Synthesis and Antibacterial Evaluation of Novel 1,5-Benzodiazepine–Coumarin Hybrids
Main Article Content
Abstract
A novel series of 1,5-benzodiazepine–coumarin hybrids 3(a–d) was efficiently synthesized via a straightforward three-step pathway using molecular hybridization strategies. The reaction sequence commenced with the preparation of 3-acetylcoumarin (1), followed by enamination with N,N-dimethylformamide dimethyl acetal (DMF-DMA) in the presence of catalytic acetic acid to afford enaminone intermediate 2. Subsequent cyclocondensation of intermediate 2 with various substituted o-phenylenediamines in ethanol using triethylamine (NEt3) under reflux conditions yielded the targeted novel hybrids 3(a–d) in high yields (72%–78%). The chemical structures of all prepared compounds were unambiguously established through 1H and 13C NMR spectroscopic analyses. The in vitro antibacterial evaluation against a representative panel of Gram-positive (S. aureus, B. cereus, L. innocua) and Gram-negative (E. coli, P. aeruginosa) bacterial strains revealed variable to excellent growth-inhibitory activities. Among the tested derivatives, compound 3d (X = NO2) demonstrated exceptional broad-spectrum antibacterial potency, exhibiting the highest inhibition zones (18.49–25.41 mm) and the lowest minimum inhibitory concentration (MIC) values (12.5–25 µg. mL-1). The structure–activity relationship (SAR) analysis underscored the decisive role of electron-withdrawing groups (-NO2 > -Cl) at the aromatic ring in enhancing antimicrobial efficacy compared to electron-donating (-CH3) or unsubstituted (-H) derivatives. Overall, these findings highlight 1,5-benzodiazepine–coumarin hybrids as promising lead structures for the development of new antibacterial agents.
Article Details
Section
How to Cite
References
1- Bajpai, S.; Kamboj, S. S.; Yadav, M.; Banik, B. K. Solvent-Free Synthesis of Bioactive Heterocycles. Curr. Organocatal. 2024, 11, 301–309.
2- Li, H.; Chen, T.; Wu, B.; Jin, X.; Liu, J.; Bao, M. Recent Advances in the Synthesis of Nitrogen-Containing Heterocycles Based on Hydrazine-Directed C–H Bond Activation/Annulation Reactions. Eur. J. Org. Chem. 2025, 28, e202401233.
3- Schutz, H. Benzodiazepines; Springer-Verlag: Heidelberg, 1982.
4- Aastha, P.; Navneet, K.; Anshu, A.; Pratima, S.; Dharma, K. 1,5-Benzodiazepines: Overview of Properties and Synthetic Aspects. Res. J. Chem. Sci. 2013, 3, 90–103.
5- Randall, L. O.; Kappel, B. In Benzodiazepines; Garattini, S., Mussini, E., Randall, L. O., Eds.; Raven Press: New York, 1973; p 27.
6- Rubin, M. A.; Albach, C. A.; Berlese, D. B.; Bonacorsa, H. G.; Bittencourt, S. R. T.; Queiroz, C. M. T.; Maixner, A. E.; Mello, C. F. Anxiolytic-like Effects of 4-Phenyl-2-trichloromethyl-3H-1,5-benzodiazepine Hydrogen Sulfate in Mice. Braz. J. Med. Biol. Res. 2000, 33, 1069–1073.
7- Aastha, P.; Navneet, K.; Anshu, A.; Pratima, S.; Dharma, K. Solvent-Free Oxalic Acid-Catalyzed Synthesis of 1,5-Benzodiazepines. J. Chil. Chem. Soc. 2013, 58, 2200–2203.
8- Hussenether, T.; Hübner, H.; Gmeiner, P.; Troschütz, R. Clozapine Derived 2,3-Dihydro-1H-1,4- and 1,5-Benzodiazepines with D4 Receptor Selectivity: Synthesis and Biological Testing. Bioorg. Med. Chem. 2004, 12, 2625–2637.
9- De Baun, J. R.; Pallos, F. M.; Baker, D. R. Substituted Benzodiazepines and Their Use as Anti-Inflammatory Agents. U.S. Patent 3,978,227, 1976.
10- Nawrocka, W.; Sztuba, B.; Opolski, A.; Wietrzyk, J.; Kowalska, M. W.; Glowiak, T. Synthesis and Antiproliferative Activity in vitro of Novel 1,5-Benzodiazepines. Part II. Arch. Pharm. (Weinheim) 2001, 334, 3–10.
11- Heinisch, G.; Huber, E.; Matuszczak, B.; Maurer, A.; Prillinger, U. Pyridazino[3,4-b][1,5]benzodiazepin-5-ones and Their Biological Evaluation as Non-Nucleoside HIV Reverse Transcriptase Inhibitors. Arch. Pharm. (Weinheim) 1997, 330, 29–34.
12- Roberge, C.; Beaudet, M. J.; Anderson, A. GABA(A)/Central Benzodiazepine Receptor and Peripheral Benzodiazepine Receptor Ligands as Inducers of Phenobarbital-Inducible CYP2B and CYP3A. Biochem. Pharmacol. 2004, 68, 1383–1389.
13- Lauffer, D. J.; Mullican, M. D. A Practical Synthesis of (S)-3-tert-Butoxycarbonylamino-2-oxo-2,3,4,5-tetrahydro-1,5-benzodiazepine-1-acetic Acid Methyl Ester as a Conformationally Restricted Dipeptidomimetic for Caspase-1 (ICE) Inhibitors. Bioorg. Med. Chem. Lett. 2002, 12, 1225–1227.
14- Agarwal, V. K.; Sharma, R.; Khadikar, P. V. Quantitative Structure-Activity Relationship Studies on 5-Phenyl-3-ureido-1,5-benzodiazepine as Cholecystokinin-A Receptor Antagonists. Bioorg. Med. Chem. 2002, 10, 3571–3581.
15- Harris, R. C.; Straley, J. M. Benzodiazepine Dyes for Acrylic Fibers. U.S. Patent 1,537,757, 1968.
16- Gawandi, S. J.; Desai, V. G.; Joshi, S.; Shingade, S.; Pissurlenkar, R. R. Assessment of Elementary Derivatives of 1,5-Benzodiazepine as Anticancer Agents with Synergy Potential. Bioorg. Chem. 2021, 117, 105331.
17- Jagtap, S. B.; Raut, H. V. Review on Preparation Methods and Different Biological Activity of 1,5-Benzodiazepines. Int. J. Pharm. Res. Appl. 2022, 7, 1067–1088.
18- Rishipathak, D.; Patil, D.; Chikhale, H. U. Synthesis and Biological Evaluation of Some Newer 1H-Benzo[b][1,5]diazepin-2(3H)-one Derivatives as Potential Anticonvulsant Agents. Pharm. Sci. 2022, 28, 630–637.
19- Chimirri, A.; Gitto, R.; Grasso, S.; Monforte, A. M.; Zappalà, M. Annelated 1,5-Benzodiazepines. Part 1. Three, Four, and Five Membered Rings. Heterocycles 1993, 36, 601–637.
20- Essaber, M.; Baouid, A.; Hasnaoui, A.; Benharref, A.; Lavergne, J. P. Synthesis of New Fused Heterocycles: Triazolo- and Oxadiazolobenzodiazepines. Synth. Commun. 1998, 28, 4097–4105.
21- El-Sayed, A. M.; Abdel-Ghany, H.; El-Saghier, A. M. M. Synthesis of Some New Fused 1,5-Benzodiazepine Derivatives. Synth. Commun. 1999, 29, 3561–3568.
22- Stahlhofen, P.; Ried, W. Über Heterocyclen, VI. Reactions of o-Phenylenediamine with Unsaturated Ketones. Chem. Ber. 1957, 90, 815–821.
23- Ried, W.; Torinus, E. Über Heterocyclen, XI. Condensation of o-Phenylenediamine with Ketones. Chem. Ber. 1959, 92, 2902–2907.
24- Missaoui, B. E.; Ouahrani, M. R.; Kouadri, Y.; Chebrouk, F.; Gherraf, N. Synthesis of Novel Heterocyclic Compounds Containing 1,5-Benzodiazepine. Asian J. Chem. 2015, 27, 2175–2177.
25- Roman, G.; Comaniță, E.; Comaniță, B. Synthesis and Reactivity of Mannich Bases. XIV. Base-Catalyzed Cyclocondensation of β-Aminoketones to 1,5-Benzodiazepines. Acta Chim. Slov. 2002, 49, 575–585.
26- Balakrishna, M. S.; Kaboudin, B. A Simple and Efficient One-Pot Synthesis of 1,5-Benzodiazepines on Solid Surface. Tetrahedron Lett. 2001, 42, 1127–1129.
27- Sabitha, G.; Reddy, G. S. K.; Reddy, K. B.; Yadav, J. S. Ytterbium(III) Triflate-Catalyzed One-Pot Synthesis of 1,5-Benzodiazepines. Adv. Synth. Catal. 2004, 346, 921–923.
28- Yadav, J. S.; Reddy, B. V. S.; Praveenkumar, S.; Nagaiah, K. Ceric Ammonium Nitrate (CAN) Catalyzed Synthesis of 1,5-Benzodiazepines. Synthesis 2005, 2005, 480–484.
29- Kumar, R.; Chaudhary, P.; Nimesh, S.; Verma, A. K.; Chandra, R. Green Approach for the Synthesis of 1,5-Benzodiazepines Catalyzed by AgNO3. Green Chem. 2006, 8, 519–521.
30- CLSI, 2012. Performance standards for antimicrobial disk susceptibility tests, approved standard, 7th ed., CLSI document M02-A11. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.
31- CLSI, 2012. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, Approved Standard, 9th ed., CLSI document M07-A9. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.