Synthesis of novel fluorinated 1,5-benzothiazepine derivatives and their biological evaluation as anticancer and antibacterial agents J. Serb. Chem. Soc. 87 (10) 1109–1116 (2022) Original scientific paper JSCS–5581 Published 1 August 2022 1109 Synthesis of novel fluorinated 1,5-benzothiazepine derivatives and their biological evaluation as anticancer and antibacterial agents SONAL R. BHABAL, SARFARAZ F. SHAIKH, ISHITA P. YELLAPURKAR, GANESH S. PAVALE and MUCHELI M. V. RAMANA* Department of Chemistry, University of Mumbai, Santacruz (E), Mumbai 400 098, India (Received 28 April 2021, revised 28 April, accepted 10 May 2022) Abstract: A series of novel fluorinated 1,5-benzothiazepine derivatives were synthesized, characterized and evaluated for in vitro anticancer and antibac- terial activity. The in vitro anticancer activity of the synthesized compounds 4a–h was evaluated against four human cancer cell lines namely lung (A549), breast (MCF-7), liver (HEPG2) and prostate (PC-3). Compounds 4c, 4d, 4g and 4h exhibited good activity with GI50 <10 µg ml-1 against all four human cancer cell lines which was comparable to standard drug adriamycin. Addition- ally, antibacterial activity of synthesized compounds was estimated using Res- azurin Microtiter Assay (REMA) and compared with standard drug ampicillin. Among the synthesized compounds, 4c, 4d, 4g and 4h showed good antibac- terial activity and all the synthesized compounds were found to be more active towards gram negative than gram positive bacteria. These promising results obtained from in vitro anticancer and antibacterial activity, inferred that the synthesized compounds are capable of being anticancer as well as antibacterial agents. Keywords: in vitro; lung cancer cell line; breast cancer cell line; liver cancer cell line; prostate cancer cell line. INTRODUCTION One of the major world problems is cancer; due to the increased cancer cases and deaths. In the year 2020, it was anticipated that there will be 19.3 million new cancer cases and 10.0 million deaths worldwide.1 Despite the fact that chemotherapy is most commonly used to treat cancer, the failure of existing chemotherapeutics to treat cancer highlights the need for new chemical entities to be developed.2 Additionally, chemotherapy in cancer treatment is usually asso- ciated with various side effects and appearance of resistance.3 Moreover, despite * Corresponding author. E-mail: mmvramana@yahoo.co.in https://doi.org/10.2298/JSC210428041B ________________________________________________________________________________________________________________________ (CC) 2022 SCS. Available on line at www.shd.org.rs/JSCS/ 1110 BHABAL et al. of progressive development in cancer chemotherapy, there are still insufficient cytotoxic agents that act selectively to cancer cells. Infections are one of the reasons for compromised immunity among cancer patients. They make patient vulnerable which leads to disturbance in treatment.4 Infectious diseases put public life in jeopardy and are responsible for a large number of deaths globally. The major issue is the resistance of pathogenic micro- organisms to the available antimicrobial agents, which makes it difficult to treat with conventional antibiotics and force clinicians to rely on restricted options.5 Therefore, the development of both new anticancer and antimicrobial entities is a necessity. In the last decades, owing to their structural properties and wide range of biological activities, benzothiazepines have piqued the interest of researchers.6,7 1,5-Benzothiazepine scaffold has been used as anticancer,8–11 antimicrobial,11–14 anti-inflammatory,14 anticonvulsant15 and anti-HIV16,17agent. Also, 1,5-benzo- thiazepine scaffold is reported as acetylcholinesterase inhibitor,18 butyrylcholin- esterase inhibitor,19 VRV-PL-8a and H+/K+ ATPase inhibitor.20 Clentiazem, diltiazem, thiazesim and quetiapine are among the commercially available drugs which contain the 1,5-benzothiazepine skeleton. Heterocycles containing fluorine atoms have a wide range of applications in pharmaceutical industry.21 The presence of a fluorine atom alters certain physi- cochemical properties such as basicity, lipophilicity, bioavailability as well as binding affinity of a drug molecule to the target protein.22 Ciprofloxacin (anti- biotic), fluconazole (antifungal), 5-fluorouracil (anticancer), paroxetine (antidep- ressant), linezolid (antibacterial), favipiravir (antiviral) and midazolam (sedative) are some of the marketed drugs that contain fluorine atom. Prasada Rao et al. reported compounds with fluorinated 1,5 Benzothiazepine skeleton as anti-cancer agents.23 Similarly, Upreti et al. reported 8-fluoro-1,5-benzothiazepine as pro- mising anti-AIDS agent.24 A series of 1,5-benzothiazepines with fluorine and 4- fluorophenyl groups have also been reported for the treatment of cancer metasta- sis.25 Based on the wide spectrum of biological activities, 1,5-benzothiazepines are good candidate and could be taken in consideration as promising anticancer and antimicrobial agents. Herein we report the synthesis, anticancer and antibacterial activity of fluorinated 1,5-benzothiazepines. Anticancer activity was evaluated in vitro using four different cell lines namely human lung cancer cell line (A549), human breast cancer cell line (MCF-7), human liver cancer cell line (HEPG2) and human prostate cancer cell line (PC-3). Similarly, antibacterial activity was performed using two Gram-positive strains and two Gram-negative strains. ________________________________________________________________________________________________________________________ (CC) 2022 SCS. Available on line at www.shd.org.rs/JSCS/ BIOLOGICAL ACTIVITY OF FLUORINATED 1,5-BENZOTHIAZEPINE 1111 EXPERIMENTAL Materials and method All reagents and chemicals were of analytical grade, procured from Sigma Aldrich (India), and used without further purification. Melting points are uncorrected and were rec- orded on Centrofix Syndicate MP apparatus. Merck silica gel 60 F254 TLC plates were used to monitor the reaction. FTIR spectra were recorded on Perkin Elmer, Frontier equipment with ATR. 1H- (300 MHz) and 13C-NMR (75 MHz) were recorded on Bruker Avance II using TMS as the internal standard in CDCl3 and DMSO-d6. ESI mass spectra were recorded on AB SCIEX 3200 QTRAP mass spectrometer. Elemental analysis (CHNS) was carried out on model EA300, Euro Vector, Italy. Staphylococcus aureus (ATCC 25923), Bacillus subtilis (ATCC 6633), Salmonella typhi (ATCC 23564) and Escherichia coli (ATCC 25922) cultures were procured from National Chemical Technology, Pune, Maharashtra and were used for antibacterial assay. Analytical and spectral data are given in the Supplementary material to this paper. Chemistry Synthesis of α,β-unsaturated ketone derivatives (3a–h).26 A mixture of 3,4-difluorobenz- aldehyde derivative (5 mmol) and acetophenone derivative (6 mmol) were dissolved in 15 ml ethanol, then NaOH 40 % solution (5 ml) was added dropwise. The temperature of reaction was maintained below 10 °C and the reaction mixture was stirred until precipitation of solid. The precipitate was then filtered, washed several times with cold water and recrystallized from aqueous ethanol. Synthesis of 1,5-benzothiazepine derivatives (4a–h), Scheme 1. A mixture of α,β-unsatur- ated ketone (5 mmol) and 2-aminothiophenol (5 mmol) were taken in methanol (10 ml) con- taining catalytic amount of glacial acetic acid. The reaction mixture was allowed to reflux until completion as indicated by TLC. After completion, the reaction was allowed to cool to room temperature and the solid obtained was filtered, washed several times with methanol and recrystallized using ethanol to afford yellow solid. Scheme 1. Synthetic pathway of fluorinated 1,5-benzothiazepine derivatives. ________________________________________________________________________________________________________________________ (CC) 2022 SCS. Available on line at www.shd.org.rs/JSCS/ 1112 BHABAL et al. Biology In vitro anticancer activity. The sulforhodamine B (SRB) assay was used to test the anti- cancer activity of the synthesized derivatives against four human cancer cell lines namely lung (A549), breast (MCF-7), liver (HEPG2) and prostate (PC-3) cancer.27 The cell lines were grown in RPMI 1640 medium for 24 h before being inoculated into 96-well plates and incub- ated at 37 °C. After that, the cells were fixed with 10 % trichloroacetic acid (TCA) and tested with drugs at four dose levels (10, 20, 40, and 80 µg ml-1) with doxorubicin serving as a con- trol. After adding the compounds, the plates were incubated for 48 h until the assay was ter- minated with the addition of cold TCA. TCA (30 %) was used to fix the cells, which were then incubated at 4 °C for 1 h before being stained with SRB solution for 20 min. Further, the excess dye was discarded by washing with 1 % acetic acid and air dried. The protein-bound dye was then eluted with a 10mM Tris base, and the absorbance was measured at 540 nm using a plate reader. Growth was calculated and expressed as the ratio of average absorbance of the test well (Ti) to the average absorbance of the control wells (C): Growth inhibition = 100(Ti/C) (1) where C = control growth and Ti = test growth in the presence of drug at the four concen- tration levels. The experiment was done in triplicate and the average values were plotted as control growth versus drug concentrations. Antibacterial assay The antimicrobial activity of synthesized compounds was investigated using the resa- zurin microtiter assay (REMA) in aseptic conditions using a 96 well microtitre plate as des- cribed previously.28 50 μl solution of test material dissolved in 2 % DMSO was added after filling all the wells of the microtiter plate with 50 μl of nutrient broth. Two-fold serial dilution was achieved by transferring 50 μl test material from the top well of the first row to the fol- lowing wells in the next row of the same column and resulted in a graded sequence of concen- trations (500, 250, 125, 62.5, 31.25, 15.63, 7.81 and 3.90 μg ml-1). After that, 50 μl of bac- terial suspension were added to each well, resulting in a final concentration of 0.5 Mcfarland standard cfu ml-1. Later, all plates containing test materials were incubated for 24 h at 37 °C. After 24 h, each well was given 0.2 % resazurin, and a visual change in colour was observed in the wells. The transition from purple to pink/colorless was taken as a positive. The MIC value for that particular sample was recorded, as the lowest concentration in the column containing the sample at which no color shift occurred, and compared to the standard drug ampicillin. RESULTS AND DISCUSSION Chemistry Synthesis of fluorinated 1,5-benzothiazepines 4a–h followed the path shown in Scheme 1. The compounds were synthesized by reaction of α,β-unsaturated ketone with 2-aminothiophenol in presence of catalytic amount of glacial acetic acid. The synthesized novel compounds 4a–h were verified by various tech- niques like IR, NMR (1H and 13C), MS and elemental analyses (CHN). FTIR spectra of the synthesized compounds 4a–h showed appearance of C–H in the range of 2844–3105 cm–1, a characteristic band in the range of 1595– –1608 cm–1 confirms presence of C=N bond in the synthesized compound, also presence of band in range of 1311–1322 cm–1 indicates presence of C–N. ________________________________________________________________________________________________________________________ (CC) 2022 SCS. Available on line at www.shd.org.rs/JSCS/ BIOLOGICAL ACTIVITY OF FLUORINATED 1,5-BENZOTHIAZEPINE 1113 Presence of band in the range of 681–688 cm–1 indicates formation of C–S–C bond. 1H-NMR spectra of synthesized compounds shows presence of three char- acteristics peaks apart from aromatic protons (δ 8.12–6.50 ppm). The three peaks in the aliphatic region are due to CH2 and CH. Two protons of CH2 are diaste- reotopic in nature (Ha and Hb), Ha shows triplet at δ 2.88–2.99 ppm with Jab value 12.4–12.7 Hz and the other Hb along with CH (Hx) shows doublet of doublet at δ 3.19–3.28 ppm with Jbx in range12.9–13.0 Hz; Jab in range 4.8–5.1 Hz and δ 4.88–4.99 ppm with Jax in range 11.8–12.5 Hz; Jab in range 4.6–5.1 Hz, respectively, due to abx system. The 13C-NMR showed characteristics peak at δ 37–38 ppm denoting CH and at δ = 59 ppm confirming presence of CH2. Hence, the interpreted data obtained from the spectra corroborated with the structure of synthesized compound. For further verification, ESI-MS was performed, m/z values obtained were in good agreement with measured mass. Further elemental analysis confirmed the purity of the synthesized compounds as the experimental composition was found to be similar with the theoretical composition. Biology In vitro anticancer activity. The in vitro anticancer activity of the synthe- sized compounds 4a–h was assessed using sulforhodamine B (SRB) assay with adriamycin as standard drug. The results were described in terms of GI50 (con- centration that reduces total cell growth by 50 values) and are delineated in Table I. The results concluded that among the synthesized compounds, compound 4c, 4d, 4g and 4h exhibited good activity with GI50 < 10 µg ml–1 against all four cell lines, while rest of the compounds exhibited moderate to poor activity with GI50 > 10 µg ml–1. TABLE I. In vitro anticancer activity (GI50 / µg ml-1); GI50 = concentration of drug causing 50 % inhibition of cell grow. For pure compounds, GI50 value ≤ 10 µg ml-1 is considered to demonstrate activity Compound Cell line A549 MCF-7 HEP G2 PC-3 4a 68.2 68.6 57.6 >80 4b 27.8 48.2 32.6 28.1 4c <10 <10 <10 <10 4d <10 <10 <10 <10 4e 22.1 <10 16.9 <10 4f 32.3 35.1 33.4 11.6 4g <10 <10 <10 <10 4h <10 <10 <10 <10 Adriamycin <10 <10 <10 <10 From the structure activity relationship, the activity of heterocyclic and halo- genated compounds was outstanding when compared to other substituents. The ________________________________________________________________________________________________________________________ (CC) 2022 SCS. Available on line at www.shd.org.rs/JSCS/ 1114 BHABAL et al. compounds were found to be in the order: –F group > –Cl group > –Br group > > –OMe group > –Me group > –H denoting that the compounds having electro- negative groups showed excellent activity. Antibacterial assay. The antibacterial activity of the synthesized compounds 4a–h were evaluated against two Gram-positive (Staphylococcus aureus and Bacillus subtilis) and two Gram-negative (Escherichia coli and Salmonella typhi) bacteria using REMA. Ampicillin was taken as positive control. The antibacterial potential of the synthesized compounds were assessed by minimum inhibitory concentration (MIC) values and are displayed in Table II. Result obtained indi- cates that all the synthesized compounds are potent antibacterial agents. Among which, compound 4c, 4d, 4g and 4h exhibited excellent activity w.r.t the standard (ampicillin) against all the bacterial strains inferring that hetero and halogenated substances show excellent results. The results outlined suggested that the synthe- sized compounds are more active towards Gram-negative strain than Gram-posi- tive strain. TABLE II. In vitro bacterial activity using REMA method (MIC / µg ml-1) Compound Strain Gram-positive Gram-negative S. aureus B. subtilis E. coli S. typhi 4a 62.5 62.5 62.5 62.5 4b 62.5 125 62.5 62.5 4c 31.25 31.25 15.625 31.25 4d 15.625 15.625 15.625 15.625 4e 62.5 125 62.5 62.5 4f 62.5 125 62.5 62.5 4g 15.625 31.25 15.625 15.625 4h 15.625 15.625 31.25 15.625 Ampicillin 31.25 31.25 15.625 31.25 CONCLUSION To conclude, we synthesized series of fluorinated 1,5-benzothiazepine deri- vatives 4a–h. The synthesized compounds were evaluated for in vitro anticancer and antibacterial activity. The in vitro anticancer activity was performed using four human cancer cell lines namely A549, MCF-7, HEPG2 and PC-3. Com- pounds 4c, 4d, 4g and 4h exhibited excellent activity with GI50 <10 µg ml–1 against all four cell lines which is comparable to standard drug adriamycin. Further, the synthesized compounds were subjected to antibacterial activity using resazurin microtiter assay (REMA) with ampicillin as standard drug. The com- pounds 4c, 4d, 4g and 4h exhibited elegant antibacterial activity and the synthe- sized compounds were found to be more active towards Gram-negative than ________________________________________________________________________________________________________________________ (CC) 2022 SCS. Available on line at www.shd.org.rs/JSCS/ BIOLOGICAL ACTIVITY OF FLUORINATED 1,5-BENZOTHIAZEPINE 1115 Gram-positive bacteria. Hence, the synthesized fluorinated 1,5-benzothiazepine derivatives have potential to be an anticancer as well as antibacterial agents. SUPPLEMENTARY MATERIAL Additional data and information are available electronically at the pages of journal website: https://www.shd-pub.org.rs/index.php/JSCS/article/view/10712, or from the corres- ponding author on request. Acknowledgements. We are thankful to Microanalytical Laboratory, University of Mum- bai, for providing characterization facilities. We are also thankful to Advanced Centre for Treatment Research and Education in Cancer (ACTREC) Anti-Cancer Drug Screening Facil- ity (ACDSF), Kharghar, Navi Mumbai, for providing anticancer activity. И З В О Д СИНТЕЗА НОВИХ ФЛУОРИСАНИХ ДЕРИВАТА 1,5-БЕНЗОТИАЗЕПИНА И ЊИХОВА БИОЛОШКА ПРОЦЕНА КАО АНТИКАНЦЕРОГЕНИХ И АНТИБАКТЕРИЈСКИХ СРЕДСТАВА SONAL R. BHABAL, SARFARAZ F. SHAIKH, ISHITA P. YELLAPURKAR, GANESH S. PAVALE и MUCHELI M. V. RAMANA Department of Chemistry, University of Mumbai, Santacruz (E), Mumbai 400 098, India Синтетисана је серија флуорованих деривата 1,5-бензотиазепина, једињења су окарактерисана и испитана је њихова in vitro антиканцерска и антибактеријска актив- ност. In vitro антиканцерска активност једињења 4a–h испитана је према ћелијским ли- нијама хуманог канцера плућа (A549), груди (MCF-7), јетре (HEPG2) и простате (PC-3). Једињења 4c, 4d, 4g и 4h имају добру активност, која износи GI50 < 10 μg ml -1 према свим испитиваним ћелијским линијама, и блиска је активности стандардног лека aдриами- цина. Такође, антибактеријска активност једињења је испитана употребом ресазурин микротитар есеја (resazurin microtiter assay, REMA) и добијене вредности су упоређене са активношћу стандардног лека aмпицилина. Од синтетисаних једињења, једињења 4c, 4d, 4g и 4h показују добру антибактеријску активност и утврђено је да су сва синте- тисана једињења активнија према грам-негативним него према грам-позитивним бакте- ријама. Резултати добијени из in vitro антиканцерске и антибактеријске активности су охрабрујући и указују да би синтетисана једињења могла да буду добри антиканцерски и антибактеријски агенси. (Примљено 28. априла 2021, ревидирано 28. априла, прихваћено 10. маја 2022) REFERENCES 1. H. Sung, J. Ferlay, R. L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, F. Bray, CA. Cancer J. Clin. 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Available on line at www.shd.org.rs/JSCS/ @Article{Bhabal2022, author = {Bhabal, Sonal R. and Shaikh, Sarfaraz F. and Yellapurkar, Ishita P. and Pavale, Ganesh S. and Ramana, Mucheli V.}, journal = {Journal of the Serbian Chemical Society}, title = {{Synthesis of novel fluorinated 1,5-benzothiazepine derivatives and their biological evaluation as anticancer and antibacterial agents}}, year = {2022}, issn = {1820-7421}, month = {may}, number = {10}, pages = {1109--1116}, volume = {87}, abstract = {A series of novel fluorinated 1,5-benzothiazepine derivatives were synthesized, characterized and evaluated for in vitro anticancer and antibac­terial activity. The in vitro anticancer activity of the synthesized compounds 4a–h was evaluated against four human cancer cell lines namely lung (A549), breast (MCF-7), liver (HEPG2) and prostate (PC-3). Compounds 4c, 4d, 4g and 4h exhibited good activity with GI50 <10 µg ml-1 against all four human cancer cell lines which was comparable to standard drug adriamycin. Addition­ally, antibacterial activity of synthesized compounds was estimated using Res­azurin Microtiter Assay (REMA) and compared with standard drug ampicillin. Among the synthesized compounds, 4c, 4d, 4g and 4h showed good antibac­terial activity and all the synthesized compounds were found to be more active towards gram negative than gram positive bacteria. These promising results obtained from in vitro anticancer and antibacterial activity, inferred that the synthesized compounds are capable of being anticancer as well as antibacterial agents.}, doi = {10.2298/JSC210428041B}, file = {:D\:/OneDrive/Mendeley Desktop/Bhabal et al. - 2022 - Synthesis of novel fluorinated 1,5-benzothiazepine derivatives and their biological evaluation as anticancer and.pdf:pdf;:01_10712_5581.pdf:PDF}, keywords = {breast cancer cell line, liver cancer cell line, lung cancer cell line, prostate cancer cell line}, publisher = {Serbian Chemical Society}, url = {https://www.shd-pub.org.rs/index.php/JSCS/article/view/10712}, }