Synthesis and In Silico Molecular Docking Studies on Substituted Piperic Acid Derivatives as Inhibitors of Bacterial DNA Gyrase

Author(s): Bhawna Chopra*, Ashwani K. Dhingra, Deo N. Prasad, Sakshi Bhardwaj, Sonal Dubey

Journal Name: Current Computer-Aided Drug Design

Volume 16 , Issue 3 , 2020

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Graphical Abstract:


Background: Piperine or piperic acid was isolated from fruits of Piper nigrum and had been reported as pharmacological valuable bioactive constituents. Keeping in view, a series of piperic acid-based N heterocyclic’s derivatives were synthesized and evaluated for antibacterial activity. All these prepared ligands were docked to study the molecular interactions and binding affinities against the protein PDB ID: 5 CDP.

Objective: To meet the real need of newer antibacterials, we designed and synthesized scaffolds with good antibacterial activity. The obtained antibacterials have been validated in terms of ligand-protein interaction and thus prove to build up as good drug candidates.

Methods: Antibacterial activity of the compounds were carried out against bacterial strains; three Grampositive and three Gram-negative bacterial strains using agar well diffusion method. In silico molecular docking studies were carried out using Glide (grid-based ligand docking) program incorporated in the Schrödinger molecular modeling package by Maestro 11.0.

Results: Compounds BC 28, BC 32, and BC 33 exhibits antibacterial activity along with Glide docking score of -8.580, -9.753 kcal/mol, and -8.813 kcal/mol, respectively. Docking studies explained hydrogen bonding, pi-pi, and hydrophobic interactions with amino acid residues which explain the binding affinity of the most docked ligand with protein.

Conclusion: In the present study, substituted piperic acid was synthesized and evaluated as antibacterial compared with standard drug ciprofloxacin and results interpret that having nitrogen as heteroatom in the heterocyclic nucleus found to be more potent than the standard drug ciprofloxacin. On comparing, substitution with electron-donating groups generates excellent antibacterial potential against the bacterial strains. It was also proved that having substitution with electron-donating groups on meta and para position with triazoline ring system exhibits greater potential while compounds which have a meta- electron-donating substituent showed lesser activity with thiazole nucleus. In addition, structure-based activities of the prepared analogs were discussed under Structure-Activity Relationship (SAR) section.

Keywords: Piperine, piperic acid, antibacterial, triazolines, analogues, docking, 5- CDP.

Singh, Y.N. Kava: an overview. J. Ethnopharmacol., 1992, 37(1), 13-45.
[] [PMID: 1453702]
Chopra, B.; Dhingra, A.K.; Kapoor, R.P.; Prasad, D.N. Piperine and Its Various Physicochemical and Biological Aspects: A Review. Open Chem. J., 2016. 3
Litzinger, D.C. Limitations of cationic liposomes for antisense oligonucleotide delivery in vivo. J. Liposome Res., 1997, 7, 51-61.
Atal, C.K.; Zutshi, U.; Rao, P.G. Scientific evidence on the role of Ayurvedic herbals on bioavailability of drugs. J. Ethnopharmacol., 1981, 4(2), 229-232.
[] [PMID: 7311598]
Balkrishna, A. Ayurved Jadi Buti Rahasya, 5th ed; Divya Prakashan Patanjali Yogpeeth, Maharishi Dayanand Gram: Haridwar, India, 2008, pp. 362-400.
Wealth of India; Publication and Information Directorate. CSIR: New Delhi, 1969, VII, 96.
Piyachaturawat, P.; Glinsukon, T.; Peugvicha, P. Postcoital antifertility effect of piperine. Contraception, 1982, 26(6), 625-633.
[] [PMID: 7168956]
Lee, E.B.; Shin, K.H.; Woo, S. Pharmacological study on piperine. Arch. Pharm. Res., 1984, 7, 127.
Mujumdar, A.M.; Dhuley, J.N.; Deshmukh, V.K.; Raman, P.H.; Naik, S.R. Anti-inflammatory activity of piperine. Jpn. J. Med. Sci. Biol., 1990, 43(3), 95-100.
[] [PMID: 2283727]
Dhuley, J.N.; Raman, P.H.; Mujumdar, A.M.; Naik, S.R. Inhibition of lipid peroxidation by piperine during experimental inflammation in rats. Indian J. Exp. Biol., 1993, 31(5), 443-445.
[PMID: 8359852]
Atal, C.K.; Dubey, R.K.; Singh, J. Biochemical basis of enhanced drug bioavailability by piperine: evidence that piperine is a potent inhibitor of drug metabolism. J. Pharmacol. Exp. Ther., 1985, 232(1), 258-262.
[PMID: 3917507]
Pathak, N.; Khandlewal, S. Cytoprotective and immunomodulating properties of Piperine on murine splinocytes: an in vitro study. Eur. J. Pharmacol., 2006, 160, 576-582.
Sunila, E.S.; Kuttan, G. Immunomodulatory and antitumor activity of Piper longum Linn. and piperine. J. Ethnopharmacol., 2004, 90(2-3), 339-346.
[] [PMID: 15013199]
Meghwal, M.; Goswami, T.K. Piper nigrum and piperine: an update. Phytother. Res., 2013, 27(8), 1121-1130.
[] [PMID: 23625885]
Panda, S.; Kar, A. Piperine lowers the serum concentrations of thyroid hormones, glucose and hepatic 5'D activity in adult male mice. Horm. Metab. Res., 2003, 35(9), 523-526.
[] [PMID: 14517767]
Li, S.; Wang, C.; Li, W.; Koike, K.; Nikaido, T.; Wang, M.W. Antidepressant-like effects of piperine and its derivative, antiepilepsirine. J. Asian Nat. Prod. Res., 2007, 9(3-5), 421-430.
[] [PMID: 17701559]
Shoba, G.; Joy, D.; Joseph, T.; Majeed, M.; Rajendran, R.; Srinivas, P.S. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med., 1998, 64(4), 353-356.
[] [PMID: 9619120]
Mujumdar, A.M.; Dhuley, J.N.; Deshmukh, V.K.; Raman, P.H.; Thorat, S.L.; Naik, S.R. Effect of piperine on pentobarbitone induced hypnosis in rats. Indian J. Exp. Biol., 1990, 28(5), 486-487.
[PMID: 2401524]
Majumdar, A.M.; Dhuley, J.N.; Deshmukh, V.K.; Raman, P.H.; Naik, S.R. Effect of piperine on bioactivity of oxyphenylbutazone in rats. Indian Drug, 1999, 36, 123.
Jerry, R.; Douglas, C.M.; Neckers, D. Laboratory Experiments in Organic Chemistry, 3rd ed; Van Nostrand Company: New York, 1979.
Ikan, R.; Natural Products–A Laboratory Guide; Academic 1991.
Rukayadi, Y.; Lau, K.Y.; Zainin, N.S.; Zakaria, M.; Abas, F. Screening antimicrobial activity of tropical edible medicinal plant extracts against five standard microorganisms for natural food preservative. Int. Food Res. J., 2013, 20(5), 2905-2910.
Zarai, Z.; Boujelbene, E.; Salem, N.B.; Gargouri, Y.; Sayari, A. Antioxidant and antimicrobial activities of various solvent extracts, piperine and piperic acid from Piper nigrum. LWT - Food. Sci. Tech. (Paris), 2013, 50(2), 634-641.
Rani, S.K.S.; Saxena, N. Udaysree, Antimicrobial Activity of Black Pepper (Piper nigrum L.). Glob. J. Pharmacol., 2013, 7(1), 87-90.
Banu, K.M.; Dinakar, A. Ananthanarayanan, Synthesis, characterization, antimicrobial screening and pharmacological screening of some substituted 1,2,3-triazoles. Indian J. Pharm. Sci., 1999, 4, 202.
Haider, S.; Alam, M.S.; Hamid, H.; Shafi, S.; Nargotra, A.; Mahajan, P.; Nazreen, S.; Kalle, A.M.; Kharbanda, C.; Ali, Y.; Alam, A.; Panda, A.K. Synthesis of novel 1,2,3-triazole based benzoxazolinones: their TNF-α based molecular docking with in-vivo anti-inflammatory, antinociceptive activities and ulcerogenic risk evaluation. Eur. J. Med. Chem., 2013, 70, 579-588.
[] [PMID: 24211633]
Chen, M.D.; Lu, S.J.; Yuag, G.P.; Yang, S.Y.; Du, X.L. Synthesis and antibacterial activity of some heterocyclic beta-enamino ester derivatives with 1,2,3-triazole. Heterocycl. Commun., 2000, 6, 421-427.
Sherement, E.A.; Tomanov, R.I.; Trukhin, R.I.; Berestovitskaya, V.M. Russ. Synthesis of 4-Aryl-5-nitro-1,2,3-triazoles. J. Org. Chem., 2004, 40, 594.
Reddy, B.J.; Reddy, V.P.; Goud, G.L.; Rao, Y.J.; Kumar, P.; Supriya, K. Synthesis of novel 1-benzyl/aryl-4-[(1-aryl-1H-1,2,3-triazol-4-yl)methoxy]methyl-1H-1,2,3-triazole derivatives and evaluation of their antimicrobial activity. Russ. J. Gen. Chem., 2016, 86, 1424-1429.
Subudhi, B.B.; Panda, P.K.; Tosh, B.K.; Sahu, S.; Majhi, P. Synthesis and Biogical Activity evaluation of some Azetidinone and Thiazolidinone derivatives of Coumarins. J. Pharm. Sci., 2005, 4(2), 87-92.
Sema, T.; Guner, V.A.; Ergene, A. Antimicrobial activity of 4-substituted- styryl-2- azetidinones. Turkish. J. Pharm. Sci., 2005, (1), 11-15.
Kumar, A.; Rajput, C.S.; Bhati, S.K. Synthesis of 3-[4′-(p-chlorophenyl)-thiazol-2′-yl]-2-[(substituted azetidinone/thiazolidinone)-aminomethyl]-6-bromoquinazolin-4-ones as anti-inflammatory agent. Bioorg. Med. Chem., 2007, 15(8), 3089-3096.
[] [PMID: 17317192]
Halve, A.K.; Bhadauria, D.; Dubey, R. N/C-4 substituted azetidin-2-ones: synthesis and preliminary evaluation as new class of antimicrobial agents. Bioorg. Med. Chem. Lett., 2007, 17(2), 341-345.
[] [PMID: 17098426]
Singh, G.S.; Elbert, M.; Phekoet, T. Synthesis and antimicrobial activity of new 2-azetidinones from N-(salicylidene)amines and 2-diazo-1,2-diarylethanones. ARKIVOC, 2007, ix, 80-90.
Meshram, J.S.; Chopde, H.N.; Pagadala, R.; Jetti, V. An efficient synthesis of novel bioactive azetidinones and thiazolidinones of 1, 5-dimethyl-2-phenyl-1h-pyrazol-3(2h)-one. Int. J. Pharma Bio Sci., 2011, 2, 667-676.
Bagherwal, A.; Baldi, A.; Nagar, R.K.; Patidar, D.K. Synthesis and antimicrobial studies of azetidinone derivatives from naphthyl amine moiety. Int. J. Chemtech Res., 2011, 3, 274-279.
James, J.P.; Bhat, I.K.; Mishra, S.K.; Shastry, C.S. Antimicrobial studies of synthesized azetidinone derivatives from sulfamethoxazole moiety. J. Chem. Pharm. Res., 2011, 3, 114-118.
Barros, C.D.; Amato, A.A.; de Oliveira, T.B.; Iannini, K.B.R.; Silva, A.L.; Silva, T.G.; Leite, E.S.; Hernandes, M.Z. Alves de Lima, Mdo.C.; Galdino, S.L.; Neves, Fde.A.; Pitta, Ida.R. Synthesis and anti-inflammatory activity of new arylidene-thiazolidine-2,4-diones as PPARgamma ligands. Bioorg. Med. Chem., 2010, 18(11), 3805-3811.
[] [PMID: 20471839]
Bozdağ-Dündar, O.; Ozgen, O.; Menteşe, A.; Altanlar, N.; Atli, O.; Kendi, E.; Ertan, R. Synthesis and antimicrobial activity of some new thiazolyl thiazolidine-2,4-dione derivatives. Bioorg. Med. Chem., 2007, 15(18), 6012-6017.
[] [PMID: 17618124]
Shankar, G.A.; Kallanagouda, R.A. New thiazolidinedione-5-acetic acid amide derivatives: synthesis, characterization and investigation of antimicrobial and cytotoxic properties. Med. Chem. Res., 2012, 21, 816-824.
Sachin, M.; Prabhat, K.; Sandeep, M. Thiazolidinediones: A Plethro of Biological Load. Inter J Pharm. Tech. Res., 2011, 3, 62-75.
Aneja, D.K.; Lohan, P.; Arora, S.; Sharma, C.; Aneja, K.R.; Prakash, O. Synthesis of new pyrazolyl-2, 4-thiazolidinediones as antibacterial and antifungal agents. Org. Med. Chem. Lett., 2011, 1(1), 15.
[] [PMID: 22373217]
Chopra, B.; Dhingra, A.K.; Prasad, D.N. Synthesis and biological evaluation of novel piperic acid analogs as potent antibacterial agents. Asian J. Biochem. Pharmaceu Res., 2017, 2(7), 25-34.
Rahman, A.; Choudhary, M.I.; Thomsen, W.J. Bioassay Techniques for Drug Development; Harwood Academic Publishers: The Netherlands, 2001, p. 16.
Glide, version 6.7; Schrödinger, LLC: New York, NY, 2015.
LigPrep, version 2.3; Schrödinger, LLC: New York, NY, 2009.
Sastry, G.M.; Adzhigirey, M.; Day, T.; Annabhimoju, R.; Sherman, W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J. Comput. Aided Mol. Des., 2013, 27(3), 221-234.
[] [PMID: 23579614]
Chan, P.F.; Srikannathasan, V.; Huang, J.; Cui, H.; Fosberry, A.P.; Gu, M.; Hann, M.M.; Hibbs, M.; Homes, P.; Ingraham, K.; Pizzollo, J.; Shen, C.; Shillings, A.J.; Spitzfaden, C.E.; Tanner, R.; Theobald, A.J.; Stavenger, R.A.; Bax, B.D.; Gwynn, M.N. Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin. Nat. Commun., 2015, 6, 10048-10048.
[] [PMID: 26640131]

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Year: 2020
Published on: 03 June, 2020
Page: [281 - 294]
Pages: 14
DOI: 10.2174/1573409915666190710092032
Price: $65

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