Medicinal Chemistry Research

, Volume 28, Issue 10, pp 1674–1682 | Cite as

Structure-based lead optimization to improve the antifungal potency of the tetrahydroimidazo pyridine inhibitors targeted to Candida albicans dihydrofolate reductase and lanosterol 14-alpha-demethylase

  • Srimai Vuppala
  • Ramesh Kumar Chitumalla
  • Bo Sun JooEmail author
  • Joonkyung JangEmail author
Original Research


We investigate the binding and inhibition profiles for a selected dataset of tetrahydroimidazo pyridine molecules against Candida albicans dihydrofolate reductase (DHFR) and lanosterol 14-alpha-demethylase (CYP51). A hit molecule was screened and identified through Lipinski’s rule of five, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and the molecular docking. Some inhibitors of our design have shown positive drug scores, good solubilities, and high docking scores over the selected dataset. The first-principles calculation based on the density functional theory was carried out to understand how the electronic distributions of frontier orbitals of molecules affect their inhibition profiles. The present structure-based approach enabled us to design new pharmacophore analogs with improved ADMET profile, drug scores, and docking scores against selected receptors.


Density functional theory Structure-based lead optimization Candida albicans dihydrofolate reductase Lanosterol 14-alpha-demethylase Molecular docking ADMET 



This study was supported by the National Research Foundation Grants funded by the Korean Government (2018R1A2A2A05019776).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2019_2404_MOESM1_ESM.docx (123 kb)
Supplementary Material.


  1. Abe F, Usui K, Hiraki T (2009) Fluconazole Modulates membrane rigidity, heterogeneity, and water penetration into the plasma membrane in Saccharomyces cerevisiae. Biochemistry 48:8494–8504CrossRefGoogle Scholar
  2. Becke AD (1993) Density‐functional thermochemistry. III. The role of exact exchange. J Chem Phys 98:5648–5652CrossRefGoogle Scholar
  3. Becke AD (1996) Density‐functional thermochemistry. IV. A new dynamical correlation functional and implications for exact‐exchange mixing. J Chem Phys 104:1040–1046CrossRefGoogle Scholar
  4. Chan JH, Hong JS, Kuyper LF, Baccanari DP, Joyner SS, Tansik RL, Boytos CM, Rudolph SK (1995) Selective inhibitors of Candida albicans dihydrofolate reductase: activity and selectivity of 5-(arylthio)-2,4-diaminoquinazolines. J Med Chem 38:3608–3616CrossRefGoogle Scholar
  5. Cheng F, Li W, Zhou Y, Shen J, Wu Z, Liu G, Lee PW, Tang Y (2012) Admetsar: a comprehensive source and free tool for assessment of chemical ADMET properties. J Chem Inf Model 52:3099–3105CrossRefGoogle Scholar
  6. Chimenti F, Bizzarri B, Maccioni E, Secci D, Bolasco A, Fioravanti R, Chimenti P, Granese A, Carradori S, Rivanera D, Lilli D, Zicari A, Distinto S (2007) Synthesis and in vitro activity of 2-thiazolylhydrazone derivatives compared with the activity of clotrimazole against clinical isolates of Candida spp. Bioorganic Med Chem Lett 17:4635–4640CrossRefGoogle Scholar
  7. Daum G, Lees ND, Bard M, Dickson R (1998) Biochemistry, cell biology and molecular biology of lipids of Saccharomyces cerevisiae. Yeast 14:1471–1510CrossRefGoogle Scholar
  8. Di Santo R (2010) Natural products as antifungal agents against clinically relevant pathogens. Nat Prod Rep 27:1084–1098CrossRefGoogle Scholar
  9. Flores MC, Márquez EA, Mora JR (2018) Molecular modeling studies of bromopyrrole alkaloids as potential antimalarial compounds: a DFT approach. Med Chem Res 27:844–856CrossRefGoogle Scholar
  10. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, revision D.01. Gaussian, Inc., Wallingford, CTGoogle Scholar
  11. Guex N, Peitsch MC (1997) SWISS-MODEL and the Swiss-Pdb viewer: an environment for comparative protein modeling. Electrophoresis 18:2714–2723CrossRefGoogle Scholar
  12. Hypercube Inc. (2007) HyperChem 8.0 package. Hypercube (2007) Inc., Gainesville, FL, USA.
  13. Jefcoate CR (1978) Measurement of substrate and inhibitor binding to microsomal cytochrome P-450 by optical-difference spectroscopy. Methods Enzymol. 52:258–279Google Scholar
  14. Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) Development and validation of a genetic algorithm for flexible docking11Edited by F. E. Cohen. J Mol Biol 267:727–748CrossRefGoogle Scholar
  15. Mabkhot Y, Alatibi F, El-Sayed N, Al-Showiman S, Kheder N, Wadood A, Rauf A, Bawazeer S, Hadda T (2016) Antimicrobial activity of some novel armed thiophene derivatives and Petra/Osiris/Molinspiration (POM) analyses. Molecules 21:222CrossRefGoogle Scholar
  16. Millar BC, Jugo J, Moore JE (2005) Fungal endocarditis in neonates and children. Pedia Cardiol 26:517–536CrossRefGoogle Scholar
  17. Molegro ApS (2009) Molegro Virtual Docker, Version 3.2.1. Molegro ApS, Aarhus, DenmarkGoogle Scholar
  18. Negi N, Ahmad A (2018) Current updates on fungal endocarditis. Fungal Biol Rev 32:1–9CrossRefGoogle Scholar
  19. Özdemir A, Turan-Zitouni G, Asım Kaplancıklı Z, İşcan G, Khan S, Demirci F (2010) Synthesis and the selective antifungal activity of 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine derivatives. Eur J Med Chem 45:2080–2084CrossRefGoogle Scholar
  20. Schiaffella F, Macchiarulo A, Milanese L, Vecchiarelli A, Costantino G, Pietrella D, Fringuelli R (2005) Design, synthesis, and microbiological evaluation of new candida albicans CYP51 inhibitors. J Med Chem 48:7658–7666CrossRefGoogle Scholar
  21. Sheehan DJ, Hitchcock CA, Sibley CM (1999) Current and emerging azole antifungal agents. Clin Microbiol Rev 12:40–79CrossRefGoogle Scholar
  22. Sousa SF, Fernandes PA, Ramos MJ (2006) Protein–ligand docking: current status and future challenges. Protein Struct Funct Bioinform 65:15–26CrossRefGoogle Scholar
  23. Taha M, Ismail NH, Imran S, Selvaraj M, Rahim A, Ali M, Siddiqui S, Rahim F, Khan KM (2015) Synthesis of novel benzohydrazone–oxadiazole hybrids as β-glucuronidase inhibitors and molecular modeling studies. Bioorganic Med Chem 23:7394–7404CrossRefGoogle Scholar
  24. Voth AR, Khuu P, Oishi K, Ho PS (2009) Halogen bonds as orthogonal molecular interactions to hydrogen bonds. Nat Chem 1:74CrossRefGoogle Scholar
  25. Xie J, Dong H, Yu Y, Cao S (2016) Inhibitory effect of synthetic aromatic heterocycle thiosemicarbazone derivatives on mushroom tyrosinase: insights from fluorescence, 1H NMR titration and molecular docking studies. Food Chem 190:709–716CrossRefGoogle Scholar
  26. Yamaguchi H (1977) Antagonistic action of lipid components of membranes from Candida albicans and various other lipids on two imidazole antimycotics, clotrimazole and miconazole. Antimicrob Agents Chemother 12:16–25CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Department of Nanoenergy EngineeringPusan National UniversityBusanRepublic of Korea
  2. 2.Infertility InstitutePohang Women’s HospitalPohangRepublic of Korea

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