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Synthesis and molecular docking of pyrimidine incorporated novel analogue of 1,5-benzodiazepine as antibacterial agent

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Abstract

A one-pot protocol involving nitrile-derived amidoxime of 1,5-benzodiazepine to synthesize its novel pyrimidine derivatives using DMAD and DABCO catalyst under microwave conditions has been described. The antibacterial activity of the synthesized compounds was examined against Gram-positive S. aureus and Gram-negative E. coli using broth micro-dilution assay. Low IC\(_{50}\) values for the synthesized compounds indicated their potential as antibacterial agents. Further, field emission scanning electron microscopic study and cell membrane leakage study ascertained that the test compounds have ability to cause cell lysis via bacterial cell membrane rupture and disintegration. In addition, molecular docking studies suggested that test compounds may act through bacterial DHFR inhibition.

Graphical Abstract

SYNOPSIS Novel pyrimidine-incorporated 1,5-benzodiazepine analogues through its nitrile-derived amidoxime using one-pot domino approach have been synthesized. Structures of all the compounds were established through IR, \(^{1}\hbox {H}\) NMR, \(^{13}\hbox {C}\) NMR and mass spectral data. Further, antibacterial activity test was performed using broth micro-dilution assay and the probable mode of action of compound (6) was examined via field emission scanning electron microscopy (FE-SEM) and molecular docking studies.

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References

  1. Tietze L F and Rackelmann N 2004 Domino reactions in the synthesis of heterocyclic natural products and analogs Pure Appl. Chem. 76 1967

    CAS  Google Scholar 

  2. (a) Kaur N and Kishore D 2014 Synthetic strategies applicable in the synthesis of privileged scaffold: 1,4-benzodiazepine Synth. Commun. 44 1375; (b) Khodairy A, El-Sayed A M, Salah H, Abdel-Ghany H 2007 Synthesis of Spiro 1,5-Benzodiazepine Attached with Different Heterocyclic Moeities Synth. Commun. 37 3245

    Article  CAS  Google Scholar 

  3. Sarro G D, Ferreri G, Gareri P, Russo E, Sarro A D, Gitto R and Chimirri A 2003 Comparative anticonvulsant activity of some 2,3-benzodiazepine derivatives in rodents Pharmacol. Biochem. Behav. 74 595

    Article  Google Scholar 

  4. Kusanur R A, Ghate M and Kulkarni M V 2004 Synthesis of spiro[indolo-1,5-benzodiazepines] from 3-acetyl coumarins for use as possible antianxiety agents J. Chem. Sci. 116 265

    Article  CAS  Google Scholar 

  5. Kumar R and Joshi Y C 2007 Synthesis, spectral studies and biological activity of 3H-1, 5-benzodiazepine derivatives Arkivoc. 13 142

    Google Scholar 

  6. Nawrocka W, Sztuba B, Opolski A, Wietrzyk J, Kowalska M W and Głowiak T 2001 Synthesis and antiproliferative activity in vitro of novel 1, 5- benzodiazepines Arch. Pharm. Med. Chem. 334 3

    Article  CAS  Google Scholar 

  7. Salve P S and Mali D S 2013 1,5-Benzodiazepine: A versatile pharmacophore Int. J. Pharm. Bio. Sci. 4 345

    CAS  Google Scholar 

  8. Braccio M D, Grossi G, Roma G, Vargiu L, Mura M and Marongiu M E 2001 1,5-Benzodiazepines. Part XII. Synthesis and biological evaluation of tricyclic and tetracyclic 1,5-benzodiazepine derivatives as nevirapine analogues Eur. J. Med. Chem. 36 935

    Article  Google Scholar 

  9. Tarnawa I, Farkas S, Berzsenyi P, Pataki A and Andrasi F 1989 Electrophysiological studies with a 2,3-benzodiazepine muscle relaxant: GYKI 52466 Eur. J. Pharmacol. 167 193

    CAS  Google Scholar 

  10. Atwal K S, Bergey J L, Hedberg A and Moreland S 1987 Synthesis and biological activity of novel calcium channel blockers: 2,5-dihydro-4-methyl-2-phenyl-1,5-benzothiazepine-3-carboxylic acid esters and 2,5-dihydro-4-methyl-2-phenyl-1,5-benzodiazepine-3-carboxylic acid esters J. Med. Chem. 30 635

    Article  CAS  Google Scholar 

  11. Bock M G, DiPardo R M, Evans B E, Rittle K E, Veber D F, Freidinger R M, Chang R S L and Lotti V J 1988 Cholecystokinin antagonists. Synthesis and biological evaluation of 4-substituted 4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepines J. Med. Chem. 31 176

    Article  CAS  Google Scholar 

  12. Aranapakam V, Albright J D, Grosu G T, Santos E G D, Chan P S, Coupet J, Ru X, Saunders T and Mazandarani H 1999 5- fluoro-2-methyl-N-[5H-pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)-yl carbonyl)-2-pyridinyl]benzamide (CL-385004) and analogs as orally active arginine vasopressin receptor antagonist Bioorg. Med. Chem. Lett. 9 1737

    Article  CAS  Google Scholar 

  13. Miyazaki Y, Matsunaga S, Tang J, Maeda Y, Nakano M, Philippe R J, Shibahara M, Liu W, Sato H, Wang L and Nolte RT 2005 Novel 4-amino-furo[2,3-d]pyrimidines as Tie-2 and VEGFR2 dual inhibitors Bioorg. Med. Chem. Lett. 15 2203

    Article  CAS  Google Scholar 

  14. Yadav S K, Patil S M M and Gupta S K 2012 Synthesis of 11-pyrimidine ring incorporated analogues of pyrrolo [2,1-C][1,4]-benzodiazepines Novel. Sci. Int. J. Pharm. Sci. 1 329

    CAS  Google Scholar 

  15. Ballell L, Robert A F, Chung G A C and Young R 2007 New thiopyrazolo[3,4-d]pyrimidine derivatives as anti-mycobacterial agents Bioorg. Med. Chem. Lett. 17 1736

    Article  CAS  Google Scholar 

  16. El-Gazzar A B A and Hafez H N 2009 Synthesis of 4-substituted pyrido[2,3-d]pyrimidin-4(1H)-one as analgesic and anti-inflammatory agents Bioorg. Med. Chem. Lett. 19 3392

    Article  CAS  Google Scholar 

  17. Sondhi S M, Singh N, Johar M and Kumar A 2005 Synthesis, anti-inflammatory and analgesic activities evaluation of some mono, bi and tricyclic pyrimidine derivatives Bioorg. Med. Chem. 13 6158

    Article  CAS  Google Scholar 

  18. Kamdar N R, Haveliwala D D, Mistry P T and Patel S K 2010 Design synthesis and in-vitro evaluation of anti tubercular and anti-microbial activity of some novel pyrano pyrimidines Eur. J. Med. Chem. 45 5056

    Article  CAS  Google Scholar 

  19. Corte B L D 2005 From 4,5,6,7–Tetrahydro-5-methylimidazo[4,5,1-jk](1,4)benzodiazepine-2(1H)-one (TIBO) to Etravirine (TMC125): Fifteen years of research on non-nucleoside inhibitors of HIV-1 reverse transcriptase J. Med. Chem. 48 1689

    Article  Google Scholar 

  20. Chatterjee T, Chatterjee B K, Majumdar D and Chakrabarti P 2015 Antibacterial effect of silver nanoparticles and the modeling of bacterial growth kinetics using a modified Gompertz model Biochim. Biophys. Acta 1850 299

    Article  CAS  Google Scholar 

  21. Abdel-Hafez N A, Ashraf, Mohamed M, Amr A E G E and Abdalla M A 2009 Antiarrhythmic activities of some newly synthesized tricyclic and tetracyclic thienopyridine derivatives Sci. Pharm. 77 539

    CAS  Google Scholar 

  22. Ivachtchenko A V, Golovina E S, Kadieva M G, Kysil V M, Mitkin O D, Tkachenko S E and Okun I M 2011 Synthesis and structure–activity relationship (SAR) of (5,7-disubstituted 3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methylamines as potent serotonin 5-HT6 receptor (5-HT6R) antagonistsJ. Med. Chem. 54 8161

    Article  CAS  Google Scholar 

  23. Sahu M and Siddiqui N 2016 A Review on biological importance of pyrimidines in the new era Int. J. Pharm. Sci. 8 8

    CAS  Google Scholar 

  24. Al-Harbi N O, Bahashwan S A, Fayed A A, Aboonq M S and Amr A E E 2013 Anti-parkinsonism, hypoglycemic and anti-microbial activities of new poly fused ring heterocyclic candidatesInt. J. Biol. Macromol. 57 165

    Article  CAS  Google Scholar 

  25. Selvam T P, James C R, Dniandev P V and Valzita S K 2012 A mini review of pyrimidine and fused pyrimidine marketed drugs Res. Pharm. 2 01

    Google Scholar 

  26. Al-Omary F A, Hassan G S, El-Messery S M, Nagi M N, Habib E S and El-Subbagh H I 2013 Non-classical antifolates. Part 2: synthesis, biological evaluation, and molecular modeling study of some new 2,6-substituted-quinazolin-4-ones Eur. J. Med. Chem. 63 33

    Article  CAS  Google Scholar 

  27. Frutos R P, Wei X, Patel N D, Tampone T G, Mulder J A, Busacca C A and Senanayake C H 2013 One-pot synthesis of 2,5-disubstituted pyrimidines from nitriles J. Org. Chem. 78 5800

    Article  CAS  Google Scholar 

  28. Abdelrazek F M and Bahbouh M S 2012 Recent advances in the chemistry of nitriles and enaminonitriles JJEES 4 47

    Google Scholar 

  29. Ghosh S, Indukuri K, Bondalapati S, Saikia A K and Rangan L 2013 Unveiling the mode of action of antibacterial labdane diterpenes from Alpinia nigra (Gaertn.) B. L. Burtt seeds Eur. J. Med. Chem. 66 101

    Article  CAS  Google Scholar 

  30. Punia K, Punia A, Chatterjee K, Mukherjee S, Fata J, Banerjee P, Raja K and Yang N L 2017 Rapid bactericidal activity of an amphiphilic polyacrylate terpolymer system comprised of same-centered comonomers with 2-carbon and 6-carbon spacer arms and an uncharged repeat unit RSC Adv. 7 10192

    Article  CAS  Google Scholar 

  31. Zhou X, Lin K, Ma X, Chui W K and Zhou W 2017 Design, synthesis, docking studies and biological evaluation of novel dihydro-1,3,5-triazines as human DHFR inhibitors Eur. J. Med. Chem. 125 1279

    Article  CAS  Google Scholar 

  32. Shanab F A A, Mousa S A S, Eshak E A, Sayed A Z and Harrasi A A 2011 Dimethylformamide dimethyl acetal (DMFDMA) in heterocyclic synthesis: Synthesis of polysubstituted pyridines, pyrimidines, pyridazine and their fused derivatives Int. J. Org. Chem. 1 207

    Google Scholar 

  33. Pareek A, Rani P, Agarwal A, Shekhawat S and Kishore D 2013 Synthesis of benzoazepino incorporated analogues of 1, 5-benzodiazepine of medicinal interest Int. J. Chem. Pharm. Sci. 4 44

    CAS  Google Scholar 

  34. Humphrey G R, Pye P J, Zhong Y L, Angelaud R, Askin D, Belyk K M, Maligres P E, Mancheno D E, Miller R A, Reamer R A and Weissman S A 2011 Development of a second generation, highly efficient manufacturing route for the HIV integrase inhibitor raltegravir potassium Org. Process. Res. Dev. 15 73

    Article  CAS  Google Scholar 

  35. Ngwerume S and Camp J E 2010 Synthesis of highly substituted pyrroles via nucleophilic catalysts J. Org. Chem. 75 6271

    Article  CAS  Google Scholar 

  36. Koyama S, Yamaguchi Y, Tanaka S and Motoyoshiya J 1997 A new substance (Yoshixol) with an interesting antibiotic mechanism from wood oil of Japanese traditional tree (Kiso-Hinoki), Chamaecyparis Obtusa Gen. Pharmacol. 28 797

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are deeply grateful for the financial support provided by Department of Science and Technology (DST), New Delhi under the CURIE (Consolidation of University Research for Innovation and Excellence in Women Universities) Scheme and MHRD, New Delhi, Under Training and Research in Frontier Areas of Science and Technology (FAST) Scheme. Authors are also thankful to Dr. Saral Kumar Gupta, Head, Department of Physics, Banasthali Vidyapith, Banasthali, Rajasthan, India for extending FE-SEM facility.

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Authors and Affiliations

  1. Department of Chemistry, Banasthali Vidyapith, Banasthali, Rajasthan, 304 022, India

    Apoorva Misra, Dharma Kishore & Jaya Dwivedi

  2. Department of Pharmacy, Banasthali Vidyapith, Banasthali, Rajasthan, 304 022, India

    Swapnil Sharma, Divya Sharma & Achal Mishra

  3. Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani, Rajasthan, 333 031, India

    Sunil Dubey

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  1. Apoorva Misra
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Misra, A., Sharma, S., Sharma, D. et al. Synthesis and molecular docking of pyrimidine incorporated novel analogue of 1,5-benzodiazepine as antibacterial agent. J Chem Sci 130, 31 (2018). https://doi.org/10.1007/s12039-018-1430-7

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