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Synthesis, in vitro potential and computational studies on 2-amino-1, 4-dihydropyrimidines as multitarget antibacterial ligands

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Abstract

In this study, we have investigated small multitargeted molecules containing 2-aminopyrimidine scaffold that may further act as precursor for developing more potent antibacterials. An efficient route to 2-amino-1,4-dihydropyrimidines by using ultrasound irradiation as the energy source was developed. In silico density functional theory calculations illustrated that tin chloride-mediated Biginelli reaction to produce 2-amino-1,4-dihydropyrimidines has energetics quite accessible under the reaction conditions. Calculated minimum inhibitory concentrations against the various bacterial strains showed that compounds 3 and 11 displayed comparable in vitro activity to ciprofloxacin in Staphylococcus aureus strains and reduced potency in Escherichia coli strains. Further, we investigated in silico ADMET profiling of synthesized compounds in order to understand the mechanism of action that help in explaining in vitro results. Lead compounds 3, 6, and 11 are predicted to have acceptable pharmacokinetic/drug-like properties. Data mining and computational analysis were employed to derive compound promiscuity phenomenon. All the compounds were found nonsubstrate towards various aminergic G-protein coupled receptors, ion-channels, kinase inhibitor, nuclear receptor ligand, protease inhibitor, and enzyme inhibitor. Compound 3 was further investigated by in silico binding to different antibacterial targets. Binding energy data revealed that that these compounds have the ability to bind with other bacterial targets. Hence, combined in silico and in vitro studies shed insights into the mechanism of synthesis and antibacterial activity of 2-amino-1,4-dihydropyrimidines. Results of this study are promising and can be used for further investigation by medicinal chemists to explore their chemical functionalization and in vivo studies.

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References

  • Ákos T, Gyorgy MK (2013) Contributions of molecular properties to drug promiscuity. J Med Chem 56:1789–1795

    Article  Google Scholar 

  • Becke AD (1993) Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys 98:5648–5652

    Article  CAS  Google Scholar 

  • Brogden RN, Carmine AA, Heel RC, Speight TM, Avery GS (1982) Trimethoprim: a review of its antibacterial activity, pharmacokinetics and therapeutic use in urinary tract infections. Drugs 23(6):405–430

    Article  CAS  PubMed  Google Scholar 

  • Capdeville R, Buchdunger E, Zimmermann J, Matter A (2002) Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 1:493–502

    Article  CAS  PubMed  Google Scholar 

  • Cravotto G, Cintas P (2006) Power ultrasound in organic synthesis: moving cavitational chemistry from academia to innovative and large-scale applications. Chem Soc Rev 35:180–196

    Article  CAS  PubMed  Google Scholar 

  • Drlica K, Malik M, Kerns RJ, Zhao X (2008) Quinolone-mediated bacterial death. Antimicrob Agents Chemother 52:385–392

    Article  CAS  PubMed  Google Scholar 

  • Egan WJ (2010) Predicting ADME properties in drug discovery. In: Merz KM, Ringe D, and Reynolds CH (eds) Drug design: structure- and ligand-based approaches, Cambridge University Press: New York, USA. pp 165–173.

  • Frisch MJ, Trucks GW, Schlegel HB et al. (2009) Gaussian 09, Rev. C.01. Gaussian, Inc., Wallingford, CT

    Google Scholar 

  • Gleeson MP (2008) Generation of a set of simple, interpretable ADMET rules of thumb. J Med Chem 51:817–834

    Article  CAS  PubMed  Google Scholar 

  • Hansen NT, Irene K, Flemming SJ, Søren B, Svava ÓJ (2006) Prediction of pH-dependent aqueous solubility of druglike molecules. J Chem Inf Model 46:2601–2609

    Article  CAS  PubMed  Google Scholar 

  • Hariharan PC, Pople JA (1973) Influence of polarization functions on MO hydrogenation energies. Theor Chim Acta 28:213–222

    Article  CAS  Google Scholar 

  • Haupt VJ, Daminelli S, Schroeder M (2013) Drug promiscuity in PDB: protein binding site similarity is key. PLoS ONE 8(6):e65894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hay PJ, Wadt WR (1985a) Ab initio effective core potentials for molecular calculations. Potentials for the transition metal atoms Sc to Hg. J Chem Phys 82:270

    Article  CAS  Google Scholar 

  • Hay PJ, Wadt WR (1985b) Ab initio effective core potentials for molecular calculations. Potentials for K to Au including the outermost core orbitals. J Chem Phys 82:299

    Article  CAS  Google Scholar 

  • Hebert M (1997) Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery. Adv Drug Deliv Rev 27:201–214

    Article  CAS  PubMed  Google Scholar 

  • Ho P-L, Que T-L, Tsang DNC, Ng TK, Chow KH, Seto WH (1999) Emergence of fluoroquinolone resistance among multiply resistant strains of Streptococcus pneumoniae in Hong Kong. Antimicrob Agents Chemother 43:1310–1313

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hutcheson JD, Setola V, Roth BL, Merryman WD (2011) Serotonin receptors and heart valve disease—it was meant 2B. Pharmacol Ther 132:146–157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson SR, Zheng W (2006) Recent progress in the computational prediction of aqueous solubility and absorption. AAPS J 8(1):E27–E40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kappe CO (1997) A reexamination of the mechanism of the biginelli dihydropyrimidine synthesis. Support for an N-acyliminium ion intermediate. J Org Chem 62(1997):7201–7204

    Article  CAS  PubMed  Google Scholar 

  • Lagoja IM (2005) Pyrimidine as constituent of natural biologically active compounds. Chem Biodivers 2:1–50

    Article  CAS  PubMed  Google Scholar 

  • Lee C, Yang W, Parr RG (1988) Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys Rev B 37:785–789

    Article  CAS  Google Scholar 

  • Marvin 15.4.6 (2015) ChemAxon. www.chemaxon.com.

  • Mason TJ, Lorimer J (2002) Applied sonochemistry: uses of power ultrasound in chemistry and processing. Wiley-VCH, Weinheim

    Book  Google Scholar 

  • McFarland JW, Berger CM, Froshauer SA, Hayashi SF, Hecker SJ, Jaynes BH, Jefson MR, Kamicker BJ, Lipinski CA, Lundy KM, Reese CP, Vu CB (1997) Quantitative structure−activity relationships among macrolide antibacterial agents:  in vitro and in vivo potency against Pasteurella multocida. J Med Chem 40(9):1340–1346

    Article  CAS  PubMed  Google Scholar 

  • Molecular Operating Environment (MOE), 2012.10; Chemical Computing Group Inc., 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7, 2016.

  • Norinder U, Bergström CA (2006) Prediction of ADMET properties. Chem Med Chem 1:920–937

    Article  CAS  PubMed  Google Scholar 

  • Pacifici G, Nottoli R (1995) Placental transfer of drugs administered to the mother. Clin Pharmacokinetics 28:235–269

    Article  CAS  Google Scholar 

  • Pearlstein R, Vaz R, Rampe D (2003) Understanding the structure activity relationship of the human ether-a-go-go-related gene cardiac K+ channel: a model for bad behavior. J Med Chem 46(11):2017–2022

    Article  CAS  PubMed  Google Scholar 

  • Peters J-U, Hert J, Bissantz C, Hillebrecht A, Gerebtzoff G, Bendels S, Tillier F, Migeon J, Fischer H, Guba W, Kansy M (2012) Can we discover pharmacological promiscuity early in the drug discovery process? Drug Disc Today 17(7–8):325–335

    Article  Google Scholar 

  • Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF chimera—a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612

    Article  CAS  PubMed  Google Scholar 

  • Proudfoot JR (2005) The evolution of synthetic oral drug properties. Bioorg Med Chem Lett 15:1087–1090

    Article  CAS  PubMed  Google Scholar 

  • Qiu X, Janson CA, Smith WW, Head M, Lonsdale J, Konstantinidis AK (2001) Refined structures of beta-ketoacyl-acyl carrier protein synthase III. J Mol Biol 307(1):341–356

    Article  CAS  PubMed  Google Scholar 

  • Rashid U, Batool I, Wadood A, Khan A, Ul-Haq Z, Chaudhary MI, Ansari FL (2013) Structure based virtual screening-driven identification of monastrol as a potent urease inhibitor. J Mol Graphics Modell 43:47–57

    Article  CAS  Google Scholar 

  • Rashid U, Hassan SF, Nazir S, Wadood A, Waseem M, Ansari FL (2015) Synthesis, docking studies, and in silico ADMET predictions of some new derivatives of pyrimidine as potential KSP inhibitors. Med Chem Res 24(1):304–315

    Article  CAS  Google Scholar 

  • Reynolds F, Knott C (1989) Pharmacokinetics in pregnancy and placental drug transfer. Oxf Rev Reprod Biol 11:389–449

    CAS  PubMed  Google Scholar 

  • Ruan B, Bovee ML, Sacher M, Stathopoulos C, Poralla K, Francklyn CS, Söll DJ (2005) A unique hydrophobic cluster near the active site contributes to differences in borrelidin inhibition among threonyl-tRNA synthetases. Biol Chem 280:571–577

    Article  CAS  Google Scholar 

  • Smith DA (1997) Physicochemical properties in drug metabolism and pharmacokinetics. In: van de Waterbeemd H, Testa B, and Folkers G (eds) Computer-assisted lead finding and optimization: Current tools for medicinal chemistry, Wiley-VCH: Weinheim, Germany. p 267

  • Smith DA, Jones BC, Walker DK (1996) Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics. Med Res Rev 16:243–266

    Article  CAS  PubMed  Google Scholar 

  • Stephen PE, Lynn LS (2013) Multitarget ligands in antibacterial research: progress and opportunities. Expert Opin Drug Disc 8:143–156

    Article  Google Scholar 

  • Stopher DA, Beresford AP, Macrae PV, Humphrey MJ (1988) The metabolism and pharmacokinetics of amlodipine in humans and animals. J Cardiovasc Pharmacol 12:S55–S59

    Article  CAS  PubMed  Google Scholar 

  • Sweet F, Fissekis JD (1973) Synthesis of 3,4-dihydro-2(1H)-pyrimidinones and the mechanism of the Biginelli reaction. J Am Chem Soc 95:8741–8749

    Article  CAS  Google Scholar 

  • Waring MJ (2009) Defining optimum lipophilicity and molecular weight ranges for drug candidates—molecular weight dependent lower log D limits based on permeability. Bioorg Med Chem 19:2844–2851

    Article  CAS  Google Scholar 

  • Watanabe M, Koike H, Ishiba T, Okada T, Seo S, Hirai K (1997) Synthesis and biological activity of methanesulfonamide pyrimidine- and N-methanesulfonyl pyrrole-substituted 3,5-dihydroxy-6-heptenoates, a novel series of HMG-CoA reductase inhibitors. Bioorg Med Chem 5:437–444

    Article  CAS  PubMed  Google Scholar 

  • Waterbeemd H, Gifford E (2003) ADMET in silico modelling: towards prediction paradise? Nat Rev Drug Discov 2:192–204

    Article  PubMed  Google Scholar 

  • Waterbeemd H, Smith DA, Jones BC (2001) Lipophilicity in PK design: methyl, ethyl, futile. J Comput Aided Mol Design 15:273–286

    Article  Google Scholar 

  • Williams RT (1978) Species variations in the pathways of drug metabolism. Environ Health Perspect 22:133–138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Y, Engkvist O, Llinàs A, Chen H (2012) Beyond size, ionization state, and lipophilicity: influence of molecular topology on absorption, distribution, metabolism, excretion, and toxicity for druglike compounds. J Med Chem 55:3667–3677

    Article  CAS  PubMed  Google Scholar 

  • Yogev R, Kolling WM, Williams T (1981) Pharmacokinetic comparison of intravenous and oral chloramphenicol in patients with Haemophilus influenzae meningitis. Pediatrics 67:656–660

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The Higher Education Commission (HEC), Pakistan is thankfully acknowledged for providing financial support to Umer Rashid for startup grant under IPFP program (HEC No: PM-IPFP/HRD/HEC/2011/346).

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Authors and Affiliations

  1. Department of Chemistry, Hazara University, Mansehra, 21120, Pakistan

    Muhammad Jawad Ahmad & Umer Rashid

  2. Department of Pharmacy, The University of Lahore, Defense Road Campus, Lahore, 53700, Pakistan

    Syed Fahad Hassan

  3. Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad, 22060, Pakistan

    Riffat Un Nisa, Khurshid Ayub & Umer Rashid

  4. Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia

    Muhammad Shahid Nadeem

  5. Nanosciences & Catalyst Division, National Center for Physics, Quaid-i-Azam University Campus, Islamabad, 44000, Pakistan

    Samina Nazir

  6. Department of Chemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan

    Farzana Latif Ansari

  7. Department of Animal Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan

    Naveeda Akhtar Qureshi

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  1. Muhammad Jawad Ahmad
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Correspondence to Umer Rashid.

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Ahmad, M.J., Hassan, S.F., Nisa, R.U. et al. Synthesis, in vitro potential and computational studies on 2-amino-1, 4-dihydropyrimidines as multitarget antibacterial ligands. Med Chem Res 25, 1877–1894 (2016). https://doi.org/10.1007/s00044-016-1613-z

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