Synthesis and antimicrobial evaluation of Azetidinone derivatives of pyridine containing hydrazides

 

Ram C. Senwar, Krishna K. Rathore, Anita Mehta

Department of Chemistry, M.L. Sukhadia University, Udaipur 313001, India

*Corresponding Author E-mail: ram.senwar09@gmail.com

Isoniazid (1a) undergoes facile condensation with indole-3-carboxaldehyde in methanolic media and glacial acetic acid as a catalyst to afford the corresponding N-((1H-indol-3-yl)methylene) nicotinohydrazide (2a). Cyclocondensation of compounds (2a) with chloro acetyl chloride, triethyl amine and 1,4-dioxane yields N-(3-chloro-2-(1H-indol-3-yl)-4-oxoazetidin-1-yl)nicotinohydrazide (3a). Further the NH proton of indole in compounds (3a) is replaced with different benzo[b]thiophenes to yield the final compound N-(3-chloro-2-(1-(3-chlorobenzo[b]thiophene -2-carbonyl)-1H-indol-3-yl)-4-oxoazetidin-1-yl) nicotinohydrazide (4a-d). In an alternative reaction Nicotinic-hydrazide (1b) is used in place of Isoniazid and reacted with indole-3-carboxaldehyde to produce N-((1H-indol-3-yl)methylene) isonicotinohydrazide  (2b). Compound (2b) on reaction with chloroacetylchloride, triethylamine and 1,4-dioxane synthesize N-(3-chloro-2-(1H-indol-3-yl)-4-oxoazetidin-1-yl)isonicotinohydrazide (3b). In the final stage of the reaction scheme the NH proton of compound (3b) is replaced with different benzo[b]thiophenes to yield the final compounds N-(3-chloro-2- (1-(3-chloro benzo[b]thiophene-2-carbonyl)-1H-indol-3-yl)-4-oxoazetidin-1-yl)isonicotinohydrazide (4e-h). The structures of these compounds were established on the basis of analytical and spectral data. The newly synthesized compounds were evaluated for their antibacterial and antifungal activities.

 

 

INTRODUCTION:

Schiff bases are organic compounds with great utility in many fields such as medicine, agriculture and in cosmetic product development. Schiff’s bases have been reported to possess anti-inflammatory activity^1,2, antimalarial activity^3,4, anti HIV^5,6, antibacterial activity^7-11, anticancer activity¹², anti-viral activity¹³,antikinetoplastid antimitotic activity ¹⁴, antitumor activity^15,16 and anticonvulsant activity¹⁷ and antimicrobial activity^18-25 .

 

Azetidinones are antibiotics which are the most commonly prescribed medicines for treatment of bacterial diseases. Among this monocyclic- β-lactum is a kind of new compound which is not only structurally simple for easy of synthesis, but also has a special feature in the biological activities like antibacterial^26-28, antimalarial²⁹, anti-Bacillus^30-32, anti-MRSA³³, Antitubercular^34-37, Anti-inflammatory^38-40, anticancer⁴¹, anit-oxidant^42,43, antimicrobial^44-48, neuroprotective agent⁴⁹, anticonvulsant^50,51, antihyperglycemic⁵², antifungal⁵³.

 

Benzo[b]thiophene is class of fused heterocycles that is of considerable interest because of the diverse range of theirbiological activities such as, anti‐cancer^54-56, anti-inflammatory^57-59 antiviral⁶⁰, anti‐microbial^61-66, antimalarial⁶⁷, anti‐tubercular⁶⁸, antioxident⁶⁹ etc.

 

 

EXPERIMENTAL:

Method and material:

The reagent grade chemicals were purchased from commercial sources and purified either by distillation or recrystallization before use. Purity of the compounds was checked on silica gel G TLC plates of 2 mm thickness using nhexane and ethylacetate as solvent system. The visualization of spot was carried out in an iodine chamber. Melting points of all synthesized compounds were taken in open capillaries and are uncorrected.  IR spectra (KBr) were recorded on a Perkin-Elmer 1300 FT IR spectrometer and ¹H NMR were determined on a Bruker WM-400 (400 MHz FT NMR) spectrometer using TMS as internal standard. Mass spectra were recorded on Shimadzu GC-MS QP 5000. Microanalyses for C, H and N were performed in Heraeus CHN Rapid Analyzer and analyses indicated by the symbols of the elements are within ± 0.4 % of the theoretical values. The physical data of synthesized compounds are given in table 1.

 

Synthesis of (1H-indol-3-ylmethylene) isonicotinohydrazide  (2a):

A mixture of equimolar (0.01 mol) quantities of Indole-3-carboxaldehyde and isoniazid were refluxed for 6 hrs in methanol with catalytic amount of glacial acetic acid. The reaction mixture was cooled at RT and pour in ice cold water. The separated product was filtered out. The Schiff base obtained was used for next step to form compound (3a). The compound (2b) was synthesized by the same method but nicotinic-hydrazide was used in place of isoniazid.

IR (KBr) cm⁻¹: 3297 (N-H str.), 3058 (C-H Ar str.), 1712 (C=O str.), 1663 (C=N str.), 1215 (C-N Str.); ¹H-NMR (DMSO-d6) δ: 9.81 (s, 1H, NH-N), 7.12-8.15 (m, 8H, Ar-H), 8.67 (s, 1H, N-H), 6.23 (s, 1H, N-C-H of benzopyrrol), 6.90 (s, 1H, N-N=CH) .

 

Synthesis of (1H-indol-3-yl)methylene-nicotinohydrazide (2b):

IR (KBr) cm⁻¹: 3274 (N-H str.), 3054 (C-H Ar str.), 1706 (C=O str.), 1654 (C=N str.), 1223 (C-N Str.); ¹H-NMR (DMSO-d6) δ: 9.74 (s, 1H, NH-N), 7.23-8.04 (m, 8H, Ar-H), 8.72 (s, 1H, N-H), 6.28 (s, 1H, N-C-H of benzopyrrol), 6.97 (s, 1H, N-N=CH) .

 

Synthesis of N-(3-chloro-2-(1H-indol-3-yl)-4-oxoazetidin-1-yl) isonicotinohydrazide   (3a):

A mixture of Schiff base (2a) (0.02mol) and Triethylamine (TEA) (0.04mol) was dissolved in 1-4-Dioxane. To this well stirred cooled solution of chloro acetyl chloride (0.04mol) was added drop wise within 20 min. The reaction mixture was refluxed for 8 hrs and left at RT for 12 hrs. The resultant mixture was concentrated, cooled, pour into ice cold water, filter, dried and recrystallized form n-Hexane which gives the compounds (3a). The Azetidinone obtained was used for final step to from final products. The compound (3b) was synthesized by the same method with compound (2b).

IR (KBr) cm⁻¹: 3316 (N-H str.), 3103 (C-H Ar str.), 1734 (C=O str. two), 1236 (C-N Str.), 745 (C-Cl Str.); ¹H-NMR (DMSO-d6) δ: 9.34 (s, 1H, NH-N), 7.07-8.19 (m, 8H, Ar-H), 7.45 (d, 1H, N-H), 6.06 (s, 1H, N-C-H of benzopyrrol), 4.33 (d, 1H, C-H azetidinone), 4.88 (d, 1H, CH-Cl of azetidinone).

 

Synthesis of N-(3-chloro-2-(1H-indol-3-yl)-4-oxoazetidin-1-yl)nicotinohydrazide   (3b):

IR (KBr) cm⁻¹: 3308 (N-H str.), 3145 (C-H Ar str.), 1746 (C=O str. two), 1242 (C-N Str.), 754 (C-Cl Str.); ¹H-NMR (DMSO-d6) δ: 9.41 (s, 1H, NH-N), 7.10-8.04 (m, 8H, Ar-H), 7.37 (d, 1H, N-H), 6.13 (s, 1H, N-C-H of benzopyrrol), 4.38 (d, 1H, C-H azitidinone), 4.92 (d, 1H, CH-Cl of azetidinone).

 

Synthesis of N-(3-chloro-2-(1-(3-chlorobenzo[b] thiophene-2-carbonyl)-1H-indol-3-yl)-4-oxoazetidin-1-yl) isonicotinohydrazide (4a):

A mixture of Azetidinone(0.01mol) (3a), different benzo[b]thiophenes(0.01mol) and catalytic amount of pyridine was suspended in methanol, and refluxed for 12 hrs. The mixture was filtered and poured on crushed ice. The solid obtained was filtered, dried and recrystallized from ethanol and other compounds (4b-4h) were also synthesized by the similar method with required change in reflux time.

IR (KBr) cm⁻¹:   3350 (NH str.) 3103 (C-H str. ArH), 1704 (C=O str. two), 1614 (C=N str.), 1247 (C-N Str.), 732 (C-Cl Str. Two), 683 (C-S-C Str.); ¹H-NMR (DMSO-d6) δ: 9.14 (s, 1H, NH-N), 7.37-8.79 (m, 12H, Ar-H), 6.78 (s, 1H, N-C-H of benzopyrrol), 4.48 (d, 1H, C-H azitidinone), 4.98 (d, 1H, CH-Cl of azetidinone).

 

N-(3-chloro-2-(1-(3-chloro-6-fluorobenzo[b]thiophene-2-carbonyl)-1H-indol-3-yl)-4-oxoazetidin-1-yl) isonicotinohydrazide (4b):

IR (KBr) cm⁻¹: 3341 (NH str.)  3145 (C-H str. Ar H),1717 (C=O str.), 1279 (C-N Str.), 759 (C-Cl Str.), 713 (C-S-C Str.), 867 (C-F Str.); ¹H-NMR (DMSO-d6) δ: 9.16 (s, 1H, NH-N), 7.78-8.40 (m, 11H, Ar-H), 6.26 (s, 1H, N-C-H of benzopyrrol), 4.34 (d, 1H, C-H azitidinone), 5.07 (d, 1H, CH-Cl of azetidinone).

 

N-(3-chloro-2-(1-(3,6-dichlorobenzo[b]thiophene-2-carbonyl)-1H-indol-3-yl)-4-oxoazetidin-1-yl) isonicotinohydrazide (4c):

IR (KBr) cm⁻¹: 3348 (NH str.)  3112 (C-H str. ArH), 1710 (C=O str.), 1258 (C-N Str.),  745 (C-Cl Str. three), 699 (C-S-C Str.); ¹H-NMR (DMSO-d6) δ: 9.14 (s, 1H, NH-N), 7.57-8.25 (m, 11H, Ar-H), 6.21 (s, 1H, N-C-H of benzopyrrol), 4.28 (d, 1H, C-H azitidinone), 5.14 (d, 1H, CH-Cl of azetidinone).

 

N-(3-chloro-2-(1-(3-chloro-6-hydroxybenzo[b]thiophene-2-carbonyl)-1H-indol-3-yl)-4-oxoazetidin-1-yl) isonicotinohydrazide (4d):

IR (KBr) cm⁻¹:   3295 (NH str.)  3094 (C-H str. ArH), 1690 (C=O str.), 1215(C-N Str.),  714 (C-Cl Str. two), 634 (C-S-C Str.), 3367 (O-H Phenol Str.); ¹H-NMR (DMSO-d6) δ: 9.01 (s, 1H, NH-N), 7.15-8.37 (m, 11H, Ar-H), 6.19 (s, 1H, N-C-H of benzopyrrol), 5.27 (d, 1H, C-H azitidinone), 4.63 (d, 1H, CH-Cl of azetidinone) 5.02 (s,1H, OH ).

 

N-(3-chloro-2-(1-(3-chloro-benzo[b]thiophene-2-carbonyl)-1H-indol-3-yl)-4-oxoazetidin-1-yl)nicotinohydrazide (4e):

IR (KBr) cm⁻¹:   3321 (NH str.) 3107 (C-H str. ArH), 1698 (C=O str. two), 1243 (C-N Str.), 738 (C-Cl Str. Two), 689 (C-S-C Str.); ¹H-NMR (DMSO-d6) δ: 9.19 (s, 1H, NH-N), 7.31-8.12 (m, 12H, Ar-H), 6.21 (s, 1H, N-C-H of benzopyrrol), 4.45 (d, 1H, C-H azitidinone), 5.03 (d, 1H, CH-Cl of azetidinone).

 

N-(3-chloro-2-(1-(3-chloro-6-fluorobenzo[b]thiophene-2-carbonyl)-1H-indol-3-yl)-4-oxoazetidin-1-yl)nicotinohydrazide (4f):

IR (KBr) cm⁻¹: 3337 (NH str.)  3141 (C-H str. Ar H),1712 (C=O str.), 1272 (C-N Str.), 749 (C-Cl Str.), 706(C-S-C Str.), 871 (C-F Str.); ¹H-NMR (DMSO-d6) δ: 9.12 (s, 1H, NH-N), 7.64-8.32 (m, 11H, Ar-H), 6.16 (s, 1H, N-C-H of benzopyrrol), 4.39 (d, 1H, C-H azitidinone), 5.09 (d, 1H, CH-Cl of azetidinone).

 

N-(3-chloro-2-(1-(3,6-dichlorobenzo[b]thiophene-2-carbonyl)-1H-indol-3-yl)-4-oxoazetidin-1-yl)nicotinohydrazide (4g):

IR (KBr) cm⁻¹: 3352 (NH str.)  3117 (C-H str. ArH), 1704 (C=O str.), 1251 (C-N Str.),  742 (C-Cl Str. three), 692 (C-S-C Str.); ¹H-NMR (DMSO-d6) δ: 9.09 (s, 1H, NH-N), 7.51-8.19 (m, 11H, Ar-H), 6.25 (s, 1H, N-C-H of benzopyrrol), 4.21 (d, 1H, C-H azitidinone), 5.17 (d, 1H, CH-Cl of azetidinone).

 

N-(3-chloro-2-(1-(3-chloro-6-hydroxybenzo[b]thiophene-2-carbonyl)-1H-indol-3-yl)-4-oxoazetidin-1-yl)nicotinohydrazide (4h):

IR (KBr) cm⁻¹:   3298 (NH str.)  3104 (C-H str. ArH), 1698 (C=O str.), 1213(C-N Str.),  724 (C-Cl Str. two), 654 (C-S-C Str.), 3361 (O-H Phenol Str.); ¹H-NMR (DMSO-d6) δ: 9.04 (s, 1H, NH-N), 7.19-8.28 (m, 11H, Ar-H), 6.12 (s, 1H, N-C-H of benzopyrrol), 5.24 (d, 1H, C-H azitidinone), 4.84 (d, 1H, CH-Cl of azetidinone) 5.07 (s,1H, OH ).

 

Biological Activity:

The compounds (4a-h) were screened for their antibacterial activity against two Gram positive bacteria S. aureus and S. pyogenes, two Gram negative bacteria E. coli and P. aeroginosa and fungal strains C. albicans, A. niger and A. clavatus for antifungal activity. Cefixime was used as a standard drug for antibacterial activity whereas Griseofulvin was used as a standard drug for antifungal activity. For evaluation of MIC, each synthesized drug was diluted obtaining 2000 microgram /ml concentration, as a stock solution. In primary screening 1000 micro/ml, 500 micro/ml, and 250 micro/ml concentrations of the synthesized drugs were taken. The active synthesized drugs found in this primary screening were further tested in a second set of dilution against all microorganisms. In secondary screening the drugs found active in primary screening were similarly diluted to obtain 200 micro/ml 100 micro/ml, 50 micro/ml, 25 micro/ml, 12.5 micro/ml, and 6.250 micro/ml concentrations. The highest dilution showing at least 99 % inhibition zone is taken as MIC. The result of this is much affected by the size of the inoculum. The test mixture should contain 108 organism/ml. For calculation of Zone of Inhibition, all the compounds were dissolved in dimethyl sulfoxide (DMSO) to give a concentration of 50 µgmL^-1. Muller-Hinton agar medium was used as culture medium. The method employed was agar disc diffusion method. The zones of inhibition were measured in mm.

 

 

 

Table I: Physical and Analytical Data of Synthesized Compounds

 

BIOLOGICAL EVALUTION:

Table-2 Antimicrobial activity (MICs µg/mL) of the synthesized compounds

 

Table-3 Antimicrobial activity of synthesized compounds: Zone of inhibition in mm (activity index)^std

(Activity index)^std = zone of inhibition of the sample/zone of inhibition of the standard

 

 

RESULT AND DISCUSSION:

Isoniazid/Nicotinic-hydrazide and indole-3-carboxaldehyde were allowed to react in methanolic media in presence of catalytic amount of glacial acetic acid to obtain compound (2a-b). Confirmation of this compound was given by strong band at 1523 cm^-1 for C=N str. in IR and singlet at 6.90 δ for N-N=CH in ¹H NMR. Compounds (3a-b) were obtained by the cyclisation of Schiff bases with chloroacetyle chloride in dioxane solvent to obtain corresponding Azetidinones. These compounds were confirmed by appearance of a peak at 745 cm^-1 for C-Cl and disappearance of a peak at 1523 cm^-1 for C=N group in IR and a doublet obtain at δ 4.33 for C-CH in Azetidinone ring in ¹H NMR. Subsequently, NH proton was replaced by substituted benzo[b]thiophene to get final compounds (4a-h).Formation of these compounds were confirmed by appearance of C-S-C linkage at 683 cm^-1 and disappearance of doublet at δ 7.45 for NH-C proton in ¹H NMR.

 

Antimicrobial activity:

From Table 3, it can be concluded that compounds 4d and 4h exhibited excellent antibacterial and antifungal activities. For antibacterial activity compounds 4d 4g and 4h showed excellent activity against Staphylococcus aureus, while compound 4b showed moderate activity. For antifungal activity, compounds 4f and 4h exhibited excellent activity against C. albicans while Compounds 4d, 4b were good to moderate against A. clavatus.

 

CONCLUSION:

In conclusion, synthesis of compounds (4a-f) was accomplished from isoniazid/nicotinic hydrazide. Antibacterial and antifungal activities of the newly synthesized compounds were evaluated and they exhibited well to moderate activities. The results indicate that compounds show better antibacterial activities compared to antifungal activity. Further, in general the compounds having –OH and -F substituent have better activities compared to other derivatives of the series. Finally, it is concluded that these potential candidates might be useful in the future to develop an effective chemotherapeutic agents.

 

ACKNOWLEDGEMENT:

The author (Ram C. Senwar) thanks to DST, New Delhi for financial assistance. The authors are thankful to Head, Department of Chemistry, M.L. Sukhadia University, Udaipur for providing laboratory facilities and also thankful to SAIF and CIF, Punjab University for providing spectral and analytical analysis. I express my sincere thanks to my research Supervisor Dr. Anita Mehta for her valuable guidance.

 

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Received on 10.02.2017         Modified on 15.02.2017

Accepted on 21.02.2017         © AJRC All right reserved