme 1.15 Synthesis of novel imidazole substituted phenyl 21 pyrrolylmethanones Scheme 1.16 Synthesis of a series of novel piperazine coupled 22 ketoconazole analogues Scheme 1.17 Synthesis of carbazole based imidazole and their 23 chloride salts Scheme 1.18 Synthesis of 2-phenyl-alkylbenzofurans 25 Scheme 2.1 Baylis-Hillman Reaction 27 Scheme 2.2 Nucleophilic Substitution of Baylis Hillman 33 derivatives Scheme 2.3 Baylis-Hillman Template 28 Scheme 2.4 Synthesis of imidazole and triazole derivatives 29 Scheme 2.5 Synthesis of electron donating group substituted 2- 30 (imidazolylmethyl) and 2-(triazolylmethyl) cinnamates Scheme 2.6 Synthesis of electron withdrawing group substituted 34 cinnamonitriles Scheme 2.7 Synthesis of β-Imidazolyl Styryl Methyl Ketone 35 v LIST OF FIGURES Figure 1.1 Commonly used fungal drugs 2 Figure 2.1 Baylis-Hillman template 28 Figure 2.2 Electron donating group substituted 2-(imidazolylmethyl) and 2- 31 (triazolylmethyl) cinnamates Figure 2.3 Electron withdrawing group substituted 2-(imidazolylmethyl) 32 cinnamates Figure 2.4 Electron withdrawing group substituted 2-(triazolylmethyl) 33 cinnamates Figure 2.5 Electron withdrawing group substituted 2-(imidazolylmethyl) 34 and 2-(triazolylmethyl) cinnamonitriles Figure 2.6 Electron donating group substituted 2-(imidazolylmethyl) styryl 35 methyl ketones Figure 2.7 2-(Imidazolylmethyl)/ 2-(aminomethyl) cinnamates 36 Figure 2.8 Inference 47 Figure 2.9 Proposed further studies 48 LIST OF TABLES Table 1 Zone of inhibition of imidazoles and triazoles 37 Table 2 Minimum inhibitory concentration of imidazoles and triazoles 43 against Cryptococcus neoformans (ATCC 32045) Table 3 MIC of imdazoles and Triazoles against Candida albicans 44 (ATCC 90028) vi LIST OF ABBREVIATIONS MIC Minimum inhibitor concentration NH4OAc Ammonium Acetate Cu(NO3)2 Copper (II) Nitrate CH3CN Acetonitrile K2CO3 Potassium Nitrate NaH- Sodium hydride THF- Tetrahydrofuran DMF- N, N – Dimethylformamide tBuOK Potassium tert-butoxide Ts p-toluenesulfonate Ms methanesulfinate PBr3 Phosphorous Tribromide EtOH Ethanol DCC N,N’-Dicyclohexylcarbodiimide vii DMAP 4-Dimethylaminopyridine NaBH4- Sodium borohydrate AcOH Acetic Acid NH2NH2 Hydrazine Hydrate POCl3 Phosphoryl chloride CS2 Carbon Disulfide AlCl3 Aluminum Chloride NaHCO3 Sodium Carbonate NaN3 Sodium azide CuSO4 Copper (II) sulfate CHCl3 Chloroform CH2Cl2 (DCM) Methylene chloride (Dichloromethane) Et3N Triethylamine LiAlH4 Lithium aluminum hydride DMA- Dimethylacetamide DMSO- Dimethyl sulfoxide MsCl Methanesulfonyl chloride DABCO 1,4-diazabicyclo[2.2.2]octane viii Ac2O Acetic anhydride H2SO4 Sulfuric acid Nu Nucleophile EWG Electron withdrawing group Py Pyridine AcCl Acetyl chloride ix Chapter 1: Introduction Fungal species are prevalent and many of them are harmless or even good for the environment. However, there are specific strains that are pathogenic. These strains usually are contagious and easily contracted when present. Dermatophytes describes fungal species that cause infections of the skin, hair, and nails and affect at least 10% of the population. Their ability to survive in these conditions comes from the ability to metabolize keratinized material.1 A common infection of the fungal variety is candidiasis. This classification of infection is usually caused by Candida albicans, which is one of the most opportunistic species of fungus in immuno- compromised patients. This type of infection can be divided into two types: superficial and systemic.1 Superficial fungal infections are commonly referred to as thrush, whether oral or vaginal, and it is distinguished by an overgrowth of a fungal species. Vaginal candidias is commonly referred to as yeast infection and affects seventy five percent of women.2 Systemic fungal infections are internal fungal infections that spread through the body, and are usually life threatening. In a hospital setting candidias is the prevalent systemic fungal infection and is ranked fourth in hospital acquired blood stream infections, and is called candidemia.3 Although candidias is the most prevalent, it is part of a much larger problem known as fungemia. Fungemia is a normal fungal infection invading the blood stream, and it is one of many health care associated infections known as mycoses. Systemic mycoses due to opportunist pathogens is most commonly attributed to fungal species, in particular Candida, Aspergillus, and Cryptococcus.4 Candida is the most prevalent form of mycoses. It has been found that sepsis caused by fungemia has increased by 207% between 1979 and 2000,5 and the list of fungemia causing species are increasing 1 every year.3-6 Mycosis is commonly associated with immuno-compromised patients although they are not the only ones at risk. One of the most common ways an immuno- competent person can contract a systemic fungal infection is through intensive care centers, specifically through catheters. A recent report from a cancer center stated that most infections were catheter-related fungemias.4-7 Over the years there have been many advances in the treatment of these fungal infections in the form of various imidazole and triazole drugs. Some of the clinically used drugs are shown below (Figure 1). 2 Figure 1: Commonly used fungal drugs However, many of these fungal species have become resistant to these common drugs over the years.7 Resistance has spurred new interest in novel structures, leading to an increased rush towards the development of new generation anti-fungal agents. The following paragraphs outline some of the recent molecules that have been synthesized for antifungal activity that showed some potency, and influenced the design of our library. Sivakumar et al. reported a simple methodology involving multicomponent coupling of diketones with aldehydes and amines for the synthesis of functionalized 8 1,2,4,5-tetrasubstituted imidazoles 4 (Scheme 1.1). Zeolite supported Cu(NO3)2 was used as a catalyst in this reaction. Specifically, this
Load more

Recommended publications
  • 194 Recent Advances in the Synthesis of New Pyrazole Derivatives
    194 RECENT ADVANCES IN THE SYNTHESIS OF NEW PYRAZOLE DERIVATIVES DOI: http://dx.medra.org/ 10.17374/targets.2019.22.194 Juan - Carlos Castillo a,b , Jaime Portilla a * a Bioorganic Compounds Research Group, Department of Chemistry, Universi dad de los Andes, Carrera 1 No. 18A - 10, Bogotá, Colombia b Grupo de Cat álisis, E scuela de Ciencias Químicas, Universidad Pedagógica y Tecnológica de Colombia UPTC, Av enida Central del Norte, Tunja, Colombia (e - mail : [email protected] ) Abstract. Pyrazoles have attracted great attention in organic and medicinal chemistry, due to their proven utility as synthetic intermediates for the preparation of diverse bioactive compounds, of coordination complexes, as well as in the design of functional materials. Consequently , the synthesis of functionalized pyrazoles is an important focus of research for synthetic organic chemists. Likewise, fuse d pyrazoles such as pyrazolo[1,5 - a]pyrimidines and pyrazolo[3,4 - b]pyridines have been widely studied due to their varied biological and physicochemical applications based on the important electronic properties of th ese N - heterocycles. Therefore, the preparation of these fused heterocycles and of their functionalized derivatives is of notable interest to both uncover novel derivatives and explore new applications. Several methods have been described in the literature for the synthesis of pyrazoles and of their fused systems in recent years , which mainly involve classi cal cyclocondensation reactions , some of these are presented in th is contribution. Contents 1. Introduction 2. Functionalized pyrazoles 2.1. Aminopyrazoles 2.2. Formylpyrazoles 3. Fused pyrazoles 3.1. Pyrazolo[1,5 - a ]pyrimidines 3.2. Pyrazolo[3,4 - b ]pyridines 3.3.
    [Show full text]
  • Aniline and Aniline Hydrochloride
    SOME AROMATIC AMINES AND RELATED COMPOUNDS VOLUME 127 This publication represents the views and expert opinions of an IARC Working Group on the Identification of Carcinogenic Hazards to Humans, which met remotely, 25 May–12 June 2020 LYON, FRANCE - 2021 IARC MONOGRAPHS ON THE IDENTIFICATION OF CARCINOGENIC HAZARDS TO HUMANS ANILINE AND ANILINE HYDROCHLORIDE 1. Exposure Characterization 1.1.2 Structural and molecular formulae, and relative molecular mass 1.1 Identification of the agent (a) Aniline 1.1.1 Nomenclature NH2 (a) Aniline Chem. Abstr. Serv. Reg. No.: 62-53-3 EC No.: 200-539-3 Molecular formula: C H N IUPAC systematic name: aniline 6 7 Relative molecular mass: 93.13 (NCBI, 2020a). Synonyms and abbreviations: benzenamine; phenylamine; aminobenzene; aminophen; (b) Aniline hydrochloride aniline oil. NH2 (b) Aniline hydrochloride Chem. Abstr. Serv. Reg. No.: 142-04-1 EC No.: 205-519-8 HCl IUPAC systematic name: aniline hydro - Molecular formula: C6H8ClN chloride Relative molecular mass: 129.59 (NCBI, Synonyms: aniline chloride; anilinium chlo- 2020b). ride; benzenamine hydrochloride; aniline. HCl; phenylamine hydrochloride; phenylam- monium chloride. 1.1.3 Chemical and physical properties of the pure substance Aniline is a basic compound and will undergo acid–base reactions. Aniline and its hydrochlo- ride salt will achieve a pH-dependent acid–base equilibrium in the body. 109 IARC MONOGRAPHS – 127 (a) Aniline Octanol/water partition coefficient (P): log Kow, 0.936, predicted median (US EPA, 2020b) Description: aniline appears as a yellowish Conversion factor: 1 ppm = 5.3 mg/m3 [calcu- to brownish oily liquid with a musty fishy lated from: mg/m3 = (relative molecular odour (NCBI, 2020a), detectable at 1 ppm 3 mass/24.45) × ppm, assuming temperature [3.81 mg/m ] (European Commission, 2016; (25 °C) and pressure (101 kPa)].
    [Show full text]
  • Synthetic Turf Scientific Advisory Panel Meeting Materials
    California Environmental Protection Agency Office of Environmental Health Hazard Assessment Synthetic Turf Study Synthetic Turf Scientific Advisory Panel Meeting May 31, 2019 MEETING MATERIALS THIS PAGE LEFT BLANK INTENTIONALLY Office of Environmental Health Hazard Assessment California Environmental Protection Agency Agenda Synthetic Turf Scientific Advisory Panel Meeting May 31, 2019, 9:30 a.m. – 4:00 p.m. 1001 I Street, CalEPA Headquarters Building, Sacramento Byron Sher Auditorium The agenda for this meeting is given below. The order of items on the agenda is provided for general reference only. The order in which items are taken up by the Panel is subject to change. 1. Welcome and Opening Remarks 2. Synthetic Turf and Playground Studies Overview 4. Synthetic Turf Field Exposure Model Exposure Equations Exposure Parameters 3. Non-Targeted Chemical Analysis Volatile Organics on Synthetic Turf Fields Non-Polar Organics Constituents in Crumb Rubber Polar Organic Constituents in Crumb Rubber 5. Public Comments: For members of the public attending in-person: Comments will be limited to three minutes per commenter. For members of the public attending via the internet: Comments may be sent via email to [email protected]. Email comments will be read aloud, up to three minutes each, by staff of OEHHA during the public comment period, as time allows. 6. Further Panel Discussion and Closing Remarks 7. Wrap Up and Adjournment Agenda Synthetic Turf Advisory Panel Meeting May 31, 2019 THIS PAGE LEFT BLANK INTENTIONALLY Office of Environmental Health Hazard Assessment California Environmental Protection Agency DRAFT for Discussion at May 2019 SAP Meeting. Table of Contents Synthetic Turf and Playground Studies Overview May 2019 Update .....
    [Show full text]
  • Synthesis of Pyrazoles Containing Benzofuran and Trifluoromethyl Moieties As Possible Anti-Inflammatory and Analgesic Agents
    Z. Naturforsch. 2015; 70(7)b: 519–526 Awatef A. Farag, Mohamed F. El Shehry, Samir Y. Abbas*, Safaa N. Abd-Alrahman, Abeer A. Atrees, Hiaat Z. Al-basheer and Yousry A. Ammar Synthesis of pyrazoles containing benzofuran and trifluoromethyl moieties as possible anti-inflammatory and analgesic agents DOI 10.1515/znb-2015-0009 and anti-inflammatory drugs present a wide range of prob- Received January 9, 2015; accepted February 4, 2015 lems such as efficacy and undesired effects including gas- trointestinal tract (GIT) disorders and other unwanted effects. This situation highlights the need for novel, safe and Abstract: Searching for new anti-inflammatory and anal- effective analgesic and anti-inflammatory compounds [1–3]. gesic agents, we have prepared a series of novel pyrazoles Since the first pyrazolin-5-one was prepared by Knorr containing benzofuran and trifluoromethyl moieties. The [4] in 1883, many papers have reported on the anti-inflam- pyrazole derivatives have been synthesized via two routes matory, analgesic and antipyretic evaluation of several starting from 5-(3-(trifluoromethyl)phenyl azo) salicylal- pyrazoles, pyrazolin-3-ones and pyrazolidine-3,5-diones dehyde. The first route involved the synthesis of 2-acetylb- [5–9]. Many of these derivatives such as phenylbutazone, enzofuran and then treatment with aldehydes to afford febrazone, feclobuzone, mefobutazone, suxibuzone and the corresponding chalcones. The cyclization of the latter ramifenazone have found their clinical application as chalcones with hydrazine hydrate led to the formation of nonsteroidal anti-inflammatory drugs (NSAIDs) [10]. new pyrazoline derivatives. The second route involved the The benzofuran derivatives have attracted due to their synthesis of benzofuran-2-carbohydrazide and then treat- biological activities and potential application as pharma- ment with formylpyrazoles, chalcones and ketene dith- cological agents [11].
    [Show full text]
  • Introduced B.,Byhansen, 16
    LB301 LB301 2021 2021 LEGISLATURE OF NEBRASKA ONE HUNDRED SEVENTH LEGISLATURE FIRST SESSION LEGISLATIVE BILL 301 Introduced by Hansen, B., 16. Read first time January 12, 2021 Committee: Judiciary 1 A BILL FOR AN ACT relating to the Uniform Controlled Substances Act; to 2 amend sections 28-401, 28-405, and 28-416, Revised Statutes 3 Cumulative Supplement, 2020; to redefine terms; to change drug 4 schedules and adopt federal drug provisions; to change a penalty 5 provision; and to repeal the original sections. 6 Be it enacted by the people of the State of Nebraska, -1- LB301 LB301 2021 2021 1 Section 1. Section 28-401, Revised Statutes Cumulative Supplement, 2 2020, is amended to read: 3 28-401 As used in the Uniform Controlled Substances Act, unless the 4 context otherwise requires: 5 (1) Administer means to directly apply a controlled substance by 6 injection, inhalation, ingestion, or any other means to the body of a 7 patient or research subject; 8 (2) Agent means an authorized person who acts on behalf of or at the 9 direction of another person but does not include a common or contract 10 carrier, public warehouse keeper, or employee of a carrier or warehouse 11 keeper; 12 (3) Administration means the Drug Enforcement Administration of the 13 United States Department of Justice; 14 (4) Controlled substance means a drug, biological, substance, or 15 immediate precursor in Schedules I through V of section 28-405. 16 Controlled substance does not include distilled spirits, wine, malt 17 beverages, tobacco, hemp, or any nonnarcotic substance if such substance 18 may, under the Federal Food, Drug, and Cosmetic Act, 21 U.S.C.
    [Show full text]
  • Heterocyclic Chemistrychemistry
    HeterocyclicHeterocyclic ChemistryChemistry Professor J. Stephen Clark Room C4-04 Email: [email protected] 2011 –2012 1 http://www.chem.gla.ac.uk/staff/stephenc/UndergraduateTeaching.html Recommended Reading • Heterocyclic Chemistry – J. A. Joule, K. Mills and G. F. Smith • Heterocyclic Chemistry (Oxford Primer Series) – T. Gilchrist • Aromatic Heterocyclic Chemistry – D. T. Davies 2 Course Summary Introduction • Definition of terms and classification of heterocycles • Functional group chemistry: imines, enamines, acetals, enols, and sulfur-containing groups Intermediates used for the construction of aromatic heterocycles • Synthesis of aromatic heterocycles • Carbon–heteroatom bond formation and choice of oxidation state • Examples of commonly used strategies for heterocycle synthesis Pyridines • General properties, electronic structure • Synthesis of pyridines • Electrophilic substitution of pyridines • Nucleophilic substitution of pyridines • Metallation of pyridines Pyridine derivatives • Structure and reactivity of oxy-pyridines, alkyl pyridines, pyridinium salts, and pyridine N-oxides Quinolines and isoquinolines • General properties and reactivity compared to pyridine • Electrophilic and nucleophilic substitution quinolines and isoquinolines 3 • General methods used for the synthesis of quinolines and isoquinolines Course Summary (cont) Five-membered aromatic heterocycles • General properties, structure and reactivity of pyrroles, furans and thiophenes • Methods and strategies for the synthesis of five-membered heteroaromatics
    [Show full text]
  • Proceedings of the Indiana Academy of Science
    Michael Addition and Derivatives of 2-Carboxamido-3-phenylindenone' E. Campaigne and David A. Templer Department of Chemistry Indiana University, Bloomington, Indiana 47405 Introduction Recently we have submitted several reports (6,7,8) dealing with the synthesis and reactions of 3-substituted 2-carboxamidoindenones. Among the reactions which these compounds undergo is a fascile Michael addition, and we wish to report here the addi- tion of a variety of nucleophiles to 2-carboxamido-3-phenylindenone (1) and some of the products derived from these compounds. The Michael reaction, now one hundred years old, is a useful synthetic tool that has led to a vast amount of research on its scope and limitations. It is the subject of an extensive review (1). The reaction generally refers to the addition of a nucleophile to a conjugated double bond which involves a series of reversible equilibrium reactions. Thus the reverse of Michael addition may occur, and products may be unstable on isolation. The synthesis of indenones via the cyclization of ylidenemalononitriles has been extensively studied in our laboratories (5). The first reported Michael addition to an in- denone was rather recent. In 1960, Koelsch (9) found that 2-carbethoxy-3-phenyl-l- indenone reacts readily with a variety of carbanions and other nucleophiles to give Michael adducts, but he was unable to alkylate the intermediate ions formed by these reactions. Addition of hydroxide, alkoxide, or amines led to the isolation of unstable crude ad- ducts, which reverted to the starting indenones on standing or in solution (10). Discussion The preparation of 3-cyano-3-phenyl-2-carboxamidoindanone (2a, Scheme 1) by the addition of cyanide to 1 has been previously reported (6).
    [Show full text]
  • Properties, Synthesis and Transformations Pedro M
    molecules Review ReviewStyrylpyrazoles: Properties, Synthesis and Styrylpyrazoles:Transformations Properties, Synthesis and Transformations Pedro M. O. Gomes, Pedro M. S. Ouro, Artur M. S. Silva * and Vera L. M. Silva * PedroLAQV-REQUIMTE, M. O. Gomes Department, Pedro M.of Chemistry, S. Ouro, Artur University M. S. of Silva Aveiro, * 3810-193and Vera Aveiro, L. M. Portugal; Silva * LAQV-REQUIMTE,[email protected] (P.M.O.G.); Department [email protected] of Chemistry, University(P.M.S.O.) of Aveiro, 3810-193 Aveiro, Portugal; [email protected]* Correspondence: (P.M.O.G.); [email protected] [email protected] (A.M.S.S.); (P.M.S.O.) [email protected] (V.L.M.S.); Tel.: +351-234-370714 (A.M.S.S.); * Correspondence:+351-234-370704 (V.L.M.S.) [email protected] (A.M.S.S.); [email protected] (V.L.M.S.); Tel.: +351-234-370714 (A.M.S.S.); +351-234-370704 (V.L.M.S.) Academic Editor: Derek J. McPhee Academic Editor: Derek J. McPhee Received: 21 November 2020; Accepted: 9 December 2020; Published: date Received: 21 November 2020; Accepted: 9 December 2020; Published: 12 December 2020 Abstract: The pyrazole nucleus and its reduced forms, pyrazolines and pyrazolidine, are privileged Abstract:scaffolds inThe medicinal pyrazole chemistry nucleus and due its to reduced their rema forms,rkable pyrazolines biological and activities. pyrazolidine, A huge are number privileged of scapyrazoleffolds inderivatives medicinal have chemistry been duestudied to their and remarkablereported over biological time. activities.This review A hugearticle number gives an of pyrazoleoverview derivatives of pyrazole have derivatives been studied that and contain reported a styryl over time.
    [Show full text]
  • [5-(4-Nitrophenyl)-2- Furyl]-4-Pyrazole-Carbaldehydes
    Article Volume 11, Issue 4, 2021, 12159 - 12169 https://doi.org/10.33263/BRIAC114.1215912169 Synthesis and Evaluation of Antimicrobial Activities of New Functional Derivatives of 3-[5-(4-Nitrophenyl)-2- Furyl]-4-Pyrazole-Carbaldehydes Marianna Barus 1,* , Diana Rotar 2 , Mykhailo Bratenko 1 , Nadiya Panasenko 1 , Viktor Zvarych 4 , Maryna Stasevych 4 , Mykhailo Vovk 3 1 Department of Medical and Pharmaceutical Chemistry, Bukovinian State Medical University, 58000 Chernivtsi, Ukraine 2 Department of Microbiology and Virology, Bukovinian State Medical University, 58000 Chernivtsi, Ukraine 3 Department of Mechanism of Organic Reactions, Institute of Organic Chemistry of National Academy of Sciences of Ukraine, 02660 Kyiv, Ukraine 4 Department of Technology of Biologically Active Substances, Pharmacy, and Biotechnology, Lviv Polytechnic National University, 79013 Lviv, Ukraine * Correspondence: [email protected]; Scopus Author ID 35793185800 Received: 1.12.2020; Revised: 28.12.2020; Accepted: 29.12.2020; Published: 2.01.2021 Abstract: The analysis of the biological potential of derivatives of 4-alkenyl- and imino functionalized pyrazoles is carried out, based on which the expediency of design of new structures with pharmacophore 5-(4-nitrophenyl)furanyl fragment is substantiated. Their synthesis method using a structural modification of 3-[5-(4-nitrophenyl)furan-2-yl]pyrazole-4-carbaldehyde to the corresponding alkenyl derivatives under the action of malononitrile, ethyl cyanoacetate, cyanoacetamide, and thioxoimidazolidine is proposed. The hydrazones, (thio)semicarbazones, and oximes were obtained by the condensation of corresponding aldehydes with hydrazides, (thio)semicarbazides, and hydroxylamine. The synthesized compounds' composition and structure were determined by elemental analysis, IR, and 1H NMR spectra. The fact existence of a mixture of E/Z-isomers among the series of obtained hydrazones of 1-phenyl-4-pyrazolecarbaldehydes was determined, and the quantitative ratio of geometric isomers was determined using 1H NMR spectroscopy data.
    [Show full text]
  • Essentials of Heterocyclic Chemistry-I Heterocyclic Chemistry
    Baran, Richter Essentials of Heterocyclic Chemistry-I Heterocyclic Chemistry 5 4 Deprotonation of N–H, Deprotonation of C–H, Deprotonation of Conjugate Acid 3 4 3 4 5 4 3 5 6 6 3 3 4 6 2 2 N 4 4 3 4 3 4 3 3 5 5 2 3 5 4 N HN 5 2 N N 7 2 7 N N 5 2 5 2 7 2 2 1 1 N NH H H 8 1 8 N 6 4 N 5 1 2 6 3 4 N 1 6 3 1 8 N 2-Pyrazoline Pyrazolidine H N 9 1 1 5 N 1 Quinazoline N 7 7 H Cinnoline 1 Pyrrolidine H 2 5 2 5 4 5 4 4 Isoindole 3H-Indole 6 Pyrazole N 3 4 Pyrimidine N pK : 11.3,44 Carbazole N 1 6 6 3 N 3 5 1 a N N 3 5 H 4 7 H pKa: 19.8, 35.9 N N pKa: 1.3 pKa: 19.9 8 3 Pyrrole 1 5 7 2 7 N 2 3 4 3 4 3 4 7 Indole 2 N 6 2 6 2 N N pK : 23.0, 39.5 2 8 1 8 1 N N a 6 pKa: 21.0, 38.1 1 1 2 5 2 5 2 5 6 N N 1 4 Pteridine 4 4 7 Phthalazine 1,2,4-Triazine 1,3,5-Triazine N 1 N 1 N 1 5 3 H N H H 3 5 pK : <0 pK : <0 3 5 Indoline H a a 3-Pyrroline 2H-Pyrrole 2-Pyrroline Indolizine 4 5 4 4 pKa: 4.9 2 6 N N 4 5 6 3 N 6 N 3 5 6 3 N 5 2 N 1 3 7 2 1 4 4 3 4 3 4 3 4 3 3 N 4 4 2 6 5 5 5 Pyrazine 7 2 6 Pyridazine 2 3 5 3 5 N 2 8 N 1 2 2 1 8 N 2 5 O 2 5 pKa: 0.6 H 1 1 N10 9 7 H pKa: 2.3 O 6 6 2 6 2 6 6 S Piperazine 1 O 1 O S 1 1 Quinoxaline 1H-Indazole 7 7 1 1 O1 7 Phenazine Furan Thiophene Benzofuran Isobenzofuran 2H-Pyran 4H-Pyran Benzo[b]thiophene Effects of Substitution on Pyridine Basicity: pKa: 35.6 pKa: 33.0 pKa: 33.2 pKa: 32.4 t 4 Me Bu NH2 NHAc OMe SMe Cl Ph vinyl CN NO2 CH(OH)2 4 8 5 4 9 1 3 2-position 6.0 5.8 6.9 4.1 3.3 3.6 0.7 4.5 4.8 –0.3 –2.6 3.8 6 3 3 5 7 4 8 2 3 5 2 3-position 5.7 5.9 6.1 4.5 4.9 4.4 2.8 4.8 4.8 1.4 0.6 3.8 4 2 6 7 7 3 N2 N 1 4-position
    [Show full text]
  • Laws 2021, LB236, § 4
    LB236 LB236 2021 2021 LEGISLATIVE BILL 236 Approved by the Governor May 26, 2021 Introduced by Brewer, 43; Clements, 2; Erdman, 47; Slama, 1; Lindstrom, 18; Murman, 38; Halloran, 33; Hansen, B., 16; McDonnell, 5; Briese, 41; Lowe, 37; Groene, 42; Sanders, 45; Bostelman, 23; Albrecht, 17; Dorn, 30; Linehan, 39; Friesen, 34; Aguilar, 35; Gragert, 40; Kolterman, 24; Williams, 36; Brandt, 32. A BILL FOR AN ACT relating to law; to amend sections 28-1202 and 69-2436, Reissue Revised Statutes of Nebraska, and sections 28-401 and 28-405, Revised Statutes Cumulative Supplement, 2020; to redefine terms, change drug schedules, and adopt federal drug provisions under the Uniform Controlled Substances Act; to provide an exception to the offense of carrying a concealed weapon as prescribed; to define a term; to change provisions relating to renewal of a permit to carry a concealed handgun; to provide a duty for the Nebraska State Patrol; to eliminate an obsolete provision; to harmonize provisions; and to repeal the original sections. Be it enacted by the people of the State of Nebraska, Section 1. Section 28-401, Revised Statutes Cumulative Supplement, 2020, is amended to read: 28-401 As used in the Uniform Controlled Substances Act, unless the context otherwise requires: (1) Administer means to directly apply a controlled substance by injection, inhalation, ingestion, or any other means to the body of a patient or research subject; (2) Agent means an authorized person who acts on behalf of or at the direction of another person but does not include a common or contract carrier, public warehouse keeper, or employee of a carrier or warehouse keeper; (3) Administration means the Drug Enforcement Administration of the United States Department of Justice; (4) Controlled substance means a drug, biological, substance, or immediate precursor in Schedules I through V of section 28-405.
    [Show full text]
  • Synthesis and Pharmacological Activities of Pyrazole Derivatives: a Review
    Review Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review Khalid Karrouchi 1,2,3, Smaail Radi 2,*, Youssef Ramli 1, Jamal Taoufik 1, Yahia N. Mabkhot 4,*, Faiz A. Al-aizari 4 and M’hammed Ansar 1 1 Medicinal Chemistry Laboratory, Faculty of Medicine and Pharmacy, Mohammed V University, 10100 Rabat, Morocco; [email protected] (K.K.); [email protected] (Y.R.); [email protected] (J.T.); [email protected] (M.A.) 2 LCAE, Department of Chemistry, Faculty of Sciences, University Mohamed I, 60000 Oujda, Morocco 3 Physicochemical service, Drugs Quality Control Laboratory, Division of Drugs and Pharmacy, Ministry of Health, 10100 Rabat, Morocco 4 Department of Chemistry, Faculty of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; [email protected] * Correspondence: [email protected] or [email protected] (S.R.); [email protected] (Y.N.M.); Tel.: +212-536-500-601 (S.R.) Received: 22 November 2017; Accepted: 5 January 2018; Published: 12 January 2018 Abstract: Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antipsychotic CDPPB, the anti-obesity drug rimonabant, difenamizole, an analgesic, betazole, a H2-receptor agonist and the antidepressant agent fezolamide have proved the pharmacological potential of the pyrazole moiety. Owing to this diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. This review highlights the different synthesis methods and the pharmacological properties of pyrazole derivatives.
    [Show full text]