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

被引:18
作者
Ahmad, Muhammad Jawad [1 ]
Hassan, Syed Fahad [2 ]
Nisa, Riffat Un [3 ]
Ayub, Khurshid [3 ]
Nadeem, Muhammad Shahid [4 ]
Nazir, Samina [5 ]
Ansari, Farzana Latif [6 ]
Qureshi, Naveeda Akhtar [7 ]
Rashid, Umer [1 ,3 ]
机构
[1] Hazara Univ, Dept Chem, Mansehra 21120, Pakistan
[2] Univ Lahore, Dept Pharm, Def Rd Campus, Lahore 53700, Pakistan
[3] COMSATS Inst Informat Technol, Dept Chem, Abbottabad 22060, Pakistan
[4] King Abdulaziz Univ, Dept Biochem, Jeddah, Saudi Arabia
[5] Natl Ctr Phys, Nanosci & Catalyst Div, Quaid I Azam Univ Campus, Islamabad 44000, Pakistan
[6] Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan
[7] Quaid I Azam Univ, Dept Anim Sci, Islamabad 45320, Pakistan
关键词
4-Arylated-2-aminopyrimidines; Ultrasound irradiation; Dihydrofolate reductase; Promiscuity binding; Density functional theory; EFFECTIVE CORE POTENTIALS; MOLECULAR CALCULATIONS; AQUEOUS SOLUBILITY; METABOLISM; PYRIMIDINE; PREDICTION; PHARMACOKINETICS; MECHANISM;
D O I
10.1007/s00044-016-1613-z
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:1877 / 1894
页数:18
相关论文
共 46 条
[1]  
[Anonymous], 2015, MARV 15 4 6
[2]   DENSITY-FUNCTIONAL THERMOCHEMISTRY .3. THE ROLE OF EXACT EXCHANGE [J].
BECKE, AD .
JOURNAL OF CHEMICAL PHYSICS, 1993, 98 (07) :5648-5652
[3]   TRIMETHOPRIM - A REVIEW OF ITS ANTIBACTERIAL ACTIVITY, PHARMACOKINETICS AND THERAPEUTIC USE IN URINARY-TRACT INFECTIONS [J].
BROGDEN, RN ;
CARMINE, AA ;
HEEL, RC ;
SPEIGHT, TM ;
AVERY, GS .
DRUGS, 1982, 23 (06) :405-430
[4]   Glivec (ST1571, Imatinib), a rationally developed, targeted anticancer drug [J].
Capdeville, R ;
Buchdunger, E ;
Zimmermann, J ;
Matter, A .
NATURE REVIEWS DRUG DISCOVERY, 2002, 1 (07) :493-502
[5]   Power ultrasound in organic systhesis: moving cavitational chemistry from academia to innovative and large-scale applications [J].
Cravotto, G ;
Cintas, P .
CHEMICAL SOCIETY REVIEWS, 2006, 35 (02) :180-196
[6]   Quinolone-mediated bacterial death [J].
Drlica, Karl ;
Malik, Muhammad ;
Kerns, Robert J. ;
Zhaol, Xilin .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2008, 52 (02) :385-392
[7]   Multitarget ligands in antibacterial research: progress and opportunities [J].
East, Stephen P. ;
Silver, Lynn L. .
EXPERT OPINION ON DRUG DISCOVERY, 2013, 8 (02) :143-156
[8]  
Egan WJ., 2010, Drug design: structure- and ligand-based approaches, P165
[9]  
Frisch MJ, 2009, GAUSSIAN 09
[10]   Generation of a set of simple, interpretable ADMET rules of thumb [J].
Gleeson, M. Paul .
JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (04) :817-834