molecules Article Efficient Synthesis of Novel Pyridine-Based Derivatives via Suzuki Cross-Coupling Reaction of Commercially Available 5-Bromo-2-methylpyridin-3-amine: Quantum Mechanical Investigations and Biological Activities Gulraiz Ahmad 1, Nasir Rasool 1,*, Hafiz Mansoor Ikram 1, Samreen Gul Khan 1, Tariq Mahmood 2, Khurshid Ayub 2, Muhammad Zubair 1, Eman Al-Zahrani 3, Usman Ali Rana 4, Muhammad Nadeem Akhtar 5 and Noorjahan Banu Alitheen 6,* 1 Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan; [email protected] (G.A.); [email protected] (H.M.I.); [email protected] (S.G.K.); [email protected] (M.Z.) 2 Department of Chemistry, COMSATS Institute of Information Technology, University Road, Tobe Camp, 22060 Abbottabad, Pakistan; [email protected] (T.M.); [email protected] (K.A.) 3 Chemistry Department, Faculty of Science, Taif University, 888-Taif, Saudi Arabia; [email protected] 4 Sustainable Energy Technologies Center, College of Engineering, P.O. Box 800, King Saud University, Riyadh 11421, Saudi Arabia; [email protected] 5 Faculty of Industrial Sciences & Technology, University Malaysia Pahang, Lebuhraya Tun, Razak 26300, Kuantan Pahang, Malaysia; [email protected] 6 Faculty of Biotechnology and Biomolecular Sciences, University Putra Malaysia, Serdang, Selangor Darul Ehsan 43400, Malaysia * Correspondence: [email protected] (N.R.); [email protected] (N.B.A.); Tel.: +92-332-7491790 (N.R.); +60-3-8946-7471 (N.B.A.); Fax: +92-41-9201032 (N.R.); +60-3-8946-7510 (N.B.A.) Academic Editor: Diego Muñoz-Torrero Received: 20 November 2016; Accepted: 6 January 2017; Published: 27 January 2017 Abstract: The present study describes palladium-catalyzed one pot Suzuki cross-coupling reaction to synthesize a series of novel pyridine derivatives 2a–2i, 4a–4i. In brief, Suzuki cross-coupling reaction of 5-bromo-2-methylpyridin-3-amine (1) directly or via N-[5-bromo-2-methylpyridine-3-yl]acetamide (3) with several arylboronic acids produced these novel pyridine derivatives in moderate to good yield. Density functional theory (DFT) studies were carried out for the pyridine derivatives 2a–2i and 4a–4i by using B3LYP/6-31G(d,p) basis with the help of GAUSSIAN 09 suite programme. The frontier molecular orbitals analysis, reactivity indices, molecular electrostatic potential and dipole measurements with the help of DFT methods, described the possible reaction pathways and potential candidates as chiral dopants for liquid crystals. The anti-thrombolytic, biofilm inhibition and haemolytic activities of pyridine derivatives were also investigated. In particular, the compound 4b exhibited the highest percentage lysis value (41.32%) against clot formation in human blood among all newly synthesized compounds. In addition, the compound 4f was found to be the most potent against Escherichia coli with an inhibition value of 91.95%. The rest of the pyridine derivatives displayed moderate biological activities. Keywords: Suzuki cross-coupling reaction; pyridine derivatives; density functional theory (DFT); anti-thrombolytic; biofilm inhibition; haemolysis Molecules 2017, 22, 190; doi:10.3390/molecules22020190 www.mdpi.com/journal/molecules Molecules 2017, 22, 190 2 of 19 1. Introduction It is generally accepted that cross-coupling reactions catalyzed by transition metals offer facile systematicMolecules routes 2017, 22 for, 190 carbon-carbon bond formation when synthesizing a variety of organic compounds2 of 19 of interest [1]. Among the various transition metals, palladium (Pd) exhibits the highest activity for 1. Introduction C–C coupling reactions [2]. The Suzuki-Miyaura cross-coupling reaction provides an appropriate and practicalIt is generally approach accepted for the that synthesis cross-coupling of biaryl reac compounds,tions catalyzed due by totransition its ability metals to tolerateoffer facile a wide systematic routes for carbon-carbon bond formation when synthesizing a variety of organic compounds range of functional groups and good reaction yields [3]. In the past, pyridine and its derivatives have of interest [1]. Among the various transition metals, palladium (Pd) exhibits the highest activity for been used as starting precursors for several useful compounds due to their availability and stability C–C coupling reactions [2]. The Suzuki-Miyaura cross-coupling reaction provides an appropriate and for directpractical cross-coupling approach for the reactions synthesis [4 of–12 biaryl]. With compounds, this approach, due to its Liu ability and to co-workers tolerate a wide have range described of the Suzukifunctional cross-coupling groups and good reactions reaction yields between [3]. In 2-aryl-1,2,3-triazole- the past, pyridine andN its-oxides derivatives and have pyridine- been usedN-oxide withas good starting yield precursors of the for final several products useful [compound5]. Pyridines due compoundsto their availability have and a number stability for of direct biological activities,cross-coupling including reactions anti-tumor [4–12]. [ 13With,14 ],this anti-viral approach [, 15Liu–17 and], anti-microbialco-workers have [ 18described,19], anti-diabetic the Suzuki [20] anti-leishmanialcross-coupling [21 reactions] and anti-oxidant between 2-aryl-1,2,3-triazole- [22]. Recently, weN-oxides have reportedand pyridine- theN efficient-oxide with synthesis good of a seriesyield of 5-aryl-2-bromo-3-hexylthiophene-based of the final products [5]. Pyridine compounds compounds have a number and of a biological thorough activities, investigation including of their biologicalanti-tumor activities [13,14], [23 anti-viral]. The biological [15–17], anti-microbial importance of[18,19], heterocyclic anti-diabetic compounds [20] anti-leishmanial inspired us [21] to now and anti-oxidant [22]. Recently, we have reported the efficient synthesis of a series of 5-aryl-2-bromo-3- synthesize some pyridine derivatives and investigate their biological activities. In the present work, hexylthiophene-based compounds and a thorough investigation of their biological activities [23]. The we carried out the successful synthesis of a series of novel pyridine derivatives by making use of biological importance of heterocyclic compounds inspired us to now synthesize some pyridine Suzuki-Miyauraderivatives and cross-coupling investigate their reactions. biological Theseactivities. novel In the pyridine present derivativeswork, we carried were out further the successful explored by the computationalsynthesis of a series studies of novel using pyridine DFT methods derivative ands theirby making biological use of activities Suzuki-Miyaura were also cross-coupling examined in the coursereactions. of this study.These novel pyridine derivatives were further explored by the computational studies using DFT methods and their biological activities were also examined in the course of this study. 2. Results and Discussion 2. Results and Discussion 2.1. Synthesis 2.1. Synthesis Recently, we have reported the successful synthesis of 5-aryl-2-bromo-3-hexylthiophene derivativesRecently, by employing we have reported the Suzuki the successful cross-coupling synthesis of reaction5-aryl-2-bromo-3-hexylthiophene [23]. Ikram and co-workers derivatives have alsoby reported employing the the application Suzuki cross-coupling of double reaction Suzuki [23]. cross-coupling Ikram and co-workers reactions have for also the reported synthesis the of application of double Suzuki cross-coupling reactions for the synthesis of 2,5-biaryl-3-hexylthiophene 2,5-biaryl-3-hexylthiophene derivatives [24]. In the present work we have utilized the commercially derivatives [24]. In the present work we have utilized the commercially available 5-bromo-2- available 5-bromo-2-methylpyridin-3-amine (1), which was coupled with a series of arylboronic acids methylpyridin-3-amine (1), which was coupled with a series of arylboronic acids in the presence of in the presence of tetrakis(triphenylphosphine)palladium(0) as a catalyst and K PO as a base to tetrakis(triphenylphosphine)palladium(0) as a catalyst and K3PO4 as a base to produce3 a4 series of producenovel a series5-aryl-2-methylpyridin-3-amine of novel 5-aryl-2-methylpyridin-3-amine molecules 2a–2i (Scheme molecules 1, Figure2a– 1).2i (Scheme1, Figure1). SchemeScheme 1. Synthesis 1. Synthesis of compoundsof compounds2a 2a––2i2i,,3 3 andand 4a––4i4i; ;ReagentsReagents and and Conditions Conditions: (i) :1 (i) (0.21 (0.2g, 1.069 g, 1.069 mmol), mmol), Pd(PPhPd(PPh3)4 (53)4 mol (5 mol %), %), arylboronic arylboronic acid acid (1.1759 (1.1759 mmol),mmol), K K33POPO4 (2.3184 (2.318 mmol), mmol), 1,4-dioxane:water 1,4-dioxane:water (2:0.5 (2:0.5 mL), mL), 18 h18 reflux, h reflux, 90 90◦ C;°C; (ii)(ii) 11 (2.0(2.0 g, 12.7 g, 12.7 mmol), mmol), acetic anhydride acetic anhydride (1.95 g, 19.1 (1.95 mmol) g, in 19.1 acetonitrile mmol) (20 in mL); acetonitrile (iii) 3 (0.1 g, 1 mmol), Pd(PPh3)4 (5 mol %), arylboronic acid (1.1 mmol), K3PO4 (1.5 mmol), 1,4-dioxane:water (20 mL); (iii) 3 (0.1 g, 1 mmol), Pd(PPh3)4 (5 mol %), arylboronic acid (1.1 mmol), K3PO4 (1.5 mmol), (2:0.5 mL), 18 h reflux, 90 °C. 1,4-dioxane:water (2:0.5 mL), 18 h reflux, 90 ◦C. Molecules 2017, 22, 190 3 of 19 Molecules 2017, 22, 190 3 of 19 Figure 1. Structures of the newly synthesized pyridine derivatives viz. 2a–2i, 3, 4a–4i. Figure 1. Structures of the newly synthesized pyridine derivatives viz. 2a–2i, 3, 4a–4i. TheseThese Suzuki Suzuki cross-coupling cross-coupling reactions reactions were were carried carried out out in in a a solvent solvent mixture mixture ofof 1,4-dioxane1,4-dioxane and waterwater in the in volumethe volume ratio ratio of 4:1,of 4:1, respectively. respectively. As As expected, expected, the the desired desired pyridine pyridine derivativesderivatives were obtainedobtained in moderate in moderate to goodto good yields. yields. The The labile labile protons protons in in compounds compounds suchsuch asas carboxyliccarboxylic acids, acids, alcoholsalcohols and and primary primary amines amines make make them them aa poor choice choice for for Suzuki Suzuki coupling coupling reactions reactions [25].