A New Series of Hydrazide-Hydrazones Based 2-Oxonicotinonitriles As Antimicrobial Agents: Design, Synthesis and Antimicrobial Evaluation
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A new series of hydrazide-hydrazones based 2-oxonicotinonitriles as antimicrobial agents: Design, synthesis and antimicrobial evaluation H.A. El-Sayed1*, A. H. Moustafa1#, M. Abd El-Moneim3, H. M. Awad2 and A. Esmat3 1Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt. 2Department of Tanning Materials and Leather Technology, National Research Centre, Dokki 12622, Cairo, Egypt. 3Department of Chemistry, Faculty of Science, Port Said University, Port Said, Egypt Una nueva serie de 2-oxonicotinonitrilos a base de hidrazida-hidrazonas como agentes antimicrobianos: Diseño, síntesis y evaluación antimicrobiana Una nova sèrie de 2-oxonicotinonitrilos a base de hidrazida-hidrazonas com agents antimicrobians: Disseny, síntesi i avaluació antimicrobiana RECEIVED: 6 JANUARY 2018; REVISED: 15 MARCH 2018; ACCEPTED: 5 APRIL 2018 lizados a excepción de los compuestos 4b, 5c, 5d y SUMMARY 6b que mostraban una actividad moderada hacia el B. subtilus. Regiospecific alkylation of 2-oxonicotinonitriles 1a,b with ethyl bromoacetate followed by hydrozinol- Palabras clave: 2-Oxonicotinonitrilo; alquilación; ysis afforded acetic acid hydrazides3a,b . The latter hidrazida ácida; hidrazida-hidrazona; antimicrobia- compounds were condensed with a variety of carbonyl na. containing compounds to give the target compounds of hydrazones 4a,b, 5a,b, 6a-h and 7a,b. The antimi- RESUM crobial activity of the new synthesized compounds do not showed activity against tested micro-organisms Alquilació regioespecífica de 2-oxonicotinonitrilos except compounds 4b, 5c, 5d and 6b showed moder- 1a,b amb bromoacetato de etilo seguida de la hidra- ate activity towards B. subtilus zinolisis permès per les hidrazides d’àcid acètic 3a,b. Aquests últims compostos es condensaven amb una Keywords: 2-Oxonicotinonitrile; alkylation; acid varietat de compostos que tenen carbonil, per donar hydrazide; hydrazide-hydrazone; antimicrobial. lloc a compostos “target” a base de hidrazones 4a,b, 5a,b, 6a-h y 7a,b. La activitat antimicrobiana dels nous compostos sintetitzats no va aparèixer contra els RESUMEN microorganismes avaluats a excepció dels compostos 4b, 5c, 5d i 6b que mostraven una activitat moderada Alquilación regioespecífica de 2-oxonicotinonitrilos versus el B. subtilus 1a,b con bromoacetato de etilo seguida de la hidrazi- nolisis permitida por las hidrazidas de ácido acético Paraules clau: 2-Oxonicotinonitrilo; alquilació; hi- 3a,b. Estos últimos compuestos se condensaban con drazida àcida; hidrazida-hidrazona; antimicrobiana. una variedad de compuestos que contienen carbonilo para dar lugar a los compuestos destinatarios a base de hidrazonas 4a,b, 5a,b, 6a-h y 7a,b. La actividad antimicrobiana de los nuevos compuestos sintetiza- *Corresponding authors:*[email protected]; ah_ dos no era evidente contra los microorganismos ana- [email protected] OCTOBER- DECEMBER 2018 | 305 1. INTRODUCTION 2-Oxonicotinonitrile (2-ONN) and its derived compounds are an important class of nitrogen containing heterocyclic systems, which have been undergo to extensive study in the recent years due to their chemical and pharmaceutical interest. Nic- otinonitriles have been reported to have antimi- crobial1,2, analgesic, anti-inflammatory, antipyret- ic3,4 anticancer2, cardiotonic5, antihypertensive6,7 properities. Another interested biological scaffold is given by hydrazide-hydrazone (CO-NHN=C) system, which are used to improve the biological activity of a main compound. For example, many compounds containing hydrazide-hydrazone moi- ety posses a wide range of remarkable biological properties such as antimalarial8, antituberculo- sis9, anti-HIV10, antimicrobial11,12, anti-inflamma- tory13 and anticonvulsant14,15. In recent years, our research efforts focused on the synthesis of func- tionalized pyridines for biological evaluation1,2,16,17. Herein, we linked hydrazide-hydrazone moiety to nicotinonitrile ring and investigate the antimicro- bial activity of such products. 2. RESULTS AND DISCUSSION 2.1. Chemistry 4-Aryl-6-naphth-2-yl-2-oxo-1,2-dihydronicoti- nonitriles 1a,b were selected as starting synthon for this research work. Compounds 1a,b have been synthesized as in literature2,16 via one pot multi- component condensation of 2-acetyl naphthalene, aromatic aldehyde (namely, 4-methyl benzalde- Scheme 3 illustrates the synthetic routes of tar- hyde and 3-methyl thiophene-2-carboxaldehyde), get compounds 4-7. Where, condensation of hy- ethyl cyanoacetate and ammonium acetate in re- drazides 3a,b with benzaldehyde, acetophenone, fluxing ethanol (Scheme 1). The spectroscopic data 4-nitroacetophene, 4-chloroacetophenone, 4-bro- and microanalysis were agreed with the assigned moacetophenone and ethyl acetoacetate afforded structure. Base mediate alkylation of compounds hydrazones 4a,b, 5a-h and 6a,b, respectively, in 1a,b produced compounds 2a,b (Scheme 2), which good yield (58-67%). The spectroscopic data and identified from IR bands as N-alkylated nicotino- microanalysis were agreed with the assigned struc- nitriles. Treatment of 2a,b with ethanolic solution ture of these compounds. The 1H NMR of com- of hydrazine hydrate under refluxing tempera- pound 5h illustrated two singlets at 2.31 and 2.35 ture afforded pyridin-1-yl acetohydrazides 3a,b ppm for 2CH3, in addition to aromatic and NH (Scheme 2). 1H NMR signals showed presence of protons signals in their regions. IR Bands of com- acetohydrazide moiety as three singlts at 4.45, 5.06 pound 6a indicated the ester-carbonyl and amide -1 1 and 9.53 ppm corresponding to NH2, CH2 and NH groups at 1747 and 1664 cm , respectively. Its H protons, respectively. NMR data confirmed that the reaction tookplace at ketonic carbonyl forming the target hydrazone, where ethoxy signals are present at 1.21 and 4.20 ppm as triplet and quartet. Another evidence for this explanation is 13C NMR data, where the ethoxy and ester-carbonyl carbons appeared at 14.20 and 64.45 and 168.4 ppm, respectively, in additon, no signal for ketonic-carbonyl carbon is present. Finally, condensation of 3a,b with acetyl acetone gave the unexpected pyrazole derivatives 7a,b via interamoleculare cyclization reaction. 1H NMR and IR data confirmed the formation of pyrazol ring. (c.f. the experimental part) (Scheme 3). 306 | AFINIDAD LXXV, 584 2.2. Antimicrobial activity at room temperature, the formed precipitate was filtered off, washed with ethanol, dried and crystal- The antimicrobial activity of new compounds were lized from methanol / acetic acid (1:2) ratio. investigated using the agar well diffusion method as 6-(Naphthalen-2-yl)-2-oxo-4-(p-tolyl)-1,2-di- modified from18, compared with Cefotaxime as con- hydro-pyridine-3-carbonitrile (1a) trol. For antifungal, Nystatin was used as standaed Yellow powder; yield 39%; m. p. 303-305 oC. IR drug. It is clearly observed that, from the obtained (KBr): 3455 cm-1 (NH), 2219 cm-1 (C=N) and 1682 -1 1 data in Table 1, all the tested compounds donot cm (C=O, amide). H NMR (DMSO-d6): δ = 2.41 showed significant antibacterial and antifungal ac- (s, 3H, CH3), 6.96 (s, 1H, pyridone H-5), 7.39 (d, 2H, tivities against the mention microorganisms, except J = 7.6 Hz, Ar-H), 7.63 (m, 4H, A-H), 8.01 (m, 4H, compounds 4b, 5c,5d and 6b showed moderate anti- A-H), 8.55 (s, 1H, Ar-H), 12.64 (br, 1H, NH). 13C microbial activity towrds B. subtilus NMR (DMSO-d6): δ = 20.94 (CH3), 97.99, 106.5, 116.6, 124.3, 127.0, 127.6, 127.9, 128.1, 128.2, 128.5, Table 1: Antimicrobial activities of some new synthesized 128.8, 129.3, 132.4,133.2, 133.8, 140.4, 151.2, 159.6, compounds (Inhibition zones mm). Diameter (mm) of 162.1 and 172.0, (C=N, Ar-C and C=O). Anal. Calcd inhibition zones against the corresponding standard for C23H16N2O (336.39): C, 82.12; H, 4.79; N, 8.33. microbial strains Found: C, 82.07; H, 4.82; N, 8.29. 4-(3-Methylthien-2-yl)-6-(naphthalen-2-yl)- Copd. No. Gm (+ve) bacteria Gm (–ve) bacteria Fungi 2-oxo-1,2-dihydropyridine-3-carbonitrile (1b) B. subtilus B. cereus P. aeruginosa E. coli Aspergillus niger Yellow powder; yield 33.5%; m. p. 283-285 oC. IR -1 -1 2a 17 19 24 18 - (KBr): 3442 cm (NH), 2217 cm (C=N) and 1640 2b 15 22 23 18 - cm-1 (C=O, amide). 1H NMR (DMSO-d ): δ = 2.32 (s, 4a 19 30 14 22 - 6 4b 33 15 16 21 16 3H, CH3), 6.95 (s, 1H, pyridone H-5), 7.13 (d, 1H, J = 5a 23 21 23 18 - 4.80 Hz, thiophene), 7.63 (m, 2H, Ar-H), 7.79 (d, 1H, 5b 22 14 12 24 - 5c 46 18 22 19 19 J = 4.80 Hz, thiophene), 8.03 (m, 4H, Ar-H), 8.53 5d 35 17 20 17 - (s, 1H, Ar-H), 12.92 (s, 1H, NH), 13C NMR (DM- 5e 25 20 21 21 20 5f 27 21 20 25 - SO-d6): δ = 15.20 (CH3), 116.2, 124.2, 127.0.127.6, 5g 30 24 21 18 - 127.9, 128.1, 128.2, 128.5, 128.9, 131.0, 131.1, 132.3, 5h 18 21 16 23 - 6a 28 28 19 24 - 133.8, 138.1, 160.2 (C=N, Ar-C and C=O). Anal. 6b 34 28 30 31 15 Calcd for C21H14N2OS (342.41): C, 73.66; H, 4.12; N, Cefotaxime 32 28 32 34 - 8.18. Found: C, 73.72; H, 4.16; N, 8.21. Nystatin - - - - 20 DMSO - - - - - General procedure for synthesis of compounds 2a,b A mixture of pyridin-2-(1H)-one-3-carbonitriles 4. EXPERIMENTAL 1a,b (10 mmol) and (11 mmol) potassium carbonate or potassium hydroxide was stirred in dry DMF (20 General mL) for 1h, followed by the addition of ethyl bro- moacetate (10 mmol), the reaction mixture was The elemental analyses were obtained on a Per- stirred at room temperature for 24 h., then poured kin Elmer 240.