Synthesis and Biological Evaluation of N-Pyrazolyl Derivatives And
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molecules Article Synthesis and Biological Evaluation of N- Pyrazolyl Derivatives and Pyrazolopyrimidine Bearing a Biologically Active Sulfonamide Moiety as Potential Antimicrobial Agent Hend N. Hafez 1,2,* and Abdel-Rhman B.A. El-Gazzar 1,2 1 Department of Chemistry, College of Science, Al-Imam Mohammad Ibn Saud Islamic University (IMSIU), P.O. Box: 90950 Riyadh 11623, Saudi Arabia; [email protected] 2 Photochemistry Department, Heterocyclic & Nucleosides Unit, National Research Centre, Dokki, Giza 12622, Egypt * Correspondence: [email protected]; Tel.: +966-50-424-7876 Academic Editor: Derek J. McPhee Received: 1 August 2016; Accepted: 25 August 2016; Published: 31 August 2016 Abstract: A series of novel pyrazole-5-carboxylate containing N-triazole derivatives 3,4; different heterocyclic amines 7a–b and 10a–b; pyrazolo[4,3-d]pyrimidine containing sulfa drugs 14a,b; and oxypyrazolo[4,3-d]pyrimidine derivatives 17, 19, 21 has been synthesized. The structure of the newly synthesized compounds was elucidated on the basis of analytical and spectral analyses. All compounds have been screened for their in vitro antimicrobial activity against three gram-positive and gram-negative bacteria as well as three fungi. The results revealed that compounds 14b and 17 had more potent antibacterial activity against all bacterial strains than reference drug Cefotaxime. Moreover compounds 4, 7b, and 12b showed excellent antifungal activities against Aspergillus niger and Candida albicans in low inhibitory concentrations but slightly less than the reference drug miconazole against Aspergillus flavus. Keywords: pyrazole derivatives; pyrazolo[4,3-d]pyrimidine; N-substituted benzenesulfonamides; antimicrobial agent 1. Introduction Antimicrobial resistance has become a serious health problem, so the increased rate of microbial infections and resistance to antimicrobial agents [1] prompted us to identify a novel structure that may be used in designing new, potent, and broad spectrum antimicrobial agents. Pyrazoles are one of the most common pharmaceutically active compounds, and have attracted much attention due to their broad spectrum of biological activities such as anti-inflammatory [2,3], COX inhibitory [4], hypoglycemic [5], CDK2/Cyclin A [6], p38 MAP kinase [7], and antidepressive activities [8], and have been widely used in biopharmaceutical and pesticides. Pyrazole plays a unique role in drug discovery programs. Pyrazole derivatives are an important class of heterocyclic compounds showing a wide range of biological activities such as antimicrobial [9–11] (Figure1). Pyrazolopyrimidines have important biological functions including herbicidal [12] and antitumor activity [13]; pyrazolopyrimidine derivatives have been found as purine analogs [14] and have significant properties as antimetabolites in purine biochemical reactions such as neuropeptide Y1 receptor antagonists [15]. Also, the pyrazolo[4,3-d]pyrimidinone class of compounds is very important in the treatment of impotence [16], used as an PDE5 inhibitor. PP30 possesses a good kinase selectivity profile used as ATP-competitive mTORC1/mTORC2 inhibitors [17,18] (Figure1). In view of these observations and as a continuation of our previous work on heterocyclic chemistry, we report herein Molecules 2016, 21, 1156; doi:10.3390/molecules21091156 www.mdpi.com/journal/molecules Molecules 2016, 21, 1156 2 of 15 Molecules 2016, 21, 1156 2 of 14 Molecules 2016, 21, 1156 2 of 14 the synthesis of some new heterocyclic-containing pyrazolo[3,2- d]pyrimidine moieties and the study of their antimicrobial activities inin comparisoncomparison toto Cefotaxime andand miconazolemiconazole asas referencereference drugs.drugs. N N N N N N H2N N N H2N N H N N H S N H NH N H N NH2 N S N 2 O N O O O N O O S S Sulphaphenazole Sulphaphenazole 3-Arylamido-thiazolyl-pyrazolo- pyrimidine3-Arylamido-thiazolyl-pyrazolo- (PP30) pyrimidine (PP30) H O H O N H N N O O N N O H N N Ac N S O N Ac N N S N O N N N N O N N N N OEt CN OEt O F CN O F 6-Aryl-piperazinylsulfonpyrazolo Cyanopyrazol Analog pyrimidine6-Aryl-piperazinylsulfonpyrazolo (PDE 5) Cyanopyrazol Analog pyrimidine (PDE 5) Figure 1.1. AntimicrobialAntimicrobial agents agents containing pyrazole moiety; pyrazolopyrimidine scaffold based potential candidates and drugs.drugs. 2. Results Results 2.1. Chemistry Pyrazoles are are one one of ofthe the most most promising promising targets targets for the for development the development of new antimicrobial of new antimicrobial agents. In ouragents. recent In work our recent [9], several work pyrazole [9], several derivatives pyrazole were derivatives designed were with designed potent antibacterial with potent and antibacterial anticancer activities.and anticancer In this activities. study, novel In this small study, molecules novel small elaborated molecules around elaborated N-substituted around N -substitutedpyrazol-5-carboxylate pyrazol-5- andcarboxylate pyrazolopyrimidine and pyrazolopyrimidine scaffolds were scaffolds synthesized. were synthesized. Ethyl 4-amino-3-(4-chlorophenyl)-1 Ethyl 4-amino-3-(4- chlorophenyl)-1H-pyrazol-H- pyrazol-5-carboxylate5-carboxylate (1) is a precursor (1) is a precursorto synthesize to synthesize pyrazole derivatives pyrazole derivativesand pyrazolopyrimidine.and pyrazolopyrimidine. Compound (Compound1) was synthesized (1) was synthesized according according to the literature to the literature [19–22]. [19 The–22 ].compound The compound (1) was (1) wasN-alkylatedN-alkylated by commercialby commercial 2-(chloromethyl)oxirane 2-(chloromethyl)oxirane to yield to ethy yieldl 4-amino-3-(4-chlorophenyl)-1-(oxiran-2-ylmethyl)- ethyl 4-amino-3-(4-chlorophenyl)-1-(oxiran-2- ylmethyl)-11H-pyrazole-5-carboxylateH-pyrazole-5-carboxylate (2) in good ( 2yield) in good(70%); yield subsequently, (70%); subsequently, the epoxy ring the epoxywas opened ring was by 1,2,4-triazoleopened by 1,2,4-triazole in ethanol using in ethanol sodium using bicarbonate sodium bicarbonateas a base to asproduce a base ( to3), produceand then ( 3was), and further then ◦ washydrolyzed further in hydrolyzed water by 3% in watersodium by hydroxide 3% sodium at hydroxide100 °C to afford at 100 theC corresponding to afford the corresponding 4-amino-3-(4- chlorophenyl)-1-[2-hydroxy-3-(14-amino-3-(4-chlorophenyl)-1-[2-hydroxy-3-(1H-1,2,4-triazol-1-yl)-propyl]-1H-1,2,4-triazol-1-yl)-propyl]-1H-pyrazole-5-carboxylicH-pyrazole-5-carboxylic acid (4) in good yieldacid ( 4(Scheme1).) in good yield (Scheme1). Cl Cl Cl Cl Cl Cl Cl Cl NH2 NH NH NH 2 NH2 2 NH2 2 NH2 ii iii NH2 i ii iii i OEt OEt N OEt N OEt N OEt N N N COOH N OEt N N N COOH N N N N N O O N O N O N O O N N N N H O O N N H 1 2 OH 1 OH 3 OH 2 N OH 3 N 4 N N 4 Scheme 1. Synthesis of triazolo pyrazole derivatives. Reagents and conditions: (i) 2-(chloromethyl)oxirane, Scheme 1. Synthesis of triazolo pyrazole derivatives. ReagentsReagents and and conditions: conditions: (i)(i) 2-(chloromethyl)oxirane, 2-(chloromethyl)oxirane , K2CO3, 120 °C,◦ 4 h; (ii) triazole, K2CO3, EtOH, reflux, 2 h; (iii) 3% NaOH, 100 °C,◦ 3 h. K2CO33,, 120 120 °C,C, 4 4 h; h; (ii) (ii) triazole, triazole, K K22COCO3,3 EtOH,, EtOH, reflux, reflux, 2 2h; h; (iii) (iii) 3% 3% NaOH, NaOH, 100 100 °C,C, 3 3h. h. The treatment of ethylcarboxylate (1) with an excess of 1,4-dibromobutane (5) in the presence of The treatment of ethylcarboxylate (1) with an excess of 1,4-dibromobutane (5) in the presence of K2CO3 in DMF at 25 °C for 5 h obtained crude ethyl-4-amino-1-(4-bromobutyl)-3-(4-chloro-phenyl)-1H- K2CO3 in DMF at 25 °C◦ for 5 h obtained crude ethyl-4-amino-1-(4-bromobutyl)-3-(4-chloro-phenyl)-1H- K2CO3 in DMF at 25 C for 5 h obtained crude ethyl-4-amino-1-(4-bromobutyl)-3-(4-chlorophenyl)-1H- pyrazole-5-carboxylate (6). Similarly, ethyl 4-amino-1-[(2E)-(4-bromobut-2-en-1-yl)-3-(4-chlorophenyl)- pyrazole-5-carboxylate (6). Similarly, ethyl 4-amino-1-[(2E)-(4-bromobut-2-en-1-yl)-3-(4-chlorophenyl)- 1H-pyrazole-5-carboxylate (9) was prepared from (1) and (E)-1,4-dibromobut-2-ene (8). Compounds (6) 1H-pyrazole-5-carboxylate (9) was prepared from (1) and (E)-1,4-dibromobut- 2-ene (8). Compounds (6) and (9), when reacted separately with different heterocyclic secondary amines, gave the corresponding desired products, (7a–d) and (10a–d), respectively, in good yields (Scheme 2). Molecules 2016, 21, 1156 3 of 15 and (9), when reacted separately with different heterocyclic secondary amines, gave the corresponding desiredMolecules 2016 products,, 21, 1156 (7a –d) and (10a–d), respectively, in good yields (Scheme2). 3 of 14 Cl Cl Cl Br NH2 N NH2 NH2 Br 5 H OEt i N OEt OEt i N N N N N O Br O H O N 1 6 7a-d Cl Cl Br Br 8 N NH NH2 2 H OEt i OEt N N N N O Br O N 9 10a-d Compd. No N Yield (%) 7a 80% N 10a 65% 7b 85% N N CH 10b 3 60% 7c 90% N O 10c 76% 7d 80% N 10d 62% Scheme 2. Synthesis of compounds 7a–d and 10a–d; (i) K2CO3, DMF, 25 °C,◦ 5 h. Scheme 2. Synthesis of compounds 7a–d and 10a–d; (i) K2CO3, DMF, 25 C, 5 h. The treatment of ethyl 4-amino-3-(4-chlorophenyl)-1H-pyrazol-5-carboxylate (1) with thiophosgene gave Thethe treatmentcorresponding of ethyl 3-isothiocyanat 4-amino-3-(4-chlorophenyl)-1 derivatives (11). HThe-pyrazol-5-carboxylate reactivity of isothiocyanate (1) with thiophosgene(11) towards gavenitrogen the nucleophile corresponding was 3-isothiocyanat investigated. Thus, derivatives interaction (11). of The (11) reactivity with sulfa of drugs isothiocyanate in dimethylformamide (11) towards nitrogenat room temperature nucleophile wasyielded investigated.