SYNTHESIS CYTOTOXIC AND ANTIMICROBIAL EVALUATION OF SOME NOVEL BENZOXAZOLE ANALOGUES

SYNTHESIS CYTOTOXIC AND ANTIMICROBIAL EVALUATION OF SOME NOVEL BENZOXAZOLE ANALOGUES

Mansi L. Patil ^{* 1}, Lalit G. Rathi ², Sanjana N. Gaikwad ³ and Swati S. Gaikwad ³

University Department of Pharmaceutical Sciences ¹, RTMNU, Nagpur - 440033, Maharashtra, India.

Institute of Pharmaceutical Education and Research Borgaon Meghe ², Wardha - 442001, Maharashtra, India.

Nagpur College of Pharmacy ³, Wanadongri, Nagpur - 441110, Maharashtra, India.

ABSTRACT: Benzoxazole and its analogues play an important role as therapeutic agents and exhibit good cytotoxic as well as antimicrobial activity. In the present study, benzoxazole analogues have been prepared by synthetic route; their spectroscopic evaluation was carried out, and then the synthesized compounds were screened for their cytotoxic activity by Allium cepa root model as well as antimicrobial activity by cup plate method. The synthesis and cytotoxic activity of a novel series of  Schiff’s base was carried out by reacting the amino group of the 4-Benzoxazol-2-yl-phenylamine with different aromatic/ heteroaromatic aldehydes in the presence of polyphosphoric acid to give 4-(1,3-Benzoxazol-2-yl)phenyl]-1-(Substituted phenyl) methanimine (4a-4h) also Diazotization reaction of (4-Benzoxazol-2-yl phenyl) with β napthol gave 2-((4-(benzo [d]oxazole-2-yl)phenyl) diazenyl) naphthalene-2-ol (4i). The cytotoxic and antimicrobial activities of the synthesized compounds were determined by using the onion root model and cup plate method, respectively. The activity data of compounds was compared with standard drugs Cefixime for antibacterial activity and miconazole for antifungal was used as a standard, and cyclophosphamide was used as a standard for Cytotoxic activity.

Benzoxazole, Schiff base, Allium cepa root model, Antimicrobial activity, Cyclophosphamide

INTRODUCTION: Medicinal chemistry as practiced encompasses both definitions but finding the biochemical pathways through which drugs exert their beneficial effects has become an important activity of the medicinal chemist ¹. The discipline of medicinal chemistry is devoted to the discovery and development of new agents for treating diseases.

Most of this activity is directed to new natural or synthetic organic compounds. Inorganic compounds continue to be important in therapy, e.g., trace elements in nutritional therapy, antacids, and radiopharmaceuticals, but organic molecules with increasingly specific pharmacological activities are clearly dominant. The development of organic compounds has grown beyond traditional synthetic methods ².

Heterocyclic compounds are acquiring more importance in recent years as these can be found in a large number of compounds that display biological activities ^3-6. Heterocyclic compounds occupy central position in organic chemistry, and considerable attention has been focused on their synthesis. In particular, the benzof used nitrogen containing heterocycles are a common heterocyclic scaffold in many biologically active and medicinally significant compounds ⁷.

Benzoxazole is an aromatic organic compound with molecular formula C₇H₅NO. Heterocyclic moiety benzoxazole finds use in research as a starting material for the synthesis of larger, usually bioactive structures. Its aromaticity makes it relatively stable, although as a heterocyclic, it has reactive sites which allow for functionalization8. Benzoxazole displays diverse pharmacological properties including antimicrobial ^9-14, multidrug resistant cancer cell activities ^15-16, anti-inflammatory ^17-19, anticonvulsant ²⁰, antidepressant ²¹, anti-HIV ^22-23, Antihypertensive ²⁴, anthelmintic ²⁵ activities.

FIG. 1: PSEUDOPTEROXAZOLE

FIG. 2: SALVIANEN

They have been used as cathepsin S inhibitor, 5-HT receptor agonist, HIV reverse transcriptase inhibitor L-697661 Fig. 9, estrogen receptor-agonist ERB-041, selective peroxisome proliferator-activated  receptor  γ  antagonist  JTP- 426467, anticancer agent NSC-693638 and orexin-1 receptor antagonist  SB-334867bis-benzoxazole natural product analogs UK-1 Fig. 6, MUK-1, DMUK-1 and 2-(2’-hydroxyphenyl) benzoxazole analogs is one of the growing number of structurally related secondary metabolites with interesting biological activity, UK-1 and analogs SB334867 Fig. 7, NSC 693638 Fig. 8 display a wide spectrum of potent anticancer activity against leukemia, lymphoma, and certain solid tumor-derived cell lines; however, this anticancer natural product does not show antibacterial or antifungal activity ²⁶.

The benzoxazole ring system also occurs in natural products, e.g. pseudopteroxazole Fig. 1, salvianen Fig. 2, Nakijol B Fig. 3 and some are biologically active e.g. herbicid fenoxaprop Fig. 4. Flunoxa-profen Fig. 5 is non-steroidal anti-inflammatory agent which contains benzoxazole nucleus ^27-30. Besides its use in medicinal chemistry, these are recognized as fluorescent probes such as anion and metal cation sensors, as photochromatic agents, and laser dyes ³¹.

FIG. 3: NAKIJINOL B

FIG. 4: FENOXAPROP

FIG. 5: FLUNOXAPROFEN

FIG. 6: R₁=CH₃, R₂=H UK1 R₁=H, R₂=CH₃ AJ19561

FIG. 7: SB334867

FIG. 8: NSC 693638

FIG. 9: L-697-661

Some Natural and Synthetic Benzoxazole Analogues with Varied Pharmacological Attributes: The goal at the outset of this research was to develop more effective cytotoxic analogues of substituted benzoxazole. The strategy employed was to examine the effect of the isosteric heterocyclic nucleus against cancer cells.

MATERIALS AND METHODS: All the solvents, chemicals, and drugs employed for the synthetic work were of SDFine/E.Merck/Loba Laboratory grade. The solvents were purified by the established methods. Few of the reagent materials used in the synthesis were obtained from Sigma Aldrich, Germany, and Alfa Aeser, United Kingdom. All the residues have been dried in vacuum desiccators and recrystallized. The melting points of the compounds were determined in open capillaries using Thieles tube. The melting points, reported herein, are in the celsius scale (°C) and are uncorrected.

Precoated silica gel-G plate (E. Merck Kieselgel 60F254) activated at 110 °C for 30 min were used for thin layer chromatography and the spots were developed in iodine chamber. Though different solvent systems were employed, R_f values are reported for better comparable solvent systems, which are mentioned in the preceding text.

The IR spectra of compounds were recorded using KBr pellets on FTIR-8400 spectrophotometer Shimadzu make at the Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University Nagpur. 1H NMR (CDCl₃) 1H-NMRBRUKER AVANCE – II 400 NMR Spectrophotometer from National Institute of Pharmaceutical Education and Research, Hyderabad. Mass Spectrophotometer Micro-mass Quatto II triple quadrapole Mass Spectrometer from The National Institute of Pharmaceutical Education and Research, Hyderabad.

Chemistry: The chemicals were purchased from the commercial vendors and were used without purification. The reactions were monitored and the purity of the products was checked by thin layer chromatography (TLC).

All the melting points were taken on a DBK Programmed Melting Point Apparatus. IR spectra were recorded on an FT-IR - 8400 S, Shimadzu Corporation, Kyoto, Japan. The 1HNMR spectra were recorded on   AVANCE – II 400 NMR Spectrophotometer and chemical shifts (δ) are reported in ppm relative to internal tetramethyl-silane (TMS). Mass analysis was carried out with a Micro-mass Quatto II triple quadrapole Mass Spectrometer.

General Method for Synthesis of 3: To a mixture of 2-amino phenol (0.02 mol, 0.218 g) and 4-amino benzoic acid (0.002mol, 0.274 g) polyphosphoric acid (10 mL) was added with stirring to form a paste. It was then refluxed on a sand bath for 5 h at 200 °C and the resulting solution was cooled to 0 °C. The resulting mixture was poured into 40% sodium bicarbonate solution with stirring till precipitate has formed. The solid was filtered, washed with water and recrystallized from ethanol ^32-35.

General Method for Synthesis of 3a-H: To the equimolar quantities of 4-Benzoxazol-2-yl-phenylamine (0.002 mol, 420 mg) and the respective aromatic aldehydes were dissolved in 10 ml of warm ethanol, and 1 ml of glacial acetic acid was added dropwise to the mixture.

The mixture was refluxed on sand bath for 6 h at 200 °C till the completion of the reaction (monitored by TLC). The reaction mixture was cooled and poured onto crushed ice. The product was filtered, dried and recrystallized using ethanol to get 4a-h ^36-40.

General Method for Synthesis of 4a: Compound IIh (4.20 mmol, 1.72 g) was dissolved in 10 mL of 6N hydrochloric acid and cooled to 0 °C. A solution of (5.04 mmol, 0.35 g) of sodium nitrite in 5 mL of water was added to it at the same temperature, and the resultant diazonium chloride solution was added drop-wise to the stirred 2-napthol solution while maintaining the temperature at 5-10 °C. The crude product was purified by dissolving in DMSO followed by precipitation with water ⁴¹.

4-(benzo[d]oxazol-2-yl) benzeneamine (3): Yield: 80 %; m.p. 238-240 °C; IR (KBr) 3052, 1575, 1498, 1618, 1247; 1HNMR (400 MHz, DMSO), δ2.86 (s, 1H, CH),), δ7.43 (m, 4H, benzoxazole), δ 7.67 (m, 4H, Ar−H), ), δ7.38( m, 5H, Benzylidine); MS m/z 266 [M + H]+.

4-(1,3-Benzoxazol-2 yl) phenyl]imino} methyl] phenol3a: Yield: 75.18 %; m.p. 256-258 °C; IR (KBr) 3060.82, 3506, 2750, 1579.59, 1057,1318; 1HNMR (400 MHz, DMSO), δ 2.70 (s, 1H, CH), δ 4.75(s, 1H, OH)  δ 7.61 (m, 4H, Ar−H), δ 7.72 (m, 4H, benzoxazole), δ8.1 (m, 4H, benzylidine); MS m/z 315 [M + H]+.

4-(1,3-Benzoxazol-2-yl)phenyl]-1-(4-nitrophenyl) methanimine 3b: Yield: 75.18%; m.p. 170-172°C; IR (KBr) 3072, 1610, 1588, 1452, 752, 1440, 1053; 1HNMR (400 MHz, DMSO), δ 8.61 (s, 1H, CH), δ 7.52 (m, 4H, Ar−H), δ 7.90 (m, 4H, benzoxazole), δ 8.34 (m, 4H, benzylidine); MS m/z 344 [M + H]+.

4-(1, 3-Benzoxazol-2-yl) phenyl]- 1-(4-chloro-phenyl) methanimine 3c: Yield: 68%; m.p. 150-152 °C; IR (KBr) 3062, 1614, 1558, 1488, 1452, 1051, 1325, 804; 1HNMR (400 MHz, DMSO), δ 8.46 (s, 1H, CH), δ 7.90 (m, 4H, Ar−H), δ 7.72 (m, 4H, benzoxazole), δ 7.69 (m, 4H, benzylidine); MS m/z 333 [M + H]+.

4-(1, 3-Benzoxazol-2-yl) phenyl] -1-(4-fluoro-phenyl) methanimine 3d: Yield: 79%; m.p. 182-184 °C; IR (KBr) ) 3056, 2889, 1631, 1587, 1506, 1452, 750, 1413, 1056; 1HNMR (400 MHz, DMSO), δ 8.22 (s,1H, CH),  δ 7.95 (m, 4H, Ar−H), δ 7.62 (m, 4H, benzoxazole), δ 7.58 (m, 4H, benzylidine); MS m/z 317 [M + H]+.

4-(1, 3-Benzoxazol-2-yl) phenyl]-1-(2-nitro-phenyl) methanimine3e: Yield: 62%; m.p. 75-78 °C; IR (KBr) 3101, 1613, 1598, 1456, 1521.73, 1344, 746; 1HNMR (400 MHz, DMSO), δ 8.12 (s, 1H, CH), δ 7.7.76(m, 4H, Ar−H), δ 7.82 (m, 4H, benzoxazole), δ 7.39 (m, 4H, benzylidine); MS m/z 344 [M + H]+.

4-(1, 3-Benzoxazol- 2-yl)phenyl] -1-(2-chloro-phenyl) methanimine3f: Yield: 71.91%; m.p. 236-238 °C; IR (KBr) 3064, 1581.52, 1657, 1413, 747, 1218; 1HNMR (400 MHz, DMSO), δ8.19 (s, 1H, CH), δ 8.82(m, 4H, Ar−H), δ 7.28 (m, 4H, benzo-xazole), δ 7.65(m, 4H, benzylidine); MS m/z 341 [M + H]+.

4-(1, 3-Benzoxazol -2-yl) phenyl]-1-(4-bromo-phenyl) methanimine 3g: Yield: 58.32%; m.p. 148-150 °C; IR (KBr) 2927, 1610, 1580, 1490, 1452 , 1054, 1320, 840; 1HNMR (400 MHz, DMSO), δ8.02 (s, 1H, CH),  δ 7.80 (m, 4H, Ar−H), δ 7.55 (m, 4H, benzoxazole), δ 7.72(m, 4H, benzylidine); MS m/z 344[M + H]+.

4-(1, 3-Benzoxazol-2-yl) phenyl]-1-(3-chloro-phenyl) methanimine 3h: Yield: 85.14%; m.p. 173-175 °C; IR (KBr) 3189, 1610, 1522, 1452, 1054, 1320, 1248; 1HNMR (400 MHz, DMSO), δ8.84 (s, 1H, CH),  δ 7.11(m, 4H, Ar−H), δ 7.86 (m, 4H, benzoxazole), δ 7.31(m, 4H, benzylidine); MS m/z 315[M + H].

2-((4-(benzo[d]oxazole-2-yl) phenyl) diazenyl) naphthalene-2-ol 4a: Yield: 73.24%; m.p. 173-175 °C; IR (KBr) 3052.14, 1602.74, 1575.08; 1HNMR (400 MHz, DMSO), δ 2.5 (s, 1H, CH),  δ 7.95(m, 4H, Ar−H), δ 8.60 (s, 1H, OH) ; MS m/z 315[M + H].

Pharmacological Evaluation:

Cytotoxic Screening: Onion root model was used for studying cytotoxic activity. Allium cepa root tip meristems have been widely used for the evaluation of cytotoxic and antimitotic activity. The inhibitory effect of synthesized compounds was evaluated on the growth of Allium cepa root meristems, and the effect was compared with standard anticancer drug cyclophosphamide. Locally available Allium cepa bulbs were grown in the dark over 100 mL tap water at ambient temperature until the roots have grown to approximately 3-4 cm. The water was changed daily. Working dilutions of all the drugs were made in tap water. Standard drug cyclophosphamide and compound IIa-h were used at 1 mg/mL and 10 mg/mL concentration. The bulbs with root tips grown up to 3-4 cm were placed over drug solution and incubation was carried out at ambient temperature ^42-49.

Growing Allium cepa Meristems: Locally available Allium cepa bulbs were grown in dark over 100 mL tap water at ambient temperature until the roots have grown to approximately 3-4 cm. The water was changed daily.

Conditions for Drug Incubation: Working dilutions of all the drugs were made in tap water. Standard drug cyclophosphamide and compound IIa-h were used at 1 mg/mL and 10 mg/mL concentration. The bulbs with root tips grown up to 3-4 cm were placed over drug solution and incubation was carried out at ambient temperature Fig. 10-15.

Cytotoxic Activity: The cytotoxic effect of synthesized compounds 3a-3h and compound 4a was evaluated on the growth of Allium cepa root meristems, and the effect was compared with standard anticancer drug cyclophosphamide. Roots of onion were exposed for 96 h to different dilutions of all the compounds and cyclo-phosphamide. Shortening and decaying of roots was considered as a measure of cytotoxic activity. A progressive increase in root length was observed in control group. After 96 h of growth in the control, the average roots length was 4.91+0.32. Incubation of bulbs in increasing concentrations of cytotoxic agents produced a growth retarding effect that was associated with decrease in root number Table 1. In the presence of compound 3a & 3c,3g root length of onion bulb was decreased significantly (p<0.05) after 72 h as compared to control at the concentration of 10 mg/mL.

The effect was even more significant (P<0.01) after 96 h of incubation. Compound 3d showed very significant activity after 96 h at 10 mg/mL concentration. Compound 3e, 3f, 3h did not show cytotoxic activity at any concentration.

FIG. 1: PHOTOGRAPHS SHOWING GROWTH OF ONION IN THE PRESENCE OF VEHICLECYCLO-PHOSPHAMIDE AND COMPOUNDS 3A, 3B, 3C AND 3G

Antimicrobial Activity: The in-vitro antimicrobial studies were carried out by agar well diffusion method against test Organisms. Nutrient broth plates were swabbed with 24 h old broth culture (100 μL) of test bacteria. Using the sterile cork borer, wells (6 mm) were made into each Petri plate. The compounds were dissolved in DMSO of 5 mg/mL and from this 2.5, 5, 10 and 20 μL (50, 75 and 100 μg/mL) were added into the wells by using sterile pipettes.

TABLE 1: ROOT LENGTH ATTAINED AFTER INCUBATION WITH VEHICLE, CYCLOPHOSPHAMIDE & COMPOUND 3A-3H AND 4A

#Values are represented as Mean±SD; (n = 6) *p<0.05 is considered significant and **p<0.01 is considered very significant when compared with control group.

Antibacterial screening of newly synthesized compounds was carried out against E. coil and B. subtilis Table 2 and antifungal activity against C. albicans Table 3 according to the cup-plate method. Cefixime for antibacterial activity and miconazole for antifungal was used as a standard. The samples were dissolved in DMSO, which showed no zone of inhibition acts as a negative control. The plates were incubated at 37 °C for 24 h for bacteria and at 28 °C for 48 h for fungi. After appropriate incubation, the diameter of zone of inhibition of each well was measured ^50-54.

Cytotoxic Activity: The cytotoxic effect of synthesized compounds 3a-3h and compound 4a was evaluated on the growth of Allium cepa root meristems, and the effect was compared with standard anticancer drug cyclophosphamide. Roots of onion were exposed for 96 h to different dilutions of all the compounds and cyclo-phosphamide. Shortening and decaying of roots were considered as a measure of cytotoxic activity. A progressive increase in root length was observed in the control group. After 96 h of growth in the control, the length of the average roots was 4.91+0.32. Incubation of bulbs in increasing concentrations of cytotoxic agents produced a growth retarding effect that was associated with decrease in root number Table 1. In the presence of compound 3a & 3c, 3g root length of onion bulb was decreased significantly (p<0.05) after 72 h as compared to control at the concentration of 10 mg/mL The effect was even more significant (P<0.01) after 96 h of incubation. Compound 3d showed very significant activity after 96 h at 10 mg/mL concentration. Compound 3e, 3f, 3h did not show cytotoxic activity at any concentration.

Antimicrobial Activity: The in-vitro antimicrobial studies were carried out by agar well diffusion method against test Organisms. Nutrient broth plates were swabbed with 24 h old broth culture (100 μL) of test bacteria. Using the sterile cork borer, wells (6 mm) were made into each Petri plate. The compounds were dissolved in DMSO of 5 mg/mL and from this 2.5, 5, 10 and 20 μL (50, 75, and 100 μg/mL) were added into the wells by using sterile pipettes. Antibacterial screening of newly synthesized compounds was carried out against E. coil and B. subtilis Table 2 and antifungal activity against C. albicans Table 3 according to cup-plate method. Cefixime for antibacterial activity and miconazole for antifungal was used as a standard.

The samples were dissolved in DMSO, which showed no zone of inhibition acts as a negative control. The plates were incubated at 37 °C for 24 h for bacteria and at 28 °C for 48 h for fungi. After appropriate incubation, the diameter of the zone of inhibition of each well was measured ^50-54.

Antibacterial Activity:

TABLE 2: THE IN-VITRO ANTIBACTERIAL ACTIVITY OF COMPOUNDS 3A-3H AND 4A

(-) No activity. (±) Standard deviation

TABLE 3: THE IN-VITRO ANTIFUNGAL ACTIVITY OF COMPOUNDS 3A-3H AND 4A

(-) No activity. (±) Standard deviation

RESULTS AND DISCUSSION: Benzoxazole analogues have been reported to possess a broad spectrum of Pharmacological properties. Hence attempts have been made to synthesize some novel benzoxazole analogues and studied their cytotoxic effects on onion roots. The structures of the synthesized compounds were assigned on the basis of elemental analysis, IR, 1H NMR, and mass spectroscopy. These compounds were also screened forcytotoxic activity. The recorded percentage of inhibition showed significant cytotoxic activity when compared to the reference cytotoxic drug cyclophosphamide. Root length was decreased significantly as compared to the standard drug of compounds 3a, 3b, 3c, 3g at the concentration of 10 mg/mL Compound, and the compounds showed very significant activity after 96h incubation. Thus the structure-activity relationship suggests that electron-withdrawing substituents at para position such as chloro and nitrosubstituent’s show significant cytotoxic activity. From the results and discussion, it is thereby concluded that substituted benzoxazole congeners exhibit mild to moderate cytotoxic profiles; thus, newer and alternative congeners can be synthesized further and evaluated for their cytotoxic profile, which may have enhanced cytotoxic activity.

Compound 3b, 3g showed greater antifungal activity against E. coli as well as compound 3c showed greater antifungal activity against B. Subtilis. Compound 3c and 3g showed greater activity against C. albicans. The presence of electron-withdrawing chloro, bromo, and nitro Substituents at para position on the aromatic ring enhanced the activity. Thus the data reveals the necessity of electron-withdrawing substituent for potent antimicrobial activity.

CONCLUSION: Benzoxazole nucleus was found to possess many pharmacological activities like anti-inflammatory, antihistaminic, antiviral, multi-drug resistant cancer cell activities, antiulcer, anticonvulsant, etc. Hence, attempts were made to synthesize benzoxazole analogues with cytotoxic activity. Several other analogues of benzoxazole can be prepared and evaluated for their cytotoxic activity. The same analogues can also be evaluated for other biological activities. Structure/analogue based drug design can be carried out in order to optimize the pharmacological profiles. This will guide the synthesis of newer potent analogs using these leads.

ACKNOWLEDGEMENT: A special thanks to the National Institute of Pharmaceutical Education and Research, Hyderabad, for spectral analysis.

CONFLICTS OF INTEREST: None authors declared competing interests.

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    How to cite this article:

    Patil ML, Rathi LG, Gaikwad SN and Gaikwad SS: Synthesis cytotoxic and antimicrobial evaluation of some novel benzoxazole analogues. Int J Pharm Sci & Res 2021; 12(6): 3281-90. doi: 10.13040/IJPSR.0975-8232.12(6).3281-90.

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