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Design, Synthesis and Biological Potential of Heterocyclic Benzoxazole Scaffolds As Promising Antimicrobial and Anticancer Agent

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Design, Synthesis and Biological Potential of Heterocyclic Benzoxazole Scaffolds As Promising Antimicrobial and Anticancer Agent Kakkar et al. Chemistry Central Journal (2018) 12:96 https://doi.org/10.1186/s13065-018-0464-8 Chemistry Central Journal RESEARCH ARTICLE Open Access Design, synthesis and biological potential of heterocyclic benzoxazole scafolds as promising antimicrobial and anticancer agents Saloni Kakkar1, Sanjiv Kumar1, Balasubramanian Narasimhan1* , Siong Meng Lim2,3, Kalavathy Ramasamy2,3, Vasudevan Mani4 and Syed Adnan Ali Shah2,5 Abstract Background: Benzoxazole is the most important class of heterocyclic compound in medicinal chemistry. It has been incorporated in many medicinal compounds making it a versatile heterocyclic compound that possess a wide spec- trum of biological activities. Results: The molecular structures of synthesized benzoxazole derivatives were confrmed by physicochemical and spectral means. The synthesized compounds were further evaluated for their in vitro biological potentials i.e. antimi- crobial activity against selected microbial species using tube dilution method and antiproliferative activity against human colorectal carcinoma (HCT 116) cancer cell line by Sulforhodamine B assay. Conclusion: In vitro antimicrobial results demonstrated that compounds 4, 5, 7 and 16 showed promising antimi- crobial potential. The in vitro anticancer activity indicated that compounds 4 and 16 showed promising anticancer activity against human colorectal cancer cell line (HCT 116) when compared to standard drug and these compounds may serve as lead compound for further development of novel antimicrobial and anticancer agents. Keywords: Benzoxazole molecules, Synthesis, Antimicrobial activity, Anticancer activity Background chemotherapeutic agents for more efective cancer treat- Colorectal cancer is one of the most dangerous forms of ment [2]. cancer, causing the deaths of many patients every year Te number of cases of multidrug resistant bacterial [1]. As such, a signifcant progress is being made con- infections is increasing at an alarming rate and clinicians tinuously towards developing novel chemotherapeutic have become reliant on vancomycin as the antibiotic for agents [2, 3]. One of the standard drugs for treatment serious infections resistant to traditional agents which of colorectal cancer is 5-fuorouracil (5-FU). However it indicated that there is a need for the development of new is associated with a lot of side efects as it not only classes of antimicrobial agents [8]. Hence there is a need afects the cancer cells but also the normal cells [3–7]. In to develop those agents whose chemical characteristics order to overcome the undesirable side efects of avail- clearly difer from those existing agents and can over- able anticancer agents there is a need to develop novel come the problem of resistance [9]. Benzoxazole belongs to one of the most important class of heterocyclic compounds which are very signifcant for medicinal feld. It has been incorporated in many medici- *Correspondence: [email protected] nal compounds that made it versatile heterocyclic com- 1 Faculty of Pharmaceutical Sciences, Maharshi Dayanand University, pound possessing wide spectrum of biological activities Rohtak 124001, India Full list of author information is available at the end of the article viz: antimicrobial [10, 11], analgesic/anti-infammatory © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kakkar et al. Chemistry Central Journal (2018) 12:96 Page 2 of 11 [12], antitumor [13], antidiabetic activity [14] etc. Keep- phenyl)acetamide (II) reaction was carried out between ing in view of the pharmacological importance of benzo- I in dry DMF and sodium azide at room temperature. xazole derivatives, the present study had synthesize some Benzo[d]oxazole-2-thiol (III) was prepared from 2-ami- new benzoxazole derivatives and evaluate their antimi- nophenol in methanol, potassium hydroxide followed by crobial and antiproliferative activities. Te design of ben- the addition of carbon-di-sulphide. Further, to a solution zoxazole molecules with antimicrobial and anticancer of III in acetone was added anhydrous potassium car- potential was based on literature as shown in Fig. 1. bonate powder followed by slow addition of 3-bromo- prop-1-yne at 0 °C and the obtain 2-(prop-2-yn-1-ylthio) Results and discussion benzo[d]oxazole (IV). Finally, II and IV were dissolved in Chemistry a mixture of t-BuOH:H2O:DMF followed by the addition A series of benzoxazole derivatives (1–20) was synthe- of sodium ascorbate and copper (II) sulfate so as to obtain sized using synthetic procedures as outlined in Scheme 1. target benzoxazole derivatives (1–20). Te synthesized Initially, 2-chloro-N-(substituted phenyl)acetamide (I) compounds were confrmed by physicochemical prop- was prepared by reacting substituted aniline with chloro- erties (Table 1) i.e. melting point, molecular formula, Rf acetyl chloride in the presence of acetone and powdered value, % yield and spectral interpretation details (Table 2) potassium carbonate. To prepare 2-azido-N-(substituted i.e. FT-IR, NMR and Mass, which are in agreement with Fig. 1 Design of benzoxazole molecules for antimicrobial and anticancer potential based on literature Kakkar et al. Chemistry Central Journal (2018) 12:96 Page 3 of 11 1. X1=X3=X4=X5= H; X2= NO2 11. X1=X2=X4=X5= H; X3= F 2. X1=X2=X4=X5= H; X3= NO2 12. X1=X2=X4=X5= H; X3= Br 3. X1=X2=X4=X5= H; X3= OCH3 13. X1=X4=X5= H; X2=X3= Cl 4. X2=X4=X5= H; X1=Cl; X3= NO2 14. X2=X3=X4=X5= H; X1 = Br 5 X1=X3=X4= Cl; X2=X5= H 15. X1=X3=X5= H; X2= CH3; X4= CH3 6. X3=X4=X5= H; X1= CH3; X2= Cl 16. X1=X3=X4=X5= H; X2 = Br 7. X2=X4=X5= H; X1= CH3; X3= Br 17. X3=X4=X5= H; X1=X2 = CH3 8. X1=X2=X4=X5= H; X3= CH2-CH3 18. X2=X3=X4=X5= H; X1 = F 9. X2=X4=X5= H; X1= CH3; X3= CH3 19. X1=X3=X4=X5= H; X2 = Cl 10. X2=X3=X4=X5= H; X1=Cl 20. X1=X2=X4=X5= H; X3= Cl Scheme 1 Synthesis of benzoxazole derivatives (1–20) the proposed molecular structures. Te three obvious bromo derivatives (7, 12, 14 and 16). Te presence of aryl peaks in the IR spectra of the title compounds at 1689– alkyl ether group (C–O–C, Ar–OCH3) in compound 1662 cm−1, 3315–2986 cm−1 and 1499–1408 cm−1 are 3 showed a band at 1194 cm−1. Further the presence of attributed to C=N group of oxazole ring, C–H and C=C chloro group (Ar–Cl) in compounds 5, 6, 10, 13, 19 and groups of aromatic ring, respectively. Te absorption 20 showed IR stretches at 744–739 cm−1. Te IR band at peak of C–F group in aromatic fuoro compounds (11 1653–1578 cm−1 indicated the presence of CONH group and 18) appeared at 1235–1207 cm−1 whereas bands at of synthesized compounds. Te compounds 1, 2 and 4 738–622 cm−1 correspond to C–Br stretching of aromatic displayed IR stretching around 1394–1341 cm−1 that Kakkar et al. Chemistry Central Journal (2018) 12:96 Page 4 of 11 Table 1 Physicochemical properties of synthesized benzoxazole derivatives Comp. Molecular mass M. formula m.p. °C Rf value % yield 1: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(3-nitrophenyl) 410.41 C18H14N6O4S 152–154 0.17 76 acetamide 2: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-nitrophenyl) 410.41 C18H14N6O4S 165–167 0.18 81 acetamide 3: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-methoxyphenyl) 395.43 C19H17N5O3S 102–104 0.23 75 acetamide 4: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-chloro-4-nitro- 444.85 C18H13ClN6O4S 144–146 0.20 86 phenyl) acetamide 5: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(2,4,5-trichlorophe- 468.74 C18H12Cl3N5O2S 189–191 0.21 79 nyl) acetamide 6: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-2-meth- 413.88 C19H16ClN5O2S 138–140 0.22 82 ylphenyl) acetamide 7: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-bromo-2- 458.33 C19H16BrN5O2S 127–129 0.22 85 methyl-phenyl) acetamide 8: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-ethylphenyl) 393.46 C20H19N5O2S 118–120 0.23 85 acetamide 9: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(2,4-dimethylphe- 393.49 C20H19N5O2S 108–110 0.23 81 nyl) acetamide 10: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-chlorophenyl) 399.85 C18H14ClN5O2S 144–146 0.19 86 acetamide 11: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-fuorophenyl) 383.40 C18H14FN5O2S 119–121 0.19 90 acetamide 12: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-bromophenyl) 444.31 C18H14BrN5O2S 172–174 0.20 77 acetamide 13: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(3,4-dichlorophe- 434.30 C18H13Cl2N5O2S 169–171 0.19 80 nyl) acetamide 14: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-bromophenyl) 444.31 C18H14BrN5O2S 131–133 0.19 81 acetamide 15: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dimethyl- 393.46 C20H19N5O2S 125–127 0.23 79 phenyl) acetamide 16: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(3-bromophenyl) 444.31 C18H14BrN5O2S 151–153 0.18 78 acetamide 17: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(2,3-dimethyl- 393.46 C20H19N5O2S 133–135 0.24 82 phenyl) acetamide 18: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-fuorophenyl) 383.40 C18H14FN5O2S 119–120 0.20 89 acetamide 19: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(3-chlorophenyl) 399.85 C18H14ClN5O2S 161–163 0.19 86 acetamide 20: 2-(5-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-chlorophenyl) 399.85 C18H14ClN5O2S 166–168 0.19 82 acetamide corresponds to C-N symmetric stretching of aromatic at 4.72–4.77 ppm and 8.27–7.82 ppm are due to –CH2 13 NO2 group.
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