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Benzoxazole Derivatives: Design, Synthesis and Biological Evaluation

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Benzoxazole Derivatives: Design, Synthesis and Biological Evaluation Kakkar et al. Chemistry Central Journal (2018) 12:92 https://doi.org/10.1186/s13065-018-0459-5 RESEARCH ARTICLE Open Access Benzoxazole derivatives: design, synthesis and biological evaluation Saloni Kakkar1, Sumit Tahlan1, Siong Meng Lim2,3, Kalavathy Ramasamy2,3, Vasudevan Mani4, Syed Adnan Ali Shah2,5 and Balasubramanian Narasimhan1* Abstract Background: A new series of benzoxazole analogues was synthesized and checked for their in vitro antibacterial, antifungal and anticancer activities. Results and discussion: The synthesized benzoxazole compounds were confrmed by IR, 1H/13C-NMR, mass and screened for their in vitro antimicrobial activity against Gram-positive bacterium: Bacillus subtilis, four Gram-negative bacteria: Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi and two fungal strains: Candida albicans and Aspergillus niger using tube dilution technique and minimum inhibitory concentration (MIC) was noted in µM and compared to ofoxacin and fuconazole. Human colorectal carcinoma (HCT116) cancer cell line was used for the determination of in vitro anticancer activity ­(IC50 value) by Sulforhodamine B assay using 5-fuorouracil as standard drug. Conclusion: The performed study indicated that the compounds 1, 10, 13, 16, 19, 20 and 24 had highest antimi- crobial activity with MIC values comparable to ofoxacin and fuconazole and compounds 4, 6, 25 and 26 had best anticancer activity in comparison to 5-fuorouracil. Keywords: Benzoxazole, Synthesis, Antimicrobial, Anticancer, Characterization Background failure of available chemotherapeutics to treat cancer A great number of deaths are occurring throughout underscores the need of developing new chemical entities the world because of infectious diseases [1]. It has been [4]. Human colorectal cancer (CRC) has poor prognosis observed that there is a rapid increase in multi drug and is the third most commonly diagnosed malignancies. resistant infections these days which are causing a rise in Terapy is very much required with better efcacy, less various public health problems. Tere are number of dis- adverse efects and improved survival rates [5]. Benzo- eases which are now hard to treat with traditional anti- xazole derivatives have gained a lot of importance in the biotics drugs and clinicians have to depend on limited past few years because of their use in intermediates for drugs such as vancomycin [2]. Because of this there is an the preparation of new biological materials. Benzoxazoles increased demand to develop newer antimicrobial agents are prominent in medicinal chemistry due to their wide [3]. One of the most dangerous diseases in the world is spectrum of pharmacological activities such as antibacte- cancer and irrespective of so much medical advance- rial [2], antifungal [6], anticancer [7], anti-infammatory ment, cancer remains the second leading cause of death [8], antimycobacterial [9], antihistamine [10], antipar- in developing as well as developed countries. Although kinson [11], inhibition of hepatitis C virus [12], 5-HT3 chemotherapy is mostly used for treating cancer, the antagonistic efect [13], melatonin receptor antagonism [14], amyloidogenesis inhibition [15] and Rho-kinase inhibition [16]. A number of marketed drugs (Fig. 1) *Correspondence: [email protected] 1 Faculty of Pharmaceutical Sciences, Maharshi Dayanand University, are available having benzoxazole as core active moiety Rohtak 124001, India like, nonsteroidal anti-infammatory drug (NSAID)— Full list of author information is available at the end of the article funoxaprofen, benoxaprofen, antibiotic—calcimycin, © 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) 12:92 Page 2 of 16 antibacterial—boxazomycin B, muscle relaxant—chlo- presence of aromatic protons in synthesized derivatives. roxazone. Prompted by the above fndings (Fig. 2) in the Te compound 26 showed singlet at 4.6 ppm because of present study, we hereby report the synthesis, antimicro- the presence of OH of Ar–OH. Te appearance of sin- bial and anticancer activities of a series of benzoxazole glet at 7.01–8.24 ppm, 7.49–8.26 ppm, 4.61–4.63 ppm derivatives. and 4.57–4.59 ppm is due to the existence of –CONH, N=CH, N–CH2 and CH2–S groups respectively. Com- Results and discussion pound 7 showed doublet around 1.22 ppm due to exist- Chemistry ence of isopropyl group at para position. Compounds 2, 3, 4, 5 and 6 showed singlet at range of 3.72–3.81 ppm Te method to synthesize the designed benzo- due to presence of OCH3 of Ar–OCH3. Finally, DMSO- xazole derivatives is given in Scheme 1. Initially, d6 was used for recording the 13C-NMR spectra of ben- 2-(chloromethyl)-1H-benzo[d]imidazole (I) was syn- zoxazole derivatives and it was observed that the spectral thesized by the reaction of ortho phenylenediamine, signals and proposed molecular structure of the prepared chloroacetic acid and hydrochloric acid. Benzo[d] compounds showed good agreement. oxazole-2-thiol (II) was synthesized by the reaction of methanolic solution of 2-aminophenol with potassium Antimicrobial activity hydroxide, followed by the addition of carbon-di-sulfde. Te screening of antibacterial and antifungal activity A mixture of I and II was stirred in the presence of tri- of the synthesized derivatives was done by tube dilu- ethylamine so as to obtain 2-(((1H-benzimidazol-2-yl) tion method [21] and the results are shown in Table 2 methyl)thio)benzoxazole (III). To a mixture of III and as well as Figs. 3 and 4. Te study revealed that the pre- anhydrous potassium carbonate in dry acetone, ethyl pared derivatives showed moderate to good antimi- chloroacetate was added so as to get ethyl 2-(2-((benzo- crobial activity against various microbial strains used. xazol-2-ylthio)methyl)-1H-benzimidazol-1-yl)acetate Particularly, compounds 1, 10, 13, 16, 19, 20 and 24 (IV). Further reaction of IV with hydrazine hydrate have shown better antimicrobial activity than the stand- yielded 2-(2-((benzoxazol-2-ylthio) methyl)-1H-benzimi- ards ofoxacin and fuconazole. Compound 10 (MICbs dazol-1-yl) acetohydrazide (V). Finally reaction of V with −3 = 1.14 × 10 µM) was found to be most efective against various substituted aldehydes gave the title compounds −3 B. subtilis. Compound 24 (MICec 1.40 10 µM) ( – ). Te physicochemical properties of newly syn- = × 1 26 was found to be active against E. coli, compound 13 thesized compounds are given in Table 1. Te molecular −3 (MICpa = 2.57 × 10 µM) against P. aeruginosa, com- structures of the synthesized compounds (1–26) were −3 pounds 19 and 20 (MICst 2.40 10 µM) against S. −1 1 13 = × determined by IR (ATR, cm ), H/ C-NMR (DMSO-d6, −3 typhi, compound 16 (MICkp = 1.22 × 10 µM) against 400 MHz, ppm) and mass spectral studies. K. pneumonia. Te results of antifungal activity indi- −1 Te presence of IR absorption band at 3214 cm in the −3 cated that compound 19 (MICan 2.40 10 µM) was spectral data of synthesized derivatives (26) corresponds = × most potent against A. niger and compound 1 (MICca to the group Ar–OH. Te C–Br stretching of aromatic 0.34 10−3 µM) was most efective against C. albicans. −1 = × bromo compounds shows band around 705 cm (19 and Te other derivatives showed average to poor antimicro- 20). Te presence of Ar–NO2 group in compounds (11, bial activity against all seven species. 12 and 13) was indicated by the appearance of asymmet- −1 ric Ar–NO2 stretches in the scale of 1347–1339 cm . Arylalkyl ether category (Ar-OCH3) present in the com- Anticancer activity pounds 2, 3, 4, 5 and 6 shows IR absorption stretching Human colorectal carcinoma [HCT-116 (ATCC CCL- 1 at 3053–2835 cm− . In case of halogen group Ar–Cl 247)] cancer cell line was used for evaluating the anti- 1 vibration appears at 747–740 cm− whereas existence of cancer activity of the prepared benzoxazole compounds Ar–F group in compounds 8, 17 and 18 was indicated using Sulforhodamine B (SRB) assay [22]. 5-Fluoroura- 1 by appearance of Ar–F stretches at 1383–1119 cm− . cil was used as standard drug and the results are shown 1 Te presence of IR stretching at 759–660 cm− refected in Table 2. Te results indicated that the compound 6 the presence of C–S group. Te presence of CO–NH (IC50 = 24.5 µM) exhibited the best anticancer activ- group is refected by the presence of absorption bands at ity in comparison with the standard drug (IC 29.2 1 50 = 1629–1605 cm− whereas the absorption bands at 3213– µM) whereas the compounds 4 and 26 displayed IC 1 1 1 50 2919 cm− , 1496–1452 cm− and 1688–1654 cm− cor- values closer to the reference drug (39.9 µM and 35.6 responds to the presence of C–H, C=C and C=N group µM, respectively). respectively. In case of 1H-NMR spectra the presence of multiplet signals between 6.85 and 8.83 ppm refected the Kakkar et al. Chemistry Central Journal (2018) 12:92 Page 3 of 16 Fig. 1 Marketed drugs containing benzoxazole SAR (structure activity relationship) studies Experimental part Te structure–activity relationship of the synthesized Te analytical grade chemicals procured from commer- benzoxazole derivatives with their antibacterial and cial sources were used as such without further purif- anticancer activity results is summarized in Fig.
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