Skip to main content

Synthesis, in vitro antimicrobial, antiproliferative, and QSAR studies of N-(substituted phenyl)-2/4-(1H-indol-3-ylazo)-benzamides

Abstract

In this study, N-(substituted phenyl)-2/4-(1H-indol-3-ylazo)-benzamides (126) were synthesized and screened for their in vitro antibacterial (Gram positive; S. aureus, B. subtilis and Gram negative; E. coli) and antifungal (C. albicans and A. niger) activities. The antimicrobial activity results indicated that compound, 4-(1H-indol-3-ylazo)-N-(4-nitro-phenyl)-benzamide (12, pMICam = 1.61) was the most potent. In general, it was found that the synthesized compounds were bacteriostatic/fungistatic in action except fungicidal for A. niger. The synthesized compounds were also evaluated for their antiproliferative activity against human colon cancer (HCT116), murine leukemia (P388), and breast cancer (MCF7) cell lines. The antiproliferative study results demonstrated 4-(1H-indol-3-ylazo)-N-p-tolyl-benzamide (2, IC50 = 0.0003 μM/mL) and 4-(1H-indol-3-ylazo)-N-p-tolyl-benzamide (21, 0.0003 μM/mL) as lead compounds for the development of novel antiproliferative agents. The QSAR studies indicated the importance of topological parameters, Kier’s alpha second-order shape indice (κα2) and Wiener index (W) in describing the antimicrobial activity of the synthesized compounds.

This is a preview of subscription content, access via your institution.

Scheme 1
Fig. 1
Fig. 2

References

  • Abdel-Jalil RJ, Momani EQEl, Hamad M, Voelter W, Mubarak MS, Smith BH, Peters DG (2010) Synthesis, antitumor activity and electrochemical behavior of some piperazinyl amidrazones. Monatsh Chem 141:251–258

    Article  CAS  Google Scholar 

  • Bajaj S, Sambi SS, Madan AK (2005) Prediction of anti-inflammatory activity of N-arylanthranilic acids: computational approach using refined Zagreb Indices. Croat Chem Acta 78(2):165–174

    CAS  Google Scholar 

  • Balaban AT (1982) Highly discriminating distance based topological indices. Chem Phys Lett 89:399–404

    Article  CAS  Google Scholar 

  • Cappucino JG, Sherman N (1999) Microbiology—a laboratory manual. Addison Wesley, Davis 263

    Google Scholar 

  • Chiyanzu I, Clarkson C, Smith PJ, Lehman J, Gut J, Rosenthal PJ, Chibale K (2005) Design, synthesis and anti-plasmodial evaluation in vitro of new 4-aminoquinoline isatin derivatives. Bioorgan Med Chem 13:3249–3261

    Article  CAS  Google Scholar 

  • Cruz-Monteagudo M, Gonzalez-Diaz H, Aguero-Chapin G, Santana L, Borges F, Dominguez ER, Podda G, Uriarte E (2007) Computational chemistry development of a unified free energy Markov model for the distribution of 1300 chemicals to 38 different environmental or biological systems. J Comput Chem 28(11):1909–1923

    PubMed  Article  CAS  Google Scholar 

  • Emami S, Falahati M, Banifafemi A, Shafiee A (2004) Stereoselective synthesis and antifungal activity of (Z)-trans-3-azolyl-2-methylchromanone oxime ethers. Bioorgan Med Chem 12:5881–5889

    Article  CAS  Google Scholar 

  • Furniss BS, Hannaford AJ, Smith PWG, Tatchell AR (1998) Vogel’s text book of practical organic chemistry. Addison Wesley, Davis, pp 34–35

    Google Scholar 

  • Giaginis C, Tsantili-Kakoulidou A, Theocharis S (2009) Quantitative structure activity relationship (QSAR) methodology in forensic toxicology: modeling post mortem redistribution of structurally diverse drugs using multivariate statistics. Forensic Sci Int 190:9–15

    PubMed  Article  CAS  Google Scholar 

  • Golbraikh A, Tropsha A (2002) Beware of q2! J Mol Graph Model 20:269–276

    PubMed  Article  CAS  Google Scholar 

  • Gonzalez-Diaz H, Prado–Prado FJ (2008) Unified QSAR and network-based computational chemistry approach to antimicrobials, part 1: multispecies activity models for antifungals. J Comput Chem 29(4):656–667

    PubMed  Article  CAS  Google Scholar 

  • Gonzalez-Diaz H, Vilar S, Santana L, Uriarte E (2007) Medicinal chemistry and bioinformatics—current trends in drugs discovery with networks topological indices. Curr Top Med Chem 7(10):1015–1029

    PubMed  Article  CAS  Google Scholar 

  • Hansch C, Fujita T (1964) p–σ–π Analysis. A method for the correlation of biological activity and chemical structure. J Am Chem Soc 86:1616–1626

    Article  CAS  Google Scholar 

  • Hansch C, Leo A, Unger SH, Kim KH, Nikaitani D, Lien EJ (1973) “Aromatic” substituent constants for structure–activity correlations. J Med Chem 16(11):1207–1216

    PubMed  Article  CAS  Google Scholar 

  • Ivachtchenko AV, Frolov EB, Mitkin OD, Tkachenko SE, Okun IM, Khvat AV (2010) Synthesis and biological activity of 5-styryl and 5-phenethyl-substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles. Bioorg Med Chem Lett 20:78–82

    PubMed  Article  CAS  Google Scholar 

  • Jacquemard U, Dias N, Lansiaux A, Bailly C, Loge C, Robert JM, Lozach O, Meijer L, Meroura JY, Routiera S (2008) Synthesis of 3,5-bis(2-indolyl)pyridine and 3-[(2-indolyl)-5-phenyl]-pyridine derivatives as CDK inhibitors and cytotoxic agents. Bioorgan Med Chem 16:4932–4953

    Article  CAS  Google Scholar 

  • Judge V, Narasimhan B, Ahuja M, Sriram D, Yogeeswari P, Clercq ED, Pannecouque C, Balzarini J (2012) Synthesis, antimycobacterial, antiviral, antimicrobial activity and QSAR studies of Isonicotinic acid-1-(substituted phenyl)-ethylidene/cycloheptylidene hydrazides. Med Chem Res 21(8):1935–1952

    Article  CAS  Google Scholar 

  • Kier LB, Hall LH (1976) Molecular connectivity in chemistry and drug research. Academic Press, New York

    Google Scholar 

  • Kier LB, Hall LH (1999) The kappa indices for modeling molecular shape and flexibility. In: Devillers J, Balaban AT (eds) Topological indices and related descriptors in QSAR and QSPR. Gordon and Breach Science Publishers, Amsterdam, The Netherlands, pp 455–489

  • Kumar A, Narasimhan B, Kumar D (2007) Synthesis, antimicrobial, and QSAR studies of substituted benzamides. Bioorgan Med Chem 15:4113–4124

    Article  CAS  Google Scholar 

  • Kumar P, Narasimhan B, Sharma D, Judge V, Narang R (2009) Hansch analysis of substituted benzoic acid benzylidene/furan-2-yl-methylene hydrazides as antimicrobial agents. Eur J Med Chem 44:1853–1863

    PubMed  Article  CAS  Google Scholar 

  • Kumar D, Judge V, Narang R, Sangwan S, Clercq ED, Balzarini J, Narasimhan B (2010) Benzylidene/2-chlorobenzylidene hydrazides: synthesis, antimicrobial activity, QSAR studies and antiviral evaluation. Eur J Med Chem 45:2806–2816

    PubMed  Article  CAS  Google Scholar 

  • Lamotte Y, Martres P, Faucher N, Laroze A, Grillot D, Ancellin N, Saintillan Y, Beneton V, Gampe RT (2010) Synthesis and biological activities of novel indole derivatives as potent and selective PPARγ modulators. Bioorg Med Chem Lett 20:1399–1404

    PubMed  Article  CAS  Google Scholar 

  • Laxmi SV, Rajitha B (2012) Synthesis and antimicrobial activity of newer indole semicarbazones. Med Chem Res 21(2):85–90

    Article  Google Scholar 

  • Lee C, Yao C, Huang S, Ko S, Tan YH, Lee-Chen G, Wang Y (2008) Novel 2-step synthetic indole compound 1,1,3-tri(3-indolyl)cyclohexane inhibits cancer cell growth in lung cancer cells and xenograft models. Cancer 113:815–825

    PubMed  Article  CAS  Google Scholar 

  • Lee J, Attila C, Cirillo SLG, Cirillo JD, Wood TK (2009) Indole and 7-hydroxyindole diminish Pseudomonas aeruginosa virulence. Microb Biotechnol 2(1):75–90

    PubMed  Article  CAS  Google Scholar 

  • Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63

    PubMed  Article  CAS  Google Scholar 

  • Narang R, Narasimhan B, Sharma S, Sriram D, Yogeeswari P, Clercq ED, Pannecouque C, Balzarini J (2012) Synthesis, antimycobacterial, antiviral, antimicrobial activity and QSAR studies of nicotinic acid benzylidene hydrazide derivatives. Med Chem Res 21(8):1557–1576

    Article  CAS  Google Scholar 

  • Narasimhan B, Judge V, Narang R, Ohlan S, Ohlan R (2007) Quantitative structure–activity relationship studies for prediction of antimicrobial activity of synthesized 2,4-hexadienoic acid derivatives. Bioorg Med Chem Lett 17:5836–5845

    PubMed  Article  CAS  Google Scholar 

  • Ozkay Y, Tunali Y, Karaca H, Isikdag I (2010) Antimicrobial activity and a SAR study of some novel benzimidazole derivatives bearing hydrazones moiety. Eur J Med Chem 45:3293–3298

    PubMed  Article  Google Scholar 

  • Ozturk A, Abdullah MI (2006) Toxicological effect of indole and its azo dye derivatives on some microorganisms under aerobic conditions. Sci Total Environ 358:137–142

    PubMed  Article  Google Scholar 

  • Pharmacopoeia of India (2007) Controller of publications, Ministry of Health Department, Govt. of India, New Delhi, vol. I, p 37

  • Prado-Prado FJ, Gonzalez-Diaz H, Vega OMDL, Ubeira FM, Chou KC (2008) Unified QSAR approach to antimicrobials. Part 3: first multi-tasking QSAR model for Input-Coded prediction, structural back-projection, and complex networks clustering of antiprotozoal compounds. Bioorgan. Med Chem 16(11):5871–5880

    Article  CAS  Google Scholar 

  • Radwan MAA, Ragab EA, Sabry NM, El-Shenawy SM (2007) Synthesis and biological evaluation of new 3-substituted indole derivatives as potential anti-inflammatory and analgesic agents. Bioorgan Med Chem 15:3832–3841

    Article  CAS  Google Scholar 

  • Randic M (1975) On characterization of molecular branching. J Am Chem Soc 97:6609–6615

    Article  CAS  Google Scholar 

  • Randic M (1993) Comparative regression analysis: regression based on a single descriptor. Croat Chem Acta 66:289–312

    CAS  Google Scholar 

  • Rodriguez-Arguelles MC, Lopez-Silva EC, Sanmartin J, Pelagatti P, Zani F (2005) Copper complexes of imidazole-2-, pyrrole-2- and indol-3-carbaldehyde thiosemicarbazones: inhibitory activity against fungi and bacteria. J Inorg Biochem 99:2231–2239

    PubMed  Article  Google Scholar 

  • Strappaghetti G, Mastrini L, Lucacchini A, Giannaccini G, Betti L, Fabbrini L (2008) Synthesis and biological affinity of new imidazo- and indol-arylpiperazine derivatives: further validation of a pharmacophore model for α1-adrenoceptor antagonists. Bioorg Med Chem Lett 18:5140–5145

    PubMed  Article  CAS  Google Scholar 

  • TSAR 3D Version 3.3, Oxford Molecular Limited, 2000

  • Velankar AD, Quintini G, Prabhu A, Weber A, Hunaeus G, Voland B, Wuest M, Orjeda C, Harel D, Varghese S, Gore V, Patil M, Gayke D, Herdemann M, Heit I, Zaliani A (2010) Synthesis and biological evaluation of novel (4 or 5-aryl)pyrazolyl-indoles as inhibitors of interleukin-2 inducible T-cell kinase (ITK). Bioorgan Med Chem 18:4547–4559

    Article  CAS  Google Scholar 

  • Wiener H (1947) Structural determination of paraffin boiling points. J Am Chem Soc 69:17–20

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Balasubramanian Narasimhan.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kumar, H., Kumar, P., Narasimhan, B. et al. Synthesis, in vitro antimicrobial, antiproliferative, and QSAR studies of N-(substituted phenyl)-2/4-(1H-indol-3-ylazo)-benzamides. Med Chem Res 22, 1957–1971 (2013). https://doi.org/10.1007/s00044-012-0181-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-012-0181-0

Keywords

  • Benzamides
  • QSAR
  • Antimicrobial
  • Antiproliferative