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Designing, Synthesis and characterization of novel Substituted pyrazol-azetidin-2-one/thiazolidin-4-one derivatives for their antimicrobial activity

Der Pharma Chemica
Journal for Medicinal Chemistry, Pharmaceutical Chemistry, Pharmaceutical Sciences and Computational Chemistry

ISSN: 0975-413X

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Research Article - Der Pharma Chemica ( 2021) Volume 13, Issue 3

Designing, Synthesis and characterization of novel Substituted pyrazol-azetidin-2-one/thiazolidin-4-one derivatives for their antimicrobial activity

Krishna Srivastava1*, Raj Bahadur Singh1, Jyoti Srivasata2 and Dinesh Gupta3
 
1Faculty of Chemical Sciences, Shri Ramswaroop Memorial university, Lucknow-Dewa Road, Barabanki 225 003, India
2Babasaheb Bhim Rao Ambedkar University, Lucknow, Uttar Pradesh 226025, India
3Center for Biomedical Research Institute, Lucknow 226 001, India
 
*Corresponding Author:
Krishna Srivastava, Faculty of Chemical Sciences, Shri Ramswaroop Memorial university, Lucknow-Dewa Road, Barabanki 225 003, India, Email: [email protected]

Received Date: Feb 06, 2021 / Accepted Date: Mar 22, 2021 / Published Date: Mar 30, 2021

Abstract

This research work includes the synthesis of (3-hydroxy-4-methoxyphenyl)-3-((1-(5-(2-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl) ethylidene)amino)thiazolidin-4-one(VIIa-f)/3-chloro-4-(substitutedphenyl)-1-((1-(5-(2-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol1yl)ethylidene) amino) azetidin-2-one(VI a-f) having a pyrazol ring, obtained from the reaction of hydrazine hydrate with chalcone along with athiazolidinone ring/azetidinonemoeity, procured after the cyclization of a schiff base by thioglycolic acid/Chloroacetyl chloride. The structure of the synthesized compounds has been established on the basis of elemental analysis, UV-Vis absorption spectroscopy, IR, 1HNMR, and mass spectral studies. The in vitro antimicrobial screening of all the novel compounds was done against S.aureus, E.coli, P.aeruginosa and B. subtilis. The activity of VIb, VIf, VId and VIIa, VIIf, VIIdVIIe compounds exhibited excellent activity while the rest showed moderate to good activity against the tested microbes.

Keywords

Chloroacetyl chloride, Thioglycoolic acid, Antimicrobial, Aromatic aldehyde, Hydrazine Hydrate, Acetophenone.

Introduction

Compounds having two different heterocyclic ring are challenging precursor models for the preparation of medicinally useful bioactive scaffolds [1,2]. A voluminous documentation exists elucidating the diverse presence of the heterocycle in nature. The heterocycle are estimated to be present in over two third of all the naturally existing compounds. The versatile functional and structural attributes associated with the heterocycle have added to their ever expanding applications in the industry as well as in biological system [3].The presence of hetero atoms like nitrogen, sulfur and oxygen are largely responsible for the innate diversity exhibited by these compounds whether in natural or artificial molecular scaffold.

Chalcones are frequently employed as precursor molecular motifs in the synthetic preparation of heterocyclic pyrazoles and related moieties manifesting certain biological properties such as antibacterial, anti-inflammatory, antifungal and analgesic which are of significant importance in the drug industry [4,7].

Azetidinones moieties are recognized as the structural backbone unit in penicillin and many other related antibiotics [8] possessing interesting microbial activities [9-10]. It has been observed that β-lactam, having chloro group at 3 position shows profound anti-tubercular, anticonvulsant, anti-inflammatory and antimicrobial activities [11-13]. They are also engaged as potent enzyme inhibitors apart from their intense effect on the central nervous system (CNS) [14,15].

As per the large body of documented evidence available Thiazolidinedione (TZD) is acknowledged as one of the most important heterocyclic ring system of Thiazole having a wide range of therapeutic action and when formulated with other heterocyclic compound exhibits enormous functional and biological diversities [16].

The importance and prominence of pyrazoles and Azetidinones/Thiazolidinedione (TZD) moieties [17,18] in drug discovery have continually attracted chemist worldwide in their pursuit for novel compounds with good antimicrobial activity, demanding their synthesis in short reaction times. In continuation of our quest to design and synthesize heterocyclic compound with better yields and biological activities we herein report the synthesis of novel heterocyclic compound having pyrazole and Azetidinones/Thiazolidinedione [19,20] (TZD) moieties.

Experimental Section

Materials and Methods

All melting points (m.p.) were determined in open capillaries on Jindal melting point apparatus and were uncorrected. The purity of the compounds was routinely checked by thin layer Chromatography (TLC) using silica gel G (Merck). The 1HNMR and 13C NMR spectra were recorded in CDCl3 and DMSO on Bruker NMR spectrophotometer at 300 MHz using teteramethyalsilane(TMS) as an internal reference and chemical shift value (δ) were given in part per million(ppm). The instruments used are: Jasco FTIR-470 spectrophotometer (KBr) with diffuse reflectance method; MS-JEOL SX102 Mass spectroscopy by using Argon/Xenon (6Kv, 10 mA) as the FAB gas and m-nitro benzyl alcohol (NBA) as the matrix. UV spectrums of the sample were carried out on double beam UV spectrophotometer.

Synthesis of (E)-3-(o-nitrophenyl)-1-phenylprop-2-en-1-one(I)

A (0.1 mole) of acetophenone and (0.1 mole), of o-nitrobenzaldehyde was stirred in ethanol (50 ml). Aqueous potassium hydroxide solution (15ml, 30%) was then added to it. The mixture was refluxed on a water bath for 10.00 hrs. The reaction was monitored by thin-layer chromatography (TLC) with the methanol- chloroform. After completion, the reaction mixture was poured into crushed ice and acidified with dilute hydrochloric acid. The chalcone precipitates out as solid. It is then filtered and crystallized from ethanol.

Yield 78 %; m.p. 124-125°C; Anal. Calcd for C15H11O3N (MW=253.25),: C 71.14, O 18.95 N 5.53found: C 71.10, O 18.89, N 5.48;.IR (KBr,cm-1): 1740(C=O),1625(CH=CH),

Synthesis of 1-(5-(o-nitrophenyl)-3-phenyl-4,5-dihydro-1H -pyrazol-1-yl) ethanone(II)

A (0.02 mole) of chalcone, (E)-3-o-nitrophenyl)-1-phenylprop-2-en-1-one, in acetic acid (20 ml) and 0.02 mole of hydrazine hydrate in absolute EtOH (30 ml) was refluxed for 8-10 hrs on a water bath. After completion of the reaction, the solution was concentrated by distillation under reduce pressure. Upon cooling, solid mass was obtained, dried and purified by recrystallization from methanol. Yield 73 %; m.p. 132-133°C; Anal. Calcd for C17 H15 N3 O3 (MW=309.32): C 66.01, O 15.52, N 13.58 found: C 65.96, O 15.4, N 13.51; IR (KBr,cm-1): 1624(C=N), 1633 (C=C-H), 2335(C-N).

Synthesis of (substituted benzylidene hydrazine(III a-f)

Hydrazine Hydrate (0.01mol), aryl aldehyde (0.01 mol),and 25 mL of absolute ethyl alcohol were refluxed for 10-12 hrs on a water bath in the presence of glacial acetic acid (1 ml). Excess solvent was removed under reduced pressure. The solid obtained was washed with cold water several times and purified by recrystallization from methanol. Characterization data of the compounds thus synthesized, are given as:

IIIa.5-(hydrazonomethyl)-2-methoxyphenol (3-OH,4-OCH3-Benzaldehyde): Yield 68 %; m.p. 94-95°C; Anal.Calcd for C8H10N2O2 (MW=166.18),: C 57.82, N 16.86, O 19.26, found: C 57.78, O 19.21, N 1680.

IIIb.(4-chlorobenzylidene)hydrazine (p-Chlorobenzaldehyde)

Yield 98 %; m.p. 116-117 °C; Anal. Calcd for C7H7N2Cl(MW=154.60),: C 54.38, N 18.12, found: C 54.33, N 18.

IIIc.4-(hydrazonomethyl)phenol (p-Hydroxybenzaldehyde)

Yield76 %; m.p. 120-121°C; Anal.Calcd for C7H8N2O(MW=136.15),: C 61.74, O 11.75, N 20.58 found: C61.68, O 11.71, N 20.49.

IIId.(2-nitrobenzylidene)hydrazine(O-nitro benzaldehyde)

Yield 82 %; m.p. 184-185 °C; Anal.Calcd for C7H7N3O2 (MW=306.79),: C 50.91, N 25.44 O 19.38 found: C 50.88; N 25.38, O 19.31.

IIIe.2-(hydrazonomethyl)pheno (o-Hydroxybenzaldehyde)

Yield 68 %; m.p. 136-137°C; Anal.Calcd for C7H8N2O (MW=136.15),: C61.75, N 20.58, O 11.75, found: C 61.69, O 11.68, N 20.47.

IIIf. 4-(hydrazonomethyl)-2-methoxyphenol (4-OH,3-OCH3-Benzaldehyde)

Yield 77 %; m.p. 111-112°C; Anal.Calcd for C8H10N2O2 (MW=166.18),: C 57.82, N 16.86, O 19.26, found: C 57.79, O 19.19, N 16.86.

Synthesis of 1-amino-3-chloro-4-(substituted phenyl) azetidin-2-one (IVa-f)

(0.01) mole of compound (IIIa-f) in dixon (50 ml) was added to chloroacetyl chloride (0.01 mole) and triethylamine (0.01 mole) at 0oC with stirring. The reaction mixture was left at room temperature for 3 hours and then refluxed for 10 hrs. Excess solvent was distilled off and the residue was poured into crushed ice and recrystallized.Characterization data of the compounds thus synthesized, are given as:

IVa.1-amino-3-chloro-4-(3-hydroxy-4-methoxyphenyl)azetidin-2-one

Yield: 68%. M.p.:133-134°C; Anal.Calcd for C10 H11N2 O3Cl(MW=242.66),: C 49.50, N 11.54, O 19.78found: C 49.42, N 11.47, O 19.66.
IR (KBr) (νmax in cm-1): 3035 v(Ar-H), 1754 (C=O, monocyclic β-lactam), 3427 (3-OH,3-hydroxyphenyl), 2348(N-N), 3431(N-Hstretch), 1678 (OCH3,p-methoxyphenyl),765(C-Cl,β- lactam),1527(C=C,Ar);1H NMR (δ in ppm) (CDCl3):4.88 (s, 1H, Ar-OH), 6.95-7.10 (m, 3H, Ar_H), 5.14 (d, 1H, Cl-CH), 4.81(d,1H,N-CH-R of β-lactam)3.38 (s,3H,Ar-OCH3).

IVb.1-amino-3-chloro-4-(4-chlorophenyl)azetidin-2-one

Yield: 58%. M.p.:152-153°C; Anal.Calcd for C9 H8N2 O Cl 2 (MW=231.08),: C 46.78, N 12.12, O06.92 found: C 46.63, N 12.07, O 6.88.;
IR (KBr) (νmax in cm-1): 2340(N-N), 3429(N-H stretch),2970 (C-H), 745 (C-Cl stretch)
3041 v(Ar-H), 1751 (C=O,monocyclicβ-lactam), 763(C-Cl,β- lactam),1527(C=C,Ar);1H NMR (δ in ppm) (CDCl3):6.70-7.45(m, 4H, Ar_H), 5.28 (d, 1H, Cl-CH), 4.83(d,1H,N-CH-R of β-lactam).

IVc.1-amino-3-chloro-4-(4-hydroxyphenyl)azetidin-2-one

Yield: 70%. M.p.:131-132°C; Anal.Calcd for C9 H9 N2 O2 Cl(MW=212.63),: C 50.84, N 13.17, O 115.05 found: C 50.77, N 13.11, O 15.01.;
IR (KBr) (νmax in cm-1): 3430 (p-OH,p-hydroxyphenyl) 3044 v(Ar-H), 1762 (C=O, monocyclic β-lactam), 3425 2345(N-N), 3440(N-Hstretch,778(C-Cl,β- lactam),1543 (C=C,Ar);1H NMR (δ in ppm) (CDCl3):4.74 (s, 1H, Ar-OH), 6.78-7.62 (m, 4H, Ar_H), 5.32 (d, 1H, Cl-CH), 4.91(d,1H,N-CH-R of β-lactam).

IVd.1-amino-3-chloro-4-(2-nitrophenyl)azetidin-2-one

Yield: 74%. M.p.:149-150°C; Anal.Calcd for C9 H8 N3 O3Cl(MW=241.63),: C 44.74, N 17.39, O 19.86 found: C 44.71, N 17.35, O 19.78.;
IR (KBr) (νmax in cm-1): 2970 (C-H) 3044 v(Ar-H), 1750 (C=O, monocyclic β-lactam),783(C-Cl, β-lactam),1522(C=C,Ar),2340(N-N), 3441(N-H stretch), 1520 (N=O str.asym),1330(N=O str,sym);1H NMR (δ in ppm) (CDCl3):6.84-7.52 (m, 4H, Ar_H), 5.26 (d, 1H, Cl-CH), 4.97(d,1H,N-CH-R of β-lactam).

IVe.1-amino-3-chloro-4-(2-hydroxyphenyl)azetidin-2-one

Yield: 58%. M.p.:162-163°C; Anal.Calcd for C9 H9 N2 O2 Cl(MW=212.63),: C 50.84, N 713.17, O 15.05 found: C 50.77, N 13.13, O 15.02.;
IR (KBr) (νmax in cm-1):3040 v(Ar-H), 1760 (C=O, monocyclic β-lactam), 3430 (o-OH,o-hydroxyphenyl),2340(N-N), 3430(N-H stretch), ,775(C-Cl,β- lactam),1533(C=C,Ar);1H NMR (δ in ppm) (CDCl3):4.72 (s, 1H, Ar-OH), 6.73-7.30 (m, 4H, Ar_H), 5.30 (d, 1H, Cl-CH), 4.88(d,1H,N-CH-R of β-lactam).

IVf.1-amino-3-chloro-4-(4-hydroxy-3-methoxyphenyl)azetidin-2-one

Yield: 72%. M.p.:110-111°C; Anal.Calcd for C102 H11N2 O3 Cl(MW=242.66),: C 49.50, N 11.54, O 19.78 found: C 49.44, N 11.47O 19.77.;
IR (KBr) (νmax in cm-1):3045 v(Ar-H), 1758 (C=O, monocyclic β-lactam), 3434 (3-OH,3-hydroxyphenyl),2338(N-N), 3429(N-Hstretch), 1685 (OCH3,p-methoxyphenyl),785(C-Cl, β-lactam),1532(C=C,Ar);1H NMR (δ in ppm) (CDCl3):4.82 (s, 1H, Ar-OH), 6.93-7.66 (m, 3H, Ar_H), 5.27 (d, 1H, Cl-CH), 4.86(d,1H,N-CH-R of β-lactam)3.28 (s,3H,Ar-OCH3).

The synthesis 3-amino-2-(substituted Phenyl)thiazolidin-4-one (Va-f)

(0.01) mole of compound (IIIa-f) and thioglycollic acid (0.01 mole) containing traces of zinc chloride (0.1 gm) in dimethylformamide (DMF) was heated under reflux for 4 hours. It was poured into crushed ice and stirred vigorously. Solidification occurred after fifteen minutes. It was filtered off and washed with cold water. Recrystallization from ethanol gave analytically pure sample. The compounds of this category were presented as:

Va.3-amino-2-(3-hydroxy-4-methoxyphenyl)thiazolidin-4-one

Yield: 72%. M.p.:188-189°C; Anal.Calcd for C10H11N2 O3 S(MW=240.28/),: C 49.99, N11.66, O 19.98 found: C 49.928, N 11.59, O 19.94.; IR (KBr) (νmax in cm-1):1652 (tert amide C=O), 3605 (Ar-OH), 1079 (C-S-C), 3070 (Aromatic C-H str.), 1588 (C=C skeletal), 2343(N-N), 3445(N-Hstretch),3430 (3-OH,3-hydroxyphenyl), 1690 (OCH3,p-methoxyphenyl;1H NMR (δ in ppm) (CDCl3):4.66 (s, 1H, Ar-OH), 7.10-7.56 (m, 3H, Ar-H), 4.65 (brs, 1H, s, replaceable-OH), 3.22 (s, -N-CHS-R 1H, ), 3.44 (s, 2H, O=CCH2-S).

Vb.3-amino-2-(4-chlorophenyl)thiazolidin-4-one

Yield: 67%. M.p.:136-137°C; Anal.Calcd for C9 H9N2 O Cl S(MW=228.78),: C 47.27, N 12.27, O07.00 found: C 47.22, N 12.19., O 06.98.; IR (KBr) (νmax in cm-1):1655 (tert amide C=O),1074 (C-S-C), 3072(Aromatic C-H str.), 1580 (C=C skeletal), 2343(N-N), 3445(N-Hstretch), 737(C-Cl stretch);1H NMR (δ in ppm) (CDCl3):6.60-7.75 (m, 4H, Ar-H), 3.28 (s, -N-CHS-R1H, ), 3.41 (s, 2H, O=CCH2-S).

Vc.3-amino-2-(4-hydroxyphenyl)thiazolidin-4-one

Yield: 58%. M.p.:190-191°C; Anal.Calcd for C9 H10N2 O2 S(MW=210.25),: C 59.41, N 03.32, O 15.25 found: C 59.36, N 13.28, O 15.19.;IR (KBr) (νmax in cm-1):1660(tert amide C=O),1070 (C-S-C), 3078(Aromatic C-H str.), 1582 (C=C skeletal), 2348(N-N), 3443(N-Hstretch), 737(C-Cl stretch), 3445 (p-OH,p-hydroxyphenyl);1H NMR (δ in ppm) (CDCl3):6.90-7.78(m, 4H, Ar-H),3.33 (s, -N-CHS-R1H, ), 3.44 (s, 2H, O=CCH2-S),4.70 (brs, 1H, s, replaceable-OH).

Vd.3-amino-2-(2-nitrophenyl)thiazolidin-4-one

Yield: 56%. M.p.:176-177°C; Anal.Calcd for C9 H9 N3 O3 S(MW=239.25),: C 45.18, N 17.56, O 20.06 found: C 45.13, N 17.51, O 20.01.;IR (KBr) (νmax in cm-1): 16850(tert amide C=O),1080 (C-S-C), 3075(Aromatic C-H str.), 1590 (C=C skeletal), 2352(N-N), 3443(N-Hstretch), 747(C-Cl stretch), 1540 (N=O str.asym),1342(N=O str,sym);1H NMR (δ in ppm) (CDCl3):6.72-7.66(m, 4H, Ar-H),3.42(s, -N-CHS-R1H, ), 3.48 (s, 2H, O=CCH2-S).

Ve.3-amino-2-(2-hydroxyphenyl)thiazolidin-4-one

Yield: 65%. M.p.:128-129°C; Anal.Calcd for C9 H10N2 O2 S(MW=210.25),: C 51.41, N 13.32, O 15.25 found: C 15.38, N 13.27, O 15.19.;IR (KBr) (νmax in cm-1): 1685(tert amide C=O),1080 (C-S-C), 3080(Aromatic C-H str.), 1575 (C=C skeletal), 2338(N-N), 3435(N-Hstretch), 745(C-Cl stretch), 3438 (o-OH,o-hydroxyphenyl);1H NMR (δ in ppm) (CDCl3):6.70-7.71(m, 4H, Ar-H),3.42(s, -N-CHS-R1H, ), 3.52 (s, 2H, O=CCH2-S),4.74 (brs, 1H, s, replaceable-OH).

Vf.3-amino-2-(4-hydroxy-3-methoxyphenyl)thiazolidin-4-one

Yield: 70%. M.p.:130-131°C; Anal.Calcd for C10 H12N2 O3 S (MW=240.28),: IR (KBr) (νmax in cm-1): 1670(tert amide C=O),1085 (C-S-C), 3073(Aromatic C-H str.), 1586(C=C skeletal), 2352(N-N), 3448(N-Hstretch), 744(C-Cl stretch), 3440 (p-OH,p-hydroxyphenyl),1690 (OCH3,p-methoxyphenyl;1H NMR (δ in ppm) (CDCl3):6.65-7.60(m, 3H, Ar-H),3.40 (s, -N-CHS-R1H, ), 3.39 (s, 2H, O=CCH2-S),4.68 (brs, 1H, s, replaceable-OH),3.35(s,3H,Ar-OCH3).

Synthesis of 3-chloro-4- (substituted phenyl) -1- ((1- (5- (2-nitrophenyl) -3 -phenyl-4, 5 – dihydro-1 H-pyrazol-1-yl ) ethylidene) amino) azetidin-2-one (VIa-f)

The target compounds were synthesized by taking (0.02) mole of compound II and (0.02) mole of 1-amino-3-chloro-4-(substituted phenyl) azetidin-2-one (IVa-f) in pyridine (30 ml) were heated under reflux on a heating mantel for 6 hrs. Consequently, the reaction mixture was added to ice cold water (100 ml). A solid started to separate out which was allowed to settle down for 1 hr. It was filtered off and washed successively with water after drying in a vacuum desiccator. The clean final compound was thus obtained.

Characterization data of the compounds thus synthesized are given in as

VIa.3-chloro-4-(3-hydroxy-4-methoxyphenyl)-1-((1-(5-(2-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)ethylidene)amino)azetidin-2-one

Yield: 72%. M.p.:120-121°C; Anal.Calcd for C27 H24 N5 O5Cl (MW=533.96),: C 60.73, N 13.12, O 14.98found: C 60.68, N 13.07, O 14.86.;
IR (KBr) (νmax in cm-1): 2970 (C-H) 3044 v(Ar-H), 1750 (C=O,monocyclicβ-lactam),783(C-Cl,β- lactam),1522(C=C,Ar),2340(N-N), 1628 (C=N), 1136 (C-N str.), 3430 (3-OH,3-hydroxyphenyl), 1677 (OCH3,p-methoxyphenyl), ;1H NMR (δ in ppm) (CDCl3):6.60-7.52 (m, 13H, Ar_H), 5.28(d, 1H, Cl-CH), 4.90(d,1H,N-CH-R of β-lactam), 2.82 (s,3H,Ar-OCH3), 5.80 (s, 1H, Ar-OH); Mass: M+ 533,412,457,335,295,242,124,105,70.

VIb.3-chloro-4-(4-chlorophenyl)-1-((1-(5-(2-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)ethylidene)amino)azetidin-2-one

Yield: 65%. M.p.:154-155°C; Anal.Calcd for C26 H21N5 O3 Cl2 (MW=522.38),: C 59.78,N 13.41, O 09.19found: C 59.71, N 13.35, O 09.11.;
IR (KBr) (νmax in cm-1): 2975 (C-H) 3048 v(Ar-H),740(C-Cl stretch), 1760 (C=O,monocyclicβ-lactam),788(C-Cl,β- lactam),1532(C=C,Ar),2340(N-N), 1638 (C=N), 1136 (C-N str.),;1H NMR (δ in ppm) (CDCl3):6.60-7.82 (m, 14H, Ar_H), 5.22(d, 1H, Cl-CH), 4.88(d,1H,N-CH-R of β-lactam),2.85 (s,3H,N=C-CH3), 3.24 (dd,1H, CH2);Mass:M+ 521,399,445,323,294,229,111,105,70.

VIc.3-chloro-4-(4-hydroxyphenyl)-1-((1-(5-(2-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)ethylidene)amino)azetidin-2-one

Yield: 58%. M.p.:163-164°C; Anal.Calcd for C26 H22N5 O4 Cl (MW=503.94),: C 61.97,N 13.90, O 12.70found: C 61.91, N13.88O 12.66.;
IR (KBr) (νmax in cm-1): 3440 (p-OH,p-hydroxyphenyl), 2977 (C-H) 3048 v(Ar-H), 1768 (C=O,monocyclicβ-lactam),788(C-Cl,β- lactam),1541(C=C,Ar),2340(N-N), 1632 (C=N), 1126 (C-N str.),;1H NMR (δ in ppm) (CDCl3):6.70-8.60 (m, 14H, Ar_H), 2.61 (d,1H,N-CH-R of β-lactam),2.3 (s,3H,N=C-CH3), 2.7 (dd,1H, CH2);Mass:M+ 503,427,381,305,295,211,105,93.

VId.3-chloro-4-(2-nitrophenyl)-1-((1-(5-(2-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)ethylidene)amino)azetidin-2-one

Yield: 60%. M.p.:123-124°C; Anal.Calcd for C26 H21N6 O5 Cl (MW=532.94),: C 58.60, N 15.77, O 15.01found: C 58.55, N 15.71, O 14.96; IR (KBr) (νmax in cm-1):2960 (C-H) 3048 v(Ar-H),1530 (N=O str.asym),1338(N=O str,sym), 1778 (C=O,monocyclicβ-lactam),785(C-Cl,β- lactam),1548(C=C,Ar),2344(N-N), 1636 (C=N), 1129 (C-N str.),;1H NMR (δ in ppm) (CDCl3):6.66-7.72 (m, 14H, Ar_H), 5.31(d, 1H, Cl-CH), 4.81(d,1H,N-CH-R of β-lactam),2.90 (s,3H,N=C-CH3), 3.33 (dd,1H, CH2);Mass: M+ 531,455,511,335,295,241,123,105.

VIe.3-chloro-4-(2-hydroxyphenyl)-1-((1-(5-(2-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)ethylidene)amino)azetidin-2-one

Yield: 75%. M.p.:115-116°C; Anal.Calcd for C26 H22N5 O4 Cl (MW=503.94),: C 61.97,N 136.90, O 12.70found: C 61.92, N 13.83, O 12.63.;
IR (KBr) (νmax in cm-1):2972 (C-H) 3048 v(Ar-H),1548 (N=O str.asym),1333(N=O str,sym), 1759 (C=O,monocyclicβ-lactam),778(C-Cl,β- lactam),1555(C=C,Ar),2344(N-N), 1641 (C=N), 1132 (C-N str.),3438 (o-OH,o-hydroxyphenyl) ;1H NMR (δ in ppm) (CDCl3):6.64-7.76 (m, 14H, Ar_H), 5.41(d, 1H, Cl-CH), 4.90(d,1H,N-CH-R of β-lactam),2.88 (s,3H,N=C-CH3), 3.38 (dd,1H, CH2),5.77 (s, 1H, Ar-OH) ;Mass: M+ 503,427,381,305,294,211,105,93.

VIf.3-chloro-4-(4-hydroxy-3-methoxyphenyl)-1-((1-(5-(2-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)ethylidene)amino)azetidin-2-one

Yield: 62%. M.p.:161-162°C; Anal.Calcd for C27 H24 N5 O5 Cl (MW=533.96),: C 60.73 N 13.12, O 14.98found: C 60.67, N 13.07O 14.93.;
IR (KBr) (νmax in cm-1): 2965 (C-H) 3044 v(Ar-H), 1760 (C=O,monocyclicβ-lactam),780(C-Cl,β- lactam),1532(C=C,Ar),2342(N-N), 1628 (C=N), 1140 (C-N str.), 3441(4-OH,4-hydroxyphenyl), 1670 (OCH3,3-methoxyphenyl), ;1H NMR (δ in ppm) (CDCl3):6.71-7.62 (m, 13H, Ar_H), 5.32(d, 1H, Cl-CH), 4.86(d,1H,N-CH-R of β-lactam), 2.88 (s,3H,Ar-OCH3), 5.78 (s, 1H, Ar-OH); Mass:M+ 533,412,335,295,242,124,105.

Synthesis of (3–hydroxyl–4–methoxyphenyl)–3- ( ( 1 - ( 5 - ( 2 – nitro phenyl ) – 3 – phenyl – 4 , 5 - dihydro-1H-pyrazol-1-yl) ethylidene) amino) thiazolidin-4-one (VIIa-f)

The target compounds were synthesized by taking (0.02 mole) of compound II and (0.02) mole of 3-amino-2-(3-hydroxy-4-methoxyphenyl) thiazolidin-4-one (IVa-f)in pyridine (30 ml). The reactants were heated under reflux on a heating mantel for 6 hrs. Consequently, the reaction mixture was added to ice cold water (100 ml). A solid started to separate out which was allowed to settle down for 1 hr. It was filtered off and washed successively with water. After drying in vacuum desiccator, The clean final compound was obtained. Characterization data of the compounds thus synthesized, are given below:

VIIa.2-(3-hydroxy-4-methoxyphenyl)-3-((1-(5-(2-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)ethylidene)amino)thiazolidin-4-one

Yield: 70%. M.p.:158-159°C; Anal.Calcd for C270 H25N5O5 S (MW=531.58),: C 61.00,N 13.17, O 15.05found: C 60.96, N 13.12, O 15.01.; IR (KBr) (νmax in cm-1):1655 (tert amide C=O), 3615 (Ar-OH), 1072(C-S-C), 3075 (Aromatic C-H str.), 1576 (C=C skeletal),1636 (C=N), 1129 (C-N str.),3428(3-OH,3-hydroxyphenyl), 1660(OCH3,p-methoxyphenyl);1H NMR (δ in ppm) (CDCl3):6.58-7.75 (m, 13H, Ar-H), 4.75 (brs, 1H, s, replaceable-OH), 3.12 (s, -N-CHS-R1H, ), 3.36 (s, 2H, O=CCH2-S), 2.92(s,3H,N=C-CH3), 3.20 (dd,1H, CH2),3.72(d,1H,NCH-R),2.91(s,3H,Ar-OCH3).
Mass:M+ 521,455,409,333,295,239,224,123,103.

VIIb.2-(4-chlorophenyl)-3-((1-(5-(2-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)ethylidene)amino)thiazolidin-4-one

Yield: 68%. M.p.:198-199°C; Anal.Calcd for C26 H22N5 O3 S Cl (MW=520),: C 60.05,N 13.47, O 09.23found: C 60.02, N 13.39, O 09.19.; IR (KBr) (νmax in cm-1):1678 (tert amide C=O),1088 (C-S-C), 3086 (Aromatic C-H str.), 1570 (C=C skeletal),1638 (C=N), 1131 (C-N str.), 575 (C-Cl); 1H NMR (δ in ppm) (CDCl3):6.70-7.78 (m, 14H, Ar-H), 3.23 (s, -N-CHS-R1H, ), 3.36 (s, 2H, O=CCH2-S), 2.95(s,3H,N=C-CH3), 3.32 (dd,1H, CH2),3.89(d,1H,NCH-R).Mass:M+ 519,443,397,321,294,227,213,111.

VIIc.2-(4-hydroxyphenyl)-3-((1-(5-(2-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)ethylidene)amino)thiazolidin-4-one

Yield: 76%. M.p.:180-181°C; Anal.Calcd for C26 H23N5 O4 S (MW=501.56),: C 62.26,N 13.96, O 112.76found: C 62.18, N 13.88, O 12.71. IR (KBr) (νmax in cm-1):1665 (tert amide C=O), 3620 (Ar-OH), 1074 (C-S-C), 3078(Aromatic C-H str.), 1580(C=C skeletal),1631 (C=N), 1136 (C-N str.);1H NMR (δ in ppm) (CDCl3):4.55 (s, 1H, Ar-OH), 6.66-8.76 (m, 14H, Ar-H), 2.73 (brs, 1H, s, replaceable-OH), 3.21 (s, -N-CHS-R1H, ), 2.9 (s, 2H, O=CCH2-S), 2.77(s,3H,N=C-CH3), 3.21 (dd,1H, CH2),3.80(d,1H,NCH-R);Mass:M+ 501,424,379,303,295,209,195,103,93.

VIId.2-(2-nitrophenyl)-3-((1-(5-(2-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)ethylidene)amino)thiazolidin-4-one

Yield: 55%. M.p.:1710-172°C; Anal.Calcd for C26 H22N6 O5 S (MW=530.56),: C 58.86,N 15.84, O 15.08found: C 58.81, N 15.78, O 15.01.; IR (KBr) (νmax in cm-1):1643 (tert amide C=O), 3624(Ar-OH), 1066 (C-S-C), 3082 (Aromatic C-H str.), 1580 (C=C skeletal),1630 (C=N), 1125 (C-N str.).1528 (N=O str.asym),1330(N=O str,sym).;1H NMR (δ in ppm) (CDCl3):6.61-7.70 (m, 13H, Ar-H),3.29 (s, -N-CHS-R 1H, ), 3.39 (s,2H, O=CCH2-S), 3.11 (s,3H,N=C-CH3), 3.10 (dd,1H,CH2), 3.73 (d,1H,NCH-R); Mass:M+ 529,453,409,333,294,2396,223,123,103.

VIIe.2-(2-hydroxyphenyl)-3-((1-(5-(2-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)ethylidene)amino)thiazolidin-4-one

Yield: 68%. M.p.:130-131°C; Anal.Calcd for C26 H23N5O4 S (MW=501.56),: C 62.26,N 13.96, O 12.76found: C 62.22, N13.88, O12.67; IR (KBr) (νmax in cm-1):1680 (tert amide C=O), 3630 (Ar-OH), 1060(C-S-C), 3070 (Aromatic C-H str.), 1582 (C=C skeletal),1644 (C=N), 1138 (C-N str.);1H NMR (δ in ppm) (CDCl3):4.60 (s, 1H, Ar-OH), 6.68-7.89 (m, 14H, Ar-H), 4.66 (brs, 1H, s, replaceable-OH), 3.38(s, -N-CHS-R1H, ), 3.31(s, 2H, O=CCH2-S), 2.90(s,3H,N=C-CH3), 3.22 (dd,1H, CH2),3.73(d,1H,NCH-R);Mass:M+ 501,425,379,303,295,209,194.103,94.

VIIf.2-(4-hydroxy-3-methoxyphenyl)-3-((1-(5-(2-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)ethylidene)amino)thiazolidin-4-one

Yield: 70%. M.p.:176-177°C; Anal.Calcd for C27 H25N5O5S (MW=531.58),: C 61.00,N 13.17,O 15.05found: C 60.92, N13.11, O 15.01.;IR (KBr) (νmax in cm-1): 3446(3-OH,3-hydroxyphenyl), 1678(OCH3,p-methoxyphenyl).1677 (tert amide C=O), 3628(Ar-OH), 1066 (C-S-C), 3075 (Aromatic C-H str.), 1574(C=C skeletal),1642(C=N), 1132 (C-N str.);1H NMR (δ in ppm) (CDCl3):2.80(s,3H,Ar-OCH3), 6.65-7.80 (m, 13H, Ar-H), 4.64 (brs, 1H, s, replaceable-OH), 3.33(s, -N-CHS-R1H, ), 3.30(s, 2H, O=CCH2-S), 2.81(s,3H,N=C-CH3), 3.26 (dd,1H, CH2),3.80(d,1H,NCH-R);Mass:M+ 531,455,409,333,295,240,225,123,103.

The potency of the synthesized compounds were tested against some gram positive (Staphylococcus aureus, Bacillus subtilis) and gram negative bacteria (E. coli, and Pseudomonas aeruginosa) using routine antimicrobial test. All the test microorganism were grown in different identical sets ofLB media containing variable concenterations of the compound(VIa-f, VIIa-f).Growth of the pathogenic test microbes was measured after 24 hrs by recording the optical density of the solution at 600nm. The optical density versus compound concenteration growth curve was plotted for each set to get the minimum inhibitory concenteration (MIC) values of the tested compounds against the pathogenic gram positive and gram negative bacteria. In a conical tube containing 10 ml of LB media, Staphylococcus aureus,Bacillussubtilis, E.coli and Pseudomonas aeruginosa,were incubated for 8 h at 37°C and their growth were measured by recording the optical density of the solution at 600 nm. 100 μl of the bacterial suspension is added into each conical tube containing the test compound with final concentrations of 1000, 500, 250, 125, 62.5, 31.25, 15.63, 7.81, 3.91, 1.95, 0.98, 0.49 and 0.244 μg ml−1 in 10 ml of LB media, respectively. The parallel control experiment was done by adding the same 100 μl of the bacterial suspension to conical tube containing 10 ml of LB media alone. The growth of bacteria for each conical tube was measured by recording the optical density of the solution at 600 nm after 24 hour time. The optical density versus compound concentration was plotted together. The drop in optical density at respective antibacterial compound concentration was taken as the MIC of that compound.

Results and Discussions

The synthesized compounds were evaluated for their potency against the test microorganism (Staphylococcus aureus, Bacillus subtilis, E.coli and Pseudomonas aeruginosa. All the synthesized compound showed moderate to excellent activity. Compound VIb VIId were the most effective against the tested pathogens while the rest displayed moderate to good activity. Compound VIb showed high potency against all the test organism but was most effective against B.subtilis (12.5 μg/mL). Compounds VIId, VIIe, VIIf showed excellent results against P.aeruginosa showing MIC values ranging from(12.5-50 μg/mL)with VIIe being most effective of all exhibiting an MIC value of (12.5 μg/mL). In Gram positive bacteria strains, compounds VIb, VIe, VIf, VIIa, VIIc, and VIId showed good activity (12.5-50 μg/mL) against S.aureus and B.subtilis where asIn Gram negative bacteria strains compounds VIc,VId, VIe, VIIe and VIIf showed tremendous potency v (12.5-50 μg/mL) against P.aeruginosa and E.coli compared with Ampicillin. All other compounds show moderate activity activity against the test microbial strains (Table 1) (Scheme 1)

S.No.   Gram positive Gram negative
  R B.subtilis S.aureus E.coli P. aeruginosa
VIa. 3-OH,4-OCH3- Benzaldehyde 50 >100 >100 50
VIb. p-Chlorobenzaldehyde 12.5 50 50 50
VIc. p-Hydroxy benzaldehyde >100 >100 50 50
VId. O-nitro benzaldehyde 50 50 12.5 25
VIe. o-Hydroxy benzaldehyde 50 >100 >100 25
VIf. 4-OH,3-OCH3- Benzaldehyde 25 50 >100 50
VIIa. 3-OH,4-OCH3- Benzaldehyde 25 12.5 100 50
VIIb. p-Chlorobenzaldehyde 100 50 50 100
VIIc. p-Hydroxy benzaldehyde 50 25 50 100
VIId. O-nitro benzaldehyde 12.5 50 100 25
VIIe. o-Hydroxy benzaldehyde 100 50 50 12.5
VIIf. 4-OH,3-OCH3- Benzaldehyde 50 100 50 25

Table 1: In Vitro Anti-Microbial Activity.

derpharmachemica-characterization

Scheme 1: Synthesis and characterization of novel Substituted pyrazol-azetidin-2-one/thiazolidin-4-one derivatives for their antimicrobial activity

Conclusion

In the present work all the synthesized novel heterocyclic products were prepared using simple procedures which involved less reaction time, affordable, cost effective reagents avoiding hazardous and toxic chemicals. The Compound VIbVIId exhibited tremendous potencies against the tested pathogens while the rest displayed moderate to good activity. Compound VIb showed high potency against all the test organisms but was most effective against B.subtilis (12.5μg/mL). Compounds VIId, VIIe, VIIf showed excellent results against P.aeruginosa showing MIC values ranging from (12.5 μg/mL-50 μg/mL) with VIIe being most effective of all exhibiting an MIC value of (12.5 μg/mL). Thus the above synthesized compounds hold promise as novel chemotherapeutic agents.

Acknowledgement

The authors express their sincere thanks to Faculty of chemical sciences Shri Ramswroop Memorial University, Barabanki, for providing laboratory facilities. They are also thankful to the director CBMR-SGPGI Lucknow and university of Lucknow for spectral data.

References

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