Green synthesis, antileishmanial activity evaluation, and in silico studies of new amino acid-coupled 1,2,4-triazoles

  • Ahmed M. El-Saghier
  • Mounier A. Mohamed
  • Omyma A. Abd-Allah
  • Asmaa M. Kadry
  • Tamer M. Ibrahim
  • Adnan A. Bekhit
Original Research


Candidates of triazole-containing amino acid derivatives 5a−k were prepared under green chemistry conditions via multicomponent reaction using lemon juice as an acidic catalyst. All compounds were characterized by different spectral and elemental analyses. They were evaluated for their in vitro antileishmanial activity against miltefosine and amphotericin B deoxycholate as reference drugs. Compounds 5c, 5d, 5e and 5f showed superior potencies to miltefosine by 200 folds. These compounds are well tolerated by experimental animals orally up to 250 mg/kg and parenterally up to 100 mg/kg. Reverse docking approach against validated leishmanial targets pinpointed mitogen-activated protein kinase (MAPK) as a possible putative antileishmanial target. In addition, in silico predictions revealed that these compounds exhibited promising drug-likeness and pharmacokinetics profile.


Green synthesis 1,2,4-triazole derivatives Antileishmanial activity In silico studies Docking on leishmanial MAPK 



The authors acknowledge Prof. Frank Boeckler (Lab. of Molecular Design and Pharmaceutical Biophysics, Eberhard Karls University of Tuebingen) for granting access to MOE and GOLD tools.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest

Ethical approval

The protocols used in this study followed the guidelines set in “The Guide for the Care and Use of Laboratory Animals”, and got approval from the ACUC, Faculty of Pharmacy, Alexandria University, Project No. 22 at 22/5/2013 and ACUC17/18.

Supplementary material

44_2018_2274_MOESM1_ESM.pdf (1.6 mb)
Supplementary Information


  1. Alviano DS, Barreto AL, Dias Fde A, Rodrigues Ide A, Rosa Mdo S, Alviano CS, Soares RM (2012) Conventional therapy and promising plant-derived compounds against trypanosomatid parasites. Front Microbiol 3:283. CrossRefPubMedPubMedCentralGoogle Scholar
  2. Atta KFM, Ibrahim TM, Farahat OOM, Al-Shargabi TQ, Marei MG, Bekhit AA, El Ashry ESH (2017) Synthesis, modeling and biological evaluation of hybrids from pyrazolo[1,5c]pyrimidine as antileishmanial agents. Future Med Chem 9(16):1913–1929. CrossRefPubMedGoogle Scholar
  3. Baell JB, Holloway GA (2010) New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem 53(7):2719–2740. CrossRefPubMedGoogle Scholar
  4. Bekhit AA, Hassan AM, Abd El Razik HA, El-Miligy MM, El-Agroudy EJ, Bekhit Ael D (2015) New heterocyclic hybrids of pyrazole and its bioisosteres: design, synthesis and biological evaluation as dual acting antimalarial-antileishmanial agents. Eur J Med Chem 94:30–44. CrossRefPubMedGoogle Scholar
  5. Birhan YS, Bekhit AA, Hymete A (2014) Synthesis and antileishmanial evaluation of some 2,3-disubstituted-4(3H)-quinazolinone derivatives. Org Med Chem Lett 4(1):10. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Blayo A-L, Brunel F, Martinez J, Fehrentz J-A (2011) Synthesis of various chiral 1,2,4-triazole-containing α-amino acids from aspartic or glutamic acids. Eur J Org Chem 2011(23):4293–4297. CrossRefGoogle Scholar
  7. Brenk R, Schipani A, James D, Krasowski A, Gilbert IH, Frearson J, Wyatt PG (2008) Lessons learnt from assembling screening libraries for drug discovery for neglected diseases. ChemMedChem 3(3):435–444. CrossRefPubMedGoogle Scholar
  8. Cansiz A, Servi S, Koparir M, Altintas M, Digrak M (2001) Synthesis and biological activities of some Mannich bases of 5-(2-furyl)-1, 2, 4-triazole-3-thiones. J Chem Soc Pak 23(4):237–239Google Scholar
  9. Cheng T, Zhao Y, Li X, Lin F, Xu Y, Zhang X, Li Y, Wang R, Lai L (2007) Computation of octanol-water partition coefficients by guiding an additive model with knowledge. J Chem Inf Model 47(6):2140–2148. CrossRefPubMedGoogle Scholar
  10. Daina A, Michielin O, Zoete V (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7:42717. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Daina A, Zoete V (2016) A boiled-egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem 11(11):1117–1121. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Delaney JS (2004) ESOL: estimating aqueous solubility directly from molecular structure. J Chem Inf Comput Sci 44(3):1000–1005. CrossRefPubMedGoogle Scholar
  13. Demirbas N, Karaoglu SA, Demirbas A, Sancak K (2004) Synthesis and antimicrobial activities of some new 1-(5-phenylamino-[1,3,4]thiadiazol-2-yl)methyl-5-oxo-[1,2,4]triazole and 1-(4-phenyl-5-thioxo-[1,2,4]triazol-3-yl)methyl-5-oxo- [1,2,4]triazole derivatives. Eur J Med Chem 39(9):793–804. CrossRefPubMedGoogle Scholar
  14. Di L (2014) The role of drug metabolizing enzymes in clearance. Expert Opin Drug Metab Toxicol 10(3):379–393. CrossRefPubMedGoogle Scholar
  15. Egan WJ, Merz Jr. KM, Baldwin JJ (2000) Prediction of drug absorption using multivariate statistics. J Med Chem 43(21):3867–3877CrossRefGoogle Scholar
  16. El-Kerdawy M, Eisa H, Barghash A, Marouf A (1989) Synthesis and some chemical behaviour of certain substituted thiosemicarbazides. J Chin Chem Soc 36:347–351. CrossRefGoogle Scholar
  17. Ghose AK, Viswanadhan VN, Wendoloski JJ (1999) A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J Comb Chem 1(1):55–68CrossRefGoogle Scholar
  18. Girmenia C (2009) New generation azole antifungals in clinical investigation. Expert Opin Investig Drugs 18(9):1279–1295. CrossRefPubMedGoogle Scholar
  19. Hann MM, Keseru GM (2012) Finding the sweet spot: the role of nature and nurture in medicinal chemistry. Nat Rev Drug Discov 11(5):355–365. CrossRefPubMedGoogle Scholar
  20. Hartshorn MJ, Verdonk ML, Chessari G, Brewerton SC, Mooij WT, Mortenson PN, Murray CW (2007) Diverse, high-quality test set for the validation of protein-ligand docking performance. J Med Chem 50(4):726–741. CrossRefPubMedGoogle Scholar
  21. Hollenberg PF (2002) Characteristics and common properties of inhibitors, inducers, and activators of CYP enzymes. Drug Metab Rev 34(1−2):17–35. CrossRefPubMedGoogle Scholar
  22. Huang SM, Strong JM, Zhang L, Reynolds KS, Nallani S, Temple R, Abraham S, Habet SA, Baweja RK, Burckart GJ, Chung S, Colangelo P, Frucht D, Green MD, Hepp P, Karnaukhova E, Ko HS, Lee JI, Marroum PJ, Norden JM, Qiu W, Rahman A, Sobel S, Stifano T, Thummel K, Wei XX, Yasuda S, Zheng JH, Zhao H, Lesko LJ (2008) New era in drug interaction evaluation: US Food and Drug Administration update on CYP enzymes, transporters, and the guidance process. J Clin Pharmacol 48(6):662–670. CrossRefPubMedGoogle Scholar
  23. Ibrahim TM, Bauer MR, Dorr A, Veyisoglu E, Boeckler FM (2015) pROC-chemotype plots enhance the interpretability of benchmarking results in structure-based virtual screening. J Chem Inf Model 55(11):2297–2307. CrossRefPubMedGoogle Scholar
  24. Jones G, Willett P, Glen RC (1995a) A genetic algorithm for flexible molecular overlay and pharmacophore elucidation. J Comput-Aided Mol Des 9(6):532–549CrossRefGoogle Scholar
  25. Jones G, Willett P, Glen RC (1995b) Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. J Mol Biol 245(1):43–53CrossRefGoogle Scholar
  26. Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) Development and validation of a genetic algorithm for flexible docking J Mol Biol 267(3):727–748. CrossRefPubMedGoogle Scholar
  27. Khanmohammadi H, Abnosi MH, Hosseinzadeh A, Erfantalab M (2008) Synthesis, biological and computational study of new Schiff base hydrazones bearing 3-(4-pyridine)-5-mercapto-1,2,4-triazole moiety. Spectrochim Acta Mol Biomol Spectrosc 71(4):1474–1480. CrossRefGoogle Scholar
  28. Khattab SN, Haiba NS, Asal AM, Bekhit AA, Guemei AA, Amer A, El-Faham A (2017) Study of antileishmanial activity of 2-aminobenzoyl amino acid hydrazides and their quinazoline derivatives. Bioorg Med Chem Lett 27(4):918–921. CrossRefPubMedGoogle Scholar
  29. Korb O, Stutzle T, Exner TE (2009) Empirical scoring functions for advanced protein-ligand docking with PLANTS. J Chem Inf Model 49(1):84–96. CrossRefPubMedGoogle Scholar
  30. Korb O, Ten Brink T, Victor Paul Raj FR, Keil M, Exner TE (2012) Are predefined decoy sets of ligand poses able to quantify scoring function accuracy? J Comput Aided Mol Des 26(2):185–197. CrossRefPubMedGoogle Scholar
  31. Mali DA, Telvekar VN (2017) Synthesis of triazolidines and triazole using DMAP. Synth Commun 47(4):324–329. CrossRefGoogle Scholar
  32. Martin YC (2005) A bioavailability score. J Med Chem 48(9):3164–3170. CrossRefPubMedGoogle Scholar
  33. Mast N, Zheng W, Stout CD, Pikuleva IA (2013) Antifungal azoles: structural insights into undesired tight binding to cholesterol-metabolizing CYP46A1. Mol Pharmacol 84(1):86–94. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Mindt TL, Struthers H, Brans L, Anguelov T, Schweinsberg C, Maes V, Tourwe D, Schibli R (2006) “Click to chelate”: synthesis and installation of metal chelates into biomolecules in a single step. J Am Chem Soc 128(47):15096–15097. CrossRefPubMedGoogle Scholar
  35. Misato T, Ko K, Honma Y, Konno K, Taniyama E (1977) JP 77-25028 (A01N9/12). Chem Abstr 87:147054aGoogle Scholar
  36. Molecular Operating Environment MOE (2016), Chemical Computing Group Inc.: Montreal, http://www.chemcomp/com
  37. Moustafa HM (2001) Synthesis and reactions of new fused heterocycles derived from 3-(o-Aminophenyl)-4-amino-5-mercapto-1, 2, 4-triazole. Synth Comm 31(1):97–109CrossRefGoogle Scholar
  38. Muegge I, Heald SL, Brittelli D (2001) Simple selection criteria for drug-like chemical matter. J Med Chem 44(12):1841–1846CrossRefGoogle Scholar
  39. Naula C, Parsons M, Mottram JC (2005) Protein kinases as drug targets in trypanosomes and Leishmania. Biochim Biophys Acta 1754(1−2):151–159. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Papadopoulou MV, Bloomer WD, Rosenzweig HS, Chatelain E, Kaiser M, Wilkinson SR, McKenzie C, Ioset JR (2012) Novel 3-nitro-1H-1,2,4-triazole-based amides and sulfonamides as potential antitrypanosomal agents. J Med Chem 55(11):5554–5565. CrossRefPubMedPubMedCentralGoogle Scholar
  41. Patil S, Jadhav S, Patil P (2012) "Natural Acid Catalyzed Synthesis of Schiff Base under Solvent-freeCondition As a Green Approach" Arch. of Appl. Sci. Res. 4:1074–1078Google Scholar
  42. Pal R, Khasnobis S, & Sarkar T (2013) "First Application of Fruit Juice of Citrus limon for Facile and GreenSynthesis of Bis- and Tris(indolyl)methanes in Water" Chemistry Journal 3:1–12Google Scholar
  43. Rajasekaran R, Chen YP (2015) Potential therapeutic targets and the role of technology in developing novel antileishmanial drugs. Drug Discov Today 20(8):958–968. CrossRefPubMedGoogle Scholar
  44. Sachdeva H, Dwivedi D, Saroj R (2013a) Alum catalyzed simple, efficient, and green synthesis of 2-[3-amino-5-methyl-5-(pyridin-3-yl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]propanoic acid derivatives in aqueous media. ScientificWorldJ 2013:716389. CrossRefGoogle Scholar
  45. Sachdeva H, Saroj R, Khaturia S, Dwivedi D (2013b) Environ-economic synthesis and characterization of some new 1,2,4-triazole derivatives as organic fluorescent materials and potent fungicidal agents. Org Chem Int 2013:19. CrossRefGoogle Scholar
  46. Salerno C, Carlucci A, Gorzalczany S, Bregni C (2014) In vitro inhibition of Leishmania braziliensis promastigotes growth by a fluconazole microemulsion. J Mol Pharm Org Process Res 2:115. CrossRefGoogle Scholar
  47. Shams el-Dine SA, Hazzaa AA (1974) Synthesis of compounds with potential fungicidal activity. Part 2 Pharm 29(12):761–763Google Scholar
  48. Shivarama Holla B, Veerendra B, Shivananda MK, Poojary B (2003) Synthesis characterization and anticancer activity studies on some Mannich bases derived from 1,2,4-triazoles. Eur J Med Chem 38(7-8):759–767CrossRefGoogle Scholar
  49. Shokri A, Emami S, Fakhar M, Teshnizi SH, Keighobadi M (2017) In vitro antileishmanial activity of novel azoles (3-imidazolylflavanones) against promastigote and amastigote stages of Leishmania major. Acta Trop 167:73–78. CrossRefPubMedGoogle Scholar
  50. Sun D-G, Hui X-P, Xu P-F, Zhang Z-Y, Guan Z-W (2007) Synthesis of novel biphenyltetrazole derivatives containing 5-methylisoxazole substituted 1,2,4-triazole. J Chin Chem Soc 54(3):795–801. CrossRefGoogle Scholar
  51. Szakacs G, Varadi A, Ozvegy-Laczka C, Sarkadi B (2008) The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Drug Discov Today 13(9-10):379–393. CrossRefPubMedGoogle Scholar
  52. Teague SJ, Davis AM, Leeson PD, Oprea T (1999) The design of leadlike combinatorial libraries. Angew Chem Int Ed Engl 38(24):3743–3748CrossRefGoogle Scholar
  53. Testa B, Kraemer SD (2007) The biochemistry of drug metabolism—an introduction. Chemistry & Biodiversity Wiley Online Library 4: 2031-2122
  54. Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45(12):2615–2623CrossRefGoogle Scholar
  55. Walker J, Gongora R, Vasquez JJ, Drummelsmith J, Burchmore R, Roy G, Ouellette M, Gomez MA, Saravia NG (2012) Discovery of factors linked to antimony resistance in Leishmania panamensis through differential proteome analysis. Mol Biochem Parasitol 183(2):166–176. CrossRefPubMedGoogle Scholar
  56. Wolf CR, Smith G, Smith RL (2000) Pharmacogenetics. Br Med JGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Ahmed M. El-Saghier
    • 1
  • Mounier A. Mohamed
    • 1
  • Omyma A. Abd-Allah
    • 1
  • Asmaa M. Kadry
    • 1
  • Tamer M. Ibrahim
    • 2
  • Adnan A. Bekhit
    • 3
    • 4
  1. 1.Chemistry Department, Faculty of ScienceSohag UniversitySohagEgypt
  2. 2.Pharmaceutical Chemistry Department, Faculty of PharmacyKafrelsheikh UniversityKafr El-SheikhEgypt
  3. 3.Pharmaceutical Chemistry Department, Faculty of PharmacyAlexandria UniversityAlexandriaEgypt
  4. 4.Pharmacy Program, Allied Health Department, College of Health SciencesUniversity of BahrainZallaqBahrain

Personalised recommendations