SN Applied Sciences

, 1:1375 | Cite as

Potent pharmacophoric aminothiazole derivatives as FabH inhibitors for antibacterial activity: in vitro and in silico approach

  • Nadine Uwabagira
  • Balladka K. SarojiniEmail author
  • Madan K. Shankar
  • Ramesh S. Gani
Research Article
Part of the following topical collections:
  1. Chemistry: Advanced Materials: Synthesis, Characterization, Applications


The present work reports the design, synthesis, characterization and antibacterial screening of novel aminothiazole derivatives as FabH inhibitor [β-ketoacyl-ACP synthase (KAS)] which plays major role in bacterial cell wall construction. The compound 5d had crystallized in monoclinic, P21/c space group which was determined by single-crystal X-ray crystallography. In vitro antibacterial activity studies were carried out on S. aureus (MCC 2043), E. faecalis (MTCC 2729), E. coli MTCC443 and C. violaceus (MCC 2216). Most of the compounds showed potent inhibition activity against Gram-negative bacteria than Gram-positive bacteria. Compound 5a showed the highest zone of inhibition of 16 mm and MIC value of 5.33 μM which is comparable to that of the standard antibiotic, streptomycin. This result was ably complimented by in silico studies where compound 5a exhibited high affinity, strong binding energy and docking score of 6.214 kcal mol−1. The most potent compounds were nonhemolytic and nontoxic to mammalian cells.


Aminothiazole Single crystal The β-ketoacyl-ACP synthase (KAS) I Antibacterial activity Molecular docking Molecular dynamic simulations 

1 Introduction

Bacterial infections cause dangerous diseases and in many nations, a great number of mortality is seen especially in developing countries. These infectious diseases spread quickly and affect mostly the immunocompromised people, pregnant women, children, and older individuals [1]. Bacterial survival mostly depends on fatty acid biosynthesis. Three pathways are required for initiation of fatty acid biosynthesis; firstly β-ketoacyl-ACP synthase (KAS) III helps the condensation of acetyl-CoA and malonyl-CoA, secondly, there is a transfer of acetate moiety from acetyl-CoA to acetyl-ACP either by acetyl-CoA:ACP transacylase or β-ketoacyl-ACP synthase (KAS) III. Thirdly, there is a decarboxylation of malonyl-ACP by synthase I to form acetyl-ACP which will be condensed with malonyl-ACP by synthase I [2]. The β-ketoacyl-ACP synthase (KAS) I is the only condensing enzyme required for the initiation of fatty acid biosynthesis [3]. Initially, this protein was inhibited by antibiotics such as thiolactomycin and cerulenin in bacteria and plants but in Saccharomyces cerevisiae and mammals there is appearance of antibiotic resistance [4]. In contrast, cerulenin specifically inhibits condensing enzyme which is β-ketoacyl thioester synthetase whereas thiolactomycin is able to inhibit the type II fatty acid synthetase [5] but inactive to type I. Extensive studies confirmed that excessive production of β-ketoacyl-ACP synthase (KAS) I contribute to thiolactomycin resistance to E. coli [6]. As some antibiotics have limitation of developing resistance or losing their potency, further research in this direction can be undertaken for optimal drug development.

Thiazole and its derivatives are known as active pharmaceutical ingredients in several drugs for their potential as anti-inflammatory [7, 8] anti-HIV, antiproliferative [9, 10], antibacterial and antifungal activity [11, 12]. Furthermore, extensive research has been carried out on thiazole scaffolds for their anticancer [13] antimicrobial [14], antiallergy [15] and as central dopamine agonist agents [16]. The most prominent role played by thiazole compounds in general is found to be against multi-drug resistant tumor [17] and in the treatment of type-2 diabetes [18].

There are many factors for bacteria to survive; among those factors fatty acid biosynthesis is essential as it is required for cell viability and growth [19]. Initiating fatty acid elongation cycles [20, 21] and involving in the feedback regulation of the biosynthetic pathway via product inhibition [22], make it a promising target for the design of novel antibacterial drugs.

In view of the above mentioned findings, in the present work, we report the design, synthesis, characterization and antibacterial activity of new series of aminothiazole derivatives against E. coli fatty acid biosynthesis (FabH). In vitro antibacterial activities were carried out on S. aureus (MCC 2043), E. faecalis (MTCC 2729), C. violaceus (MCC 2216) and E. coli (MTCC443). In addition, docking simulations were performed to position all synthesized compounds into the E. coli FabH active site to determine the probable binding conformation. The ten novel synthesized compounds were well characterized by 1H NMR, 13C NMR, FTIR, LCMS data and elemental analysis. The results of such studies are presented in this paper.

2 Results and discussion

2.1 Chemistry

The synthesis of new series of compounds is outlined in Scheme 1. The key intermediate, substituted phenylthiourea 2 was obtained from the reaction of ammonium thiocyanate on substituted aniline derivative 1 in concentrated HCl under reflux condition [23]. The substituted 4-phenacylbromides 4 were prepared by bromination of respective acetophenones 3 in chloroform solvent [24]. The new series of substituted phenyl thiazol-2-amine 5aj was synthesized by refluxing a mixture of substituted phenylthiourea derivatives 2 and 4-substituted phenacylbromides 4 in ethanol in the absence of any catalyst. The formation of the title compounds 5aj was confirmed by their analytical and spectral data.
Scheme 1

Synthesis of the title compounds (5aj)

The spectral details of representative compound 5a are as follows: in the IR spectrum of 5a, an absorption band found at 3126 cm−1 was attributed to NH stretch. The absorption bands seen at 1494 cm−1 and 1616 cm−1 were due to the stretching frequency of –C=N– and –C=C– respectively. The presence of nitro group in the product was evidenced by two prominent absorption bands appearing at 1552 cm−1 and 1319 cm−1 for the antisymmetric and symmetric stretching frequencies of NO2 group. Likewise, an absorption band appeared at 725 cm−1 proved the presence of –C–Cl stretching. On recording 1H NMR spectrum, the formation of thiazole amine derivative 5a was supported by the presence of respective signals for the protons present in the molecule. A singlet seen at δ (ppm) 7.44 could be accounted for the thiazole ring proton. The two sets of ortho and meta protons of 4-nitro phenyl ring were seen as doublets centered at 8.25 (J = 8 Hz) and 8.12 (J = 8 Hz) respectively. A doublet appeared at δ (ppm) 7.66 (J = 2.6 Hz) and 7.62 (J = 2.7 Hz) was accounted for one of ortho and meta protons of 3,4-dichlorophenyl ring respectively, and two singlets found at δ (ppm) 7.47 and δ (ppm) 8.17 were assigned to another ortho proton of 3,4-dichlorophenyl ring and thiazole proton respectively. The exocyclic NH proton appeared at δ (ppm) 10.58 as a singlet. This data confirmed the formation of the title compound 5a.

Furthermore, it was supported by recording 13C NMR spectrum. The signals appeared in the spectrum could be assigned to the exact number of carbon atoms including magnetically equivalent ones. Molecular mass of 5a was determined by LCMS and was found to be 366.00 (M+H)+.

Similarly, the structure of all the synthesized molecules was determined by spectroscopic characterization and is given in experimental section.

2.2 Single crystal X-ray crystallography of the compound 5d

In order to determine the three dimensional structure of the title compounds, they were subjected to crystal growth by slow evaporation technique in suitable solvent. However, only the compound 5d was crystallized in a defractable form and the details of the crystal structure and data refinement are given in Table 1.
Table 1

Crystal data and structure refinement details for compound 5d



Empirical formula


Formula weight


Temperature (K)


Wavelength (Kα, Å)


Crystal system, space group



Unit cell dimensions (Å, °)

a = 14.0755(10)

b = 8.5068(3)

c = 15.4086(10)

β = 108.390(7)

Volume Å3



Calculated density (Mg m−3)



Absorption coefficient (mm−1)


F (000)


Crystal size (mm)

0.210 × 0.230 × 0.25

Theta range for data collection (°)

2.7 to 50.0

Limiting indices

− 16 ≤ h ≤ 16, − 10 ≤ k ≤ 10, − 18 ≤ l ≤ 18

Reflections collected/unique[R(int)]

17,243/3087 [0.042]

Refinement method

Full-matrix least-squares on F2



R value


Goodness-of-fit on F2


Largest diff. peak and hole (e. Å−3)

0.30 and −0.26

Molecular structure of the compound 5d, showing the atomic numbering system. Displacement ellipsoids are drawn at the 50% probability. Dotted lines indicate intermolecular hydrogen bonds. The 5d molecule crystallized in monoclinic crystal system (space group P21/c) with unit cell parameters a = 14.0755(10), b = 8.5068(3), c = 15.4086(10), β = 108.390(7), volume = 1750.77(19) Å3 and Z = 4. The ORTEP of 5d is shown in Fig. 1. The thiazole ring (Cg1: S1/C9/N1/C11/C10) makes a dihedral angle of 72.65(14)° and 25.47(14)° with methyl phenyl ring (Cg2:C1–C6) and chlorophenyl ring (Cg3:C12–C17), respectively. The dihedral angle between Cg2 and Cg3 is 82.24(14)°. Intramolecular hydrogen bonds N1–H1…Br1 and N2–H2…Br2 were observed. As one of the products in condensation was HBr (Scheme 1), the nitrogen of thiazole ring in compound 5d, got protonated converting to quaternary nitrogen and the Br existed as counter ion which is evident from Fig. 1.
Fig. 1

The ORTEP of compound 5d

In the crystal structure (Table 2 and Fig. 2), the molecules are stabilized through intermolecular interactions of the type C15–Cl1…Cg1, Cg2…Cg2 (3.77(17) Å, slippage 1.301, symmetry = − x, 1 − y, − z) and Cg3…Cg3 [(3.72(17) Å, slippage 1.283, symmetry = 1 − x, 1 − y, 1 − z).
Table 2

Intermolecular and intramolecular interactions



H/X…A/Cg Å

D…A/Cg Å

D–H/X…A/Cg (°)



















1 − X, 1 − Y, 1 − Z

Fig. 2

Packing of the compounds: a view along c-axis

3 Biological evaluations

3.1 Antibacterial studies

All the tested compounds exhibited moderate activity against the four strains taken for evaluation (Fig. 3). Among tested compounds 5a, 5b, 5c, 5d, 5e and 5i have inhibited E. coli (MTCC443) effectively than other bacterial strains. The compounds 5a, 5e, 5f and 5i were found to be active against C. violaceum (MCC 2216) whereas 5a, 5e, 5g and 5h were effective against E. faecalis (MTCC 2729). The nitro and halo substitutions on either side of the phenyl rings affected the bactericidal property of the tested thiazole derivatives. But none of the title compounds were potent enough to arrest the growth of S. aureus (MCC 2043).
Fig. 3

Antibacterial activity by zone of inhibition (mm)

The compounds which exhibited notable zone of inhibition for the microbes were taken for the determination of MIC along with the standard streptomycin (Fig. 4). Among the active ones, the compound 5a emerged as most potent one against all the tested strains with MIC of 5.33 µM which is comparable to standard drug (streptomycin).
Fig. 4

Minimal inhibition concentration (MIC) in µM

3.2 Fatty acids inhibition activity

In the positive standard which is E. coli MTCC443, assays were conducted to estimate different fatty acids levels and after the study, the fatty acid levels were found to be considerably low in the tested samples incubated along with E. coli. For saturated fatty acids, palmitic and stearic acids percentage for 5a, 5b, 5c and 5e were (1.862, 1.592); (1.446, 1.740); (2.322, 1.679) and (3.504, 2.486) respectively and the control (bacterial culture) was having three times greater the amount of fatty acid and was (3.634, 4.554). For monounsaturated fatty acids, only palmitoleic acid was 1.676, 1.502, 0.891 and 0.377% for 5a, 5b, 5c and 5e while the positive control was 2.158%.

However, (ω-3) polyunsaturated fatty acids were not detected in the positive control and the samples treated with test compounds as well. Besides, (ω-6) polyunsaturated fatty acids (PUFA) were present and the percentage was almost zero indicating complete inhibition. For ω-6 PUFA (Linoleic acids) percentage of inhibition for 5a, 5b, 5c and 5e was 0.512, 0.614, 2.779 and 0.635% respectively and 7.121% for the control. The ω-6 PUFA (Arachidonic acids) percentage for 5a, 5b, 5c and 5e was 0.512, 0.604, 0.601 and 0.361% respectively and 5.251% for the control. The other fatty acids such as oleic, myristoleic, alpha linoleic, eicosapentaenoic, docosapentaenoic, docosahexaenoic, gamma linoleic and dihomo gamma linoleic acids were not found in the tested samples treated with the test samples. Among the tested compounds, compound 5a emerged as most potent one. The (Fig. 5) shows the results of E. coli fatty acid content after treating with the tested compounds. This result probably shows the ability of the tested compounds in reducing the bacterial (E. coli) fatty acid content.
Fig. 5

E. coli fatty acid content (%)

3.3 Hemolysis assay

The tested compounds were effective in inhibiting essential fatty acids in the microbial cell. It is assumed that similar array of fatty acids are also present in the human cells. So the evaluation of toxicity to human cells by the tested compounds was carried out by haemolysis assay. The percentage of haemolysis ranged between 0.88 and 12.27. The human blood toxicity activity of the tested compounds at minimum tested concentration of 12.5 µg mL−1 is in ascending order was as follows: 5a < 5c < 5b < 5e < 5j. The maximum concentration of 100 µg mL−1 could do lysis only up to 12.27% for compound 5j. The hemolysis assay showed that all tested compounds were less toxic on human blood especially the compound 5a and 5b. All the tested compounds were found to possess minimum toxicity towards human blood cells as it was evidenced by the value given in Table 3 and Fig. 6.
Table 3

Percentage of hemolysis

Sample code

Sample concentration (µg mL−1)

Sample  % haemolysis





























































The least concentration and hemolysis % are in bold to show how the compound concentration is directly proportional to the % of hemolytic activity

Fig. 6

Hemolysis essay results

The Fig. 6 showed how the tested compounds are less toxic on human blood even at higher concentration (100 µg mL−1), the toxicity is less. Except the compound 5j, the toxicity of the rest tested compounds is nearly indirectly proportional to the concentration of the sample and could be tolerable (5b, 5a, 5c and 5e respectively).

3.4 Molecular docking studies

The E. coli FabH (PDB ID: 5BNR) protein was docked into the active site of the model structure of FabH using Schrödinger Software, the ligands were prepared by ligprep, protein was prepared by protein preparation wizards, the Glide was generated by receptor grid generation for bioactive conformation searching then docking was done by extra precision (XP). The root mean square deviation (RMSD) was found to be 0.2949 which is reasonable as generally it should be less than 2. The binding models as well as the ligand interaction diagrams of the potent compounds and E. coli FabH are depicted in the figures below.

Interaction of 5a:

The E. coli FabH amino acids formed two strong hydrogen bonds (Asn274 with distance between the bond of 2.78 Å, angle of 112.7) and Cys112 with distance between the bond of 2.19 Å, angle of 158.2 Å) and two halogen bonds (Asn210 with distance of 2.85 Å, angle of 127.3 Å and dihedral of 39.6 Å), (Arg36 with distance of 2.52, angle of 127.2 Å, dihedral of 113.3 Å) with the compound 5a (Fig. 7).
Fig. 7

Docking poses of the compound 5a with E. coli FabH (PDB Id-5BNR)

Interaction of 5b:

The E. coli FabH amino acids formed two strong hydrogen bonds (Asn274 with distance of 2.28, angle of 112.4 Å), Cys112 with distance of 2.23 Å, angle of 99.3 Å), one π–cation with Arg249 with distance of 4.68 Å, angle of 66.4 Å, dihedral of 159.3) and one aromatic hydrogen with Gly209 with distance of 2.46 Å, angle of 121.9 Å and dihedral of 49 Å (Fig. 8).
Fig. 8

Docking pose of the compound 5b with E. coli FabH (PDB Id-5BNR)

The interaction of 5c:

The E. coli FabH amino acids formed five bonds: One π–cation with (Met1 with distance between the bond of 2.2 Å, angle of 94.2, and dihedral of 53.6), three aromatic hydrogen bonds: (Asp123 with distance between the bond of 2.74 Å, angle of 109.7 Å and dihedral of 158.7 Å), Ile174 with distance of 2.46 Å, angle of 92.3 Å, dihedral of 121.6 Å) and (Met1 with distance of 0.82 Å, angle of 125.3 Å, dihedral of 179.1 Å) and one halogen bonds with Lys127 with distance between the bond of 1.63 Å, angle of 143.5 Å and dihedral of 30.4 Å) (Fig. 9).
Fig. 9

Docking pose of the compound 5c with E. coli FabH (PDB Id-5BNR)

The interaction of 5e

The E. coli FabH amino acids formed one strong hydrogen bonds (Ser169 with distance between the bonds was 2. 17 Å, angle of 116.3 Å), two aromatic hydrogen bonds with Asp123 with distance between the bond was 2.72 Å, angle of 136.1 Å) and (Ile175 with distance between the bond of 2.21 Å, angle of 104.5 Å). Two halogen bonds with (Ile175 with distance of 3.27 Å, angle of 156.6 Å, dihedral of 24.9 Å) and (Lys127 with distance of 2.86 Å, angle of 116.0 Å, dihedral of 40.9 Å) (Fig. 10). The Table 4 showed Bonds, hydrophobic interactions and D-scores of the synthesized compounds.
Fig. 10

Docking pose of the compound 5e with E. coli FabH (PDB Id-5BNR)

Table 4

Bonds, hydrophobic interactions and D-scores of the synthesized compounds




π–π or π–cation bonds

Aromatic, Halogen bonds

Hydrophobic interactions

D-score (kcal mol−1)


Open image in new window

Cys112, Asn247


Arg36, Asn210

Ile156, 250, Ala221,216, Phe304, 392, Val217, 304

− 6.214


Open image in new window

Asn274, Cys112



Ile250, Ala246, 208, Phe213, 304, Met207, Val212, Gly152, 209, Leu248, Trp32

− 5.774


Open image in new window



Ile174, Asp123, Lys127, Met1

Ile174, Ala167, 168, Met1

− 5.838


Open image in new window




Ile155, 156, 250, Phe157, Phe213, 304, Trp32, Ala143, Met207, Leu142

− 6.648


Open image in new window



Ile175, Asp123, Lys127

Ile5, 174, Met1, Pro172, Gly173

− 5.862


Open image in new window



Cys112, Gly209

Val212, 215, Phe157, Phe213, 304, Gly209, Ile155, 156, Val215, 217, Ala216

− 6.455


Open image in new window



Gly209, Cys112

Trp32, Phe157,213, 304, 308, Gly209, 305, Ile156, Ala216, Val212, 215

− 6.413


Open image in new window

Ala246, Asn247

Arg249, His244

Arg36, Gly209

Trp32, 304, 310, Phe157, 213, Val215, 217, Gly152, Gly305, Ala216, Ile156, 250

− 6.226


Open image in new window




Gly305, Ala216, Phe157, 213, 304, Val212, 215, 217, Trp32, Ile155, 156

− 6.407


Open image in new window

Ala246, Arg36



Ile155, 250, Phe157, 213, 304, Gly152, Leu142, Trp32

− 6.642

D-score is in bold to emphasize the binding affinity of the ligand and the protein

3.5 Molecular dynamic simulations of the compound 5a

While docking, protein flexibility was not considered, in that occasion, molecular dynamic simulations were done with the Desmond program to confirm the mode of ligand binding as well as the stability of protein–ligand complex. The compound 5a was showing the promising results and so was taken for molecular dynamic simulations (Figs. 11, 12, 13).
Fig. 11

Protein information

Fig. 12

Ligand information

Fig. 13

Protein–ligand RMSD

(RMSD) stands for the root mean square deviation and is the measurement of the atoms displaced and the last is directly proportional to the reference time.

The RMSD for frame x is:
$$RMSD_{x} = \sqrt {\frac{1}{N}\sum\limits_{i = 1}^{N} {(r_{i}^{\prime } (t_{x} )) - (r_{i} (t_{ref} ))^{2} } }$$

N, the number of selected atoms; tref, the reference time (first frame, t = 0); r′ = the position of selected atom in the frame x which is recorded at time tx.

Protein RMSD

found on the left Y-axis, RMSD is calculated on the basis of selected atom and its analysis gives the structural conformation.

Ligand RMSD

found on right-Y-axis and showed the ligand stability.

The root mean square fluctuation (RMSF) characterizing local change with the protein chain showing the flexibility of each residue.

The RMSF for residue i is:
$$RMSF_{i} = \sqrt {\frac{1}{T}\sum\limits_{t = 1}^{T} {\left\langle {(r_{i}^{\prime } (t)) - (r_{i} (t_{ref} ))^{2} } \right\rangle } }$$

Here, T is the trajectory time over which the RMSF is calculated, tref is the reference time; r′ is the position of the atom i at time t after superposition on the reference frame.

Throughout this simulation, the protein secondary structure elements (SSE) were checked. Alpha-helices (red colour) and beta-strands (blue colour) are observed. Each and every trajectory frame of SSE is summarized in the Fig. 14. The plot below explains deeply the residues index distribution in the structure of the protein Fig. 15.
Fig. 14

Protein RMSF

Fig. 15

Protein secondary structure

The Ligand Root Mean Square Fluctuation (L-RMSF) is useful for characterizing local change with the ligand chain showing the flexibility of each residue (Figs. 16, 17, 18).
Fig. 16

The residues index distribution in the structure of the protein

Fig. 17

Ligand RMSF

Fig. 18

The ligand fluctuations

The RMSF for atom i is:
$$RMSF_{i} = \sqrt {\frac{1}{T}\sum\limits_{t = 1}^{T} {(r_{i}^{\prime } (t)) - (r_{i} (t_{ref} ))^{2} } }$$

Here, t is the trajectory time over which the RMSF is calculated, tref is the reference time; r′ is the position of the atom i at time t after superposition on the reference frame.

The ligand RMSF gives the intuitions on how the ligand and protein interact as well as their entropic role and binding event. In the Fig. 19, with respect to the protein, the ligand fluctuations are shown in the ‘Fit Ligand on the Protein line.
Fig. 19

Protein–ligand contacts

Protein–ligand interactions were checked throughout the simulation and were having four categories such as hydrogen bonds, hydrophobic, ionic and water bridges. Simulation Interaction Diagram’ panel below showed interactions fractions over the course of the trajectory, for example, a value of 0.7 suggests that 70% of the simulation time and the specific interaction was maintained (Figs. 20, 21).
Fig. 20

Protein–ligand contacts (cont.)

Hydrogen bonds

complex stability is the must and this is provided by hydrogen bonds. The affinity of the ligand on the protein is shown by hydrogen bonds. However, hydrogen-binding property is very important in drug design because of its specificity in drug metabolization and adsorption.

Hydrophobic contacts

these complain π–cation, π–π, and other no specific interactions.

Ionic interactions

these characterize between two oppositely charged atoms.

Water bridges

are hydrogen-bonded protein–ligand interactions mediated by a water molecule.

Fig. 21

The Figure 21 clearly showed that the contact is maintained and is showed by a darker shade of orange colour. From the figure above, we can detect more than 6 specific contacts which are Phe392, Val304, Met204, Phe201, Ala162 and Gly106

The Fig. 22 showed ligand–protein contact and indicated more than 30% of interactions meaning that the amino acid residues can H-bond with H-bond acceptor of the ligand. This trajectory was done through 50 nsec (Figs. 23, 24).
Fig. 22

Ligand–protein contact

Fig. 23

The figure 23 shows the rotatable bond in the ligand, on left Y-axis is the potential expressed in Kcal/mol and the torsion potential relationship gives awareness into the conformational strain the ligand is undergoing to keep a protein- bond conformation

Fig. 24

Ligand properties

Ligand RMSD

Here, we see the Root mean square deviation of the ligand with respect to the reference conformation.

Radius of gyration (rGyr)

it helps in exhibition of conformational stability and the smaller the value of the radius of gyration, the better folding of the molecule. This stability is maintained by the constancy of the said radius.

Intramolecular hydrogen bonds (intraHB)

Number of internal hydrogen bonds (HB) within a ligand molecule, here they were not detected.

Molecular surface area (MolSA)

Molecular surface calculation with 1.4 Å probe radius which is value of equivalent to a van der Waals surface.

Solvent accessible surface area (SASA)

Surface area of a molecule accessible by a water molecule.

Polar surface area (PSA)

Solvent accessible surface area in a molecule contributed only by oxygen and nitrogen atoms.

Generally, Cys–Hie–Asn triad tunnel is the catalytic active site of FabH. Since this triad is conserved in bacteria and plays a significant role in chain elongation regulation and substrate binding, any interaction between the said triad and substrate revealed an important role in substrate-binding [25]. The potency of the compounds is explained by their interactions with Cys112, Hie244 or Asn247 residues of the proteins FabH. Studies on E. coli FabH confirmed that Hie244 and Asn247 are required for decarboxylation and Cys112 is essential in transacylation [26]. Thiolactomycin has shown its efficacy to inhibit fatty acid synthase system but not acetyl-CoA carboxylase. Since some of our compounds were having interactions with Hie244 or Asn247; this might explain their potency on acetyl-CoA carboxylase as they were required in decarboxylation of the mentioned protein. In addition to this, all the synthesized compounds had many good interactions with hydrophobic amino acids. The docking results with the synthesized compounds revealed that they fit well into the binding-site, display favourable interactions with the crucial amino acid residues of E. coli FabH and suggest good affinity for the enzyme. However, the potency of the compound 5a was mentioned in E. coli by reducing the content of fatty acids. This is a serious issue since E. coli is known to cause idiopathic epilepsy by its capability of penetrating blood–brain–barrier (BBB). E. coli β-ketoacyl-ACP synthase (KAS) I which contributes to thiolactomycin resistance in E. coli was inhibited as shown by in silico results. This enzyme is essential for bacterial survival as it is involved in fatty acid biosynthesis. The in vitro results showed that compounds are effectively inhibiting all the essential fatty acids required for bacterial cell wall construction since they can completely inhibit the function of arachidonic acids.

The synthesized compounds can be divided by two rings: ring A and ring B, each ring possesses at least either halogen atom or nitro group. Compound 5a has two chlorine atoms on ring A and one nitro group on ring B, having interactions with Asn274 and Cys112, makes it promising antibacterial drugs as shown by in vitro and in silico studies on E. coli FabH. This is clearly explained by its in vitro antibacterial capacity. Compound 5b has nitro group on ring A, fluorine atom on the ring B and, it showed interaction with Asn274 and Cys112. As the compounds 5a and 5b showed the interaction with Cys112 and Asn247 which were two amino acids of the said triad, their ability in inhibition could be confirmed by the fatty acid inhibition results. However, all the synthesized compounds have many hydrophobic interactions with the mentioned protein. Hydrophobic interactions make a large contribution to the stability of the protein structure. Having hydrophobic interactions can alter the protein stability as well as activity. In general, all the synthesized compounds have minimal activity on the rest of tested microorganisms.

4 Conclusions

New aminothiazole derivatives were well designed synthesized and screened for their antibacterial activities. Their structure was assigned by analytical and spectroscopic techniques such as NMR, FT-IR and LCMS. The structure of the compound 5d was supported by single crystal XRD results. The ten novel synthesized thiazole derivatives showed promising potency against the tested bacterial microorganisms. The compounds (5a, 5b, 5c, 5d, 5e and 5i) were potent against E. coli (MTCC 443), while compounds (5a, 5e, 5f and 5i) showed promising potency against C. violaceum MCC 2216. Compounds 5a, 5e, 5g and 5h showed potent activity against E. faecalis MTCC 2729. The potency of the mentioned compounds against E. coli (MTCC 443) was confirmed by in silico studies against E. coli FabH (PDB ID-5BNR). However none of tested compounds were potent enough to inhibit the growth of S. Aureus (MCC 2043). Among all tested compounds, the compound 5a was the most potent one against all tested strains with MIC of 5.33 µM which was comparable with standard streptomycin. Molecular docking results of the title compounds showed many interactions of them with the E. coli β-ketoacyl-ACP synthase (KAS) I which contributes to thiolactomycin resistance in E. coli. This enzyme is essential for bacterial survival as it is involved in fatty acid biosynthesis. The in vitro fatty acids inhibition results showed that compounds are effectively inhibiting all the essential fatty acids required for bacterial cell wall construction since they can completely inhibit the function of arachidonic acids. It is well understood that E. coli even penetrates blood–brain barrier [27], hence its capacity of generating idiopathic epilepsy [28]. In silico results complemented in vitro study results. All the tested compounds were found to possess minimum toxicity towards human blood cells. Molecular dynamic simulations done for the compound 5a emphasized the affinity as well as the stability of the ligand with the protein during contact.

5 Experimental sections

All required reagents were used as received from suppliers without further purification. The melting point was measured in open capillary tube and correction is not applied. The IR-spectrum was recorded on Shimadzu FT-IR Prestige-21 spectrophotometer in ATR mode and is expressed in cm−1. The mass spectrum was obtained using Shimadzu LC MS-8030 mass spectrometer operating at 70 eV. The 1H NMR and 13C NMR spectra were recorded on a Bruker AVANCE II 400 MHz instrument in CDCl3/DMSO-d6 solvent and TMS as an internal standard. The purity of the compound and completion of the reaction were monitored by TLC using Merck silica gel 60 F256 coated Aluminum with petroleum ether: ethyl acetate (8:2) as mobile phase. Elemental analysis was carried out.

5.1 General procedure for the synthesis of title compounds 5a–j

Equimolar amounts of substituted phenylthioureas 2 (0.01 M) and 4-substituted phenacylbromides 4 (0.01 M) in 30 mL ethanol was heated under reflux for 24 h. The TLC (ethyl acetate/petroleum ether, 8:2) was used to confirm the completion of the reaction. After cooling, separated solid was filtered, dried and recrystallized from ethanol to yield compounds 5aj. The spectral data confirming the identity of the synthesized compounds are given below.

5.1.1 N-(3,4-Dichlorophenyl)-4-(4-nitrophenyl)thiazol-2-amine (5a)

Orange solid, MP: 180–182 °C; Yield: 65%. IR (KBr, νcm−1): 3126 (NH stretch), 3047 (C–H stretch), 1616 (C=C), 1552 (N–O asym stretch), 1494 (C=N), 1319 (N–O sym. stretch), 725 (C–Cl).1HNMR (400 MHz, DMSO-d6): δ (ppm) 7.62–7.65 (d, J = 8 Hz, ortho protons of 4-NO2-phenyl); 8.24–8.26(d, J = 8 Hz, meta protons of 4-NO2-phenyl), 8.11–8.13 (d, J = 8 Hz, ortho proton of 3,4-dichlorophenyl), 8.17 (s, ortho proton of 3,4-dichlorophenyl ring), 7.47 (s, thiazole proton), and the exocyclic NH proton appeared at δ (ppm) 10.58 as a singlet. 13CNMR (100 MHz, DMSO-d6, δ ppm):162.7, 148.1, 146.2, 140.6, 131.3, 130.2, 126.2, 123.7, 122.6, 118.0, 116.7 and 107.8). Elemental analysis: Anal. Calcd.C, 49.20; H, 2.48; N, 11.47. Found: C, 49.25; H, 2.46; N, 11.48; LCMS: (m/z): C15H8N3Cl2O2S: 366.00 (M+H)+, 368.00 (M+H+2)+, 370.00 (M+H+4)+.

5.1.2 4-(4-Fluorophenyl)-N-(4-nitrophenyl) thiazol-2-amine (5b)

Orange solid, MP: 180–182 °C; Yield: 65%. IR (KBr, νcm−1): 3130 (NH stretch), 3045 (C–H stretch), 1094(C=N), 1616 (C=C), 1554 (N–O asym stretch), 1319 (N–O sym stretch), 1056 (C–F). 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 7.12–7.14 [2H, d, (J = 8 Hz), ortho protons of 4-nitrophenyl]; 8.17–8.19 [(2H, d (J = 8 Hz) meta protons of 4-nitrophenyl]; 7.90–7.93 [2H, dd (J = 12 Hz, J = 4 Hz) (HF ortho) meta protons 4-fluorophenyl], 7.93–7.95 [2H, dd [J = 8 Hz, J = 4 Hz) (HF meta) 4-fluorophenyl ring],and the exocyclic NH proton appeared at δ (ppm) 10.94 as a singlet. 13CNMR (100 MHz, DMSO-d6, δ ppm): 161.8, 151.4, 149.7, 146.9, 140.3, 127.7, 125.6, 116.1, 115.4 and 114.1. Elemental analysis: Calcd.C, 57.14; H, 3.20; N, 13.33. Found: C, 57.15; H, 3.19; N, 13.34.). LCMS: (m/z): C15H10N3FO2S: 356.05 (M+H)+.

5.1.3 4-(4-Chlorophenyl)-N-(3,4-dichlorophenyl)thiazol-2-amine (5c)

Lemon yellow solid, MP: 118–120 °C; Yield: 65%. IR (KBr, νcm−1): 3178 (NH stretch), 3039 (C–H stretch), 1632 (C=N), 725 (C–Cl). 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 7.26 (thiazole), 7.88–7.90 (d, 2H, J = 8 Hz, ortho protons of -4-chlorophenyl ring); 7.43–7.40(d, 2H, J = 12 Hz, metaprotons of 4-chlorophenyl ring), 8.09–8.10 (d, 1H, J = 4 Hz, ortho proton of 3,4-dichlorophenyl ring), 7.45 (s, ortho proton of 3,4-dichlorophenyl ring), 7.60–7.63 [dd, (J = 12 Hz, J = 4 Hz, (meta proton of 3,4-dichlorophenyl ring)], and the exocyclic NH proton appeared at δ (ppm) 10.45 as a singlet. 13CNMR (100 MHz, DMSO-d6, δ ppm):162.4, 148.9, 140.8, 133.0, 132.2, 131.3, 130.2, 128.4, 127.0, 122.3, 117.9, 116.6 and 103.9. Elemental analysis: Calcd: Anal. Calcd.C, 49.20; H, 2.48; N, 11.47. Found: C, 49.21; H, 2.47; N, 11.48. LCMS: (m/z): C15H9N2Cl3S: 355.85 (M+H)+, 357.85 (M+H+2)+, 359.85 (M+H+4)+, 361.85 (M+H+6)+.

5.1.4 N-(2,6-Dimethylphenyl)-4-(4-chlorophenyl) thiazol-2-amine (5d)

Greyish white solid, MP: 220–222 °C; Yield: 65%. IR (KBr, νcm−1): 3143 (NH stretch), 3043 (Ar–H stretch), 2929 (C–H alkyl stretch), 1573 (C=C), 1184 (C=N), 729 (C–Cl). 1HNMR (400 MHz, DMSO-d6): δ (ppm) 6.63 (Ar–H-thiazole), 7.66–7.68 (d, 2H, J = 8 Hz, ortho protons of 4-chlorophenyl); 7.25–7.28 (d, 2H, J = 8.8 Hz, meta protons of 4-chlorophenyl ring), 7.20–7.21 (d, 2H, J = 4 Hz, meta proton of 2,6-methylphenyl ring), 7.19–7.20 (d, 1H, J = 4 Hz, 1H, meta proton of 2,6-dimethylphenyl ring), 7.17–7.16 (d, Ar–H, J = 4 Hz; para proton of 2,6-dimethylphenyl ring), 2.32 (s, 6H, alkyl.13CNMR (100 MHz, DMSO-d6, δ ppm): 168.4, 149.1, 137.7, 135.9, 133.4, 131.8, 128.2, 127.0, 126.7, 101.8 and 17.9. Elemental analysis: Anal. Calcd.C, 64.86; H, 4.80; N, 8.90. Found: C, 64.85; H, 4.81; N, 8.89. LCMC: (m/z):C17H15N2ClS:315.00 (M+H)+, 317.00 (M+H+2)+.

5.1.5 N-(3-Chloro-2-methylphenyl)-4-(4-nitrophenyl)thiazol-2-amine (5e)

Yellow solid, MP: 180–182 °C; Yield: 65%. IR (KBr, νcm−1): 3130 (NH stretch), 3039 (Ar–H stretch), 2860 (C–H alkyl stretch),1618 (C=C), 1554 (N–O asym stretch), 1494 (C=N), 1319 (N–O sym stretch),725 (C–Cl).1H-NMR (400 MHz, DMSO-d6): δ (ppm) 9.61 (s, N–H), 7.59 (s, 1H thiazole), 8.08–8.10 [d, (J = 8 Hz, ortho protons of 4-nitrophenyl ring)]; 8.21–8.23 [(d, (J = 8 Hz) meta protons of 4-nitrophenyl ring]; 8.25 [s, para proton of 2-methyl-3-chlorophenyl ring), 7.94–7.96 (d, J = 8 Hz, ortho proton of 2-methyl-3-chlorophenylring), 7.17–7.23 (dd, J = 24 Hz, J = 8 Hz, meta proton of 2-methyl-3-chlorophenyl ring). 13CNMR (100 MHz, DMSO-d6, δ ppm): 165.5, 147.8, 146.1, 140.5, 134.1, 127.2, 126.8, 124.1, 123.7, 120.0, 107.6 and 14.8. Elemental analysis: Anal. Calcd. C, 55.57; H, 3.50; N, 12.15. Found: C, 55.58; H, 3.48; N, 12.14. LCMS: (m/z): C16H12N3ClO2S: 346.00 (M+H)+, 348.00 (M+H+2)+.

5.1.6 N-(3-Chloro-2-methylphenyl)-4-(4-chlorophenyl)thiazol-2-amine (5f)

White solid, MP: 200–202 °C; Yield: 65%. IR (KBr, νcm−1): 3130 (NH stretch), 3039 (Ar–H stretch), 2926(C–H alkyl stretch), 1494 (C=N), 1618 (C=C), 1056 (C–F). 1H-NMR (400 MHz, DMSO-d6): δ (ppm), 7.93–7.95 [dd, (J = 16 Hz, J = 8 Hz, H–Cl ortho) meta protons of 4-chlorophenyl ring)]; 7.84–7.85 [(d, (J = 4 Hz, H–Cl meta) ortho protons of 4-chlorophenyl ring]; 7.82–7.83 (d, (J = 4 Hz, ortho proton), 7.13 (s, thiazol proton. 7.43–7.45 (d, J = 8 Hz, meta proton of 2-methyl-3-chlorophenyl ring), 7.34–7.36 (d, J = 8 Hz, ortho proton of 2-methyl-3-chlorophenyl ring), 2.35 (s, 3H, 4-chlorophenyl ring) and the exocyclic NH proton appeared at δ (ppm) 9.45 as a singlet.13CNMR (100 MHz, DMSO-d6, δ ppm): 166.1, 164.0, 146.1, 140.3, 134.4, 130.0, 129.9, 127.7, 126.9, 124.8, 120.7, 115.3, 114.8, 102.7 and 14.9. Elemental analysis:Anal. Calcd.C, 60.28; H, 3.79; N, 8.79. Found: C, 60.26; H, 3.80; N, 8.78. LCMS: (m/z):C16H12N2ClFS: 319.00(M+H)+, 321.00 (M+H+2)+.

5.1.7 N-(3-Chloro-2-methylphenyl)-4-(4-methoxyphenyl)thiazol-2-amine(5g)

Off white solid, MP: 208–210 °C; Yield: 65%. IR (KBr, νcm−1): 3053(NH stretch), 3053 (Ar–H), 2966 (C–H-alkyl), 1562 (C=C), 1506(C=N), 1055 (C–O stretch), 732 (C–Cl). 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 11.32 (s, N–H), 7.42–7.44(Ar–H, d, J = 8 Hz, protons of 2-methyl3-chlorophenyl)]; 7.33–7.35 (d, J = 8 Hz) protons of 2-methyl-3-chlorophenyl ring]; 7.23–7.25 [d, (J = 8 Hz) protons of 4-methoxyphenyl ring], 7.00–7.02 [d, J = 8 Hz], 4-meta protons of methoxyphenyl ring, 7.74–7.72 (2H, d, ortho 4-methoxyphenyl ring), 3.8 (s, 3H of alkyl methoxy), 2.5 (3H, s, alkyl).13CNMR (100 MHz, DMSO-d6, δ ppm): 159.2, 140.1, 139.7, 134.4, 129.1, 127.2, 113.7, 100.9 and 14.8. Elemental analysis: Anal. Calcd. C, 61.72; H, 4.57; N, 8.47. Found: C, 61.74; H, 4.55; N, 8.46. LCMS: (m/z):C17H15N2ClOS: 331.05 (M+H+), 333.05 (M+H+2)+.

5.1.8 4-(4-Chlorophenyl)-N-(4-fluoro-2-methylphenyl)thiazol-2-amine (5h)

Pale violet solid, MP: 135–137 °C; Yield: 65%; IR (KBr, νcm−1): 3126 (NH), 3049 (Ar–H), 2856(C–H-alkyl), 1616 (C=C), 1496 (C=N), 1056 (C–F), 725 (C–Cl), 1H NMR (CDCl3, 400 MHz) δ ppm: 2.26 (s, 3H alkyl). 7.64–7.65 (d, 2H, ortho protons of 4-chlorophenylring),6.94–6.96 (d, 2H, meta protonsof 4-chlorophenyl ring), 7.66–7.67 (d, 1H, J = 4 Hz, proton of 2-methyl-4-fluorophenyl ring), 7.49–7.52 (dd, 2H, J = 12 Hz, J = 4 Hz, meta protons of 2-methyl-4-fluorophenyl ring). 13C-NMR (DMSO-d6, 100 MHz) δ ppm: 166.2, 159.7, 157.3, 148.8, 135.5, 133.3, 132.5, 128.3, 127.1, 123.6, 116.9, 112.8, 102.8 and 18.1). Elemental analysis: Anal. Calcd. C, 60.28; H, 3.79; N, 8.79. Found: C, 60.29; H, 3.78; N, 8.80. LCMS: (m/z): C16H12N2ClFS:318.95 (M+H+), 320.95(M+H+2)+.

5.1.9 N-(2,6-Dimethylphenyl)-4-(4-fluorophenyl)thiazol-2-amine (5i)

Peach solid, MP: 150–152 °C; Yield: 69.29%; IR (KBr, νcm−1): 3126 (NH), 3047 (Ar–H), 2856 (CH alkyl), 1616 (C=C), 1496 (C=N), 1056 (C–F), 725 (C–Cl). 1H NMR (CDCl3, 400 MHz) δ ppm: 2.32 (s, 6H, alkyl), 6.57 (s, thiazole), 7.21–7.13 (m, 3H, 2,6-dimethylphenyl ring),7.73–6.99 (dd, J = 16 Hz, J = 4 Hz, 2H of meta 4-fluorophenyl ring), 7.01–6.97 (dd, J = 16 Hz, J = 4 Hz, 2H of ortho 4-fluorophenyl ring). 13C-NMR (DMSO-d6, 100 MHz) δ ppm: 168.6, 162.7, 160.3, 149.4, 137.9, 136.0, 131.2, 128.3, 127.4, 126.8, 115.1, 114.9, 100.8 and 18.0. Elemental analysis: Anal. Calcd. C, 53.11; H, 2.67; N, 8.26. Found: C, 53.13; H, 2.66; N, 8.24. LCMS: (m/z): C15H9N2Cl2FS:295.05 (M+H)+.

5.1.10 N-(2,6-Dimethylphenyl)-4-(4-nitrophenyl)thiazol-2-amine (5j)

Yellow solid, MP: 158–160 °C; Yield: 50.13%; IR (KBr, νcm−1): 3169 (NH), 3051 (Ar–H), 2846 (C–H alkyl), 1595 (C=C),1504 (N–O asym stretch), 1504 (C=N), 1321 (N–O symstretch), 1056 (C–F). 1H NMR (CDCl3, 400 MHz) δ ppm: 2.32 (s, 6H, alkyl); 7.86 (s, Ar–H, thiazole ring); 7.21–7.15 (m, 3H, 2,6-dimethylphenyl ring); 8.14–8.12 (d, J = 8 Hz, 2H of ortho 4-nitrophenyl ring), 7.87–7.85 (d, J = 8 Hz, 2H of meta of 4-nitrophenyl ring).13C-NMR (DMSO-d6, 100 MHz) δ ppm: 168.7, 148.3, 145.9, 140.7, 137.5, 135.9, 128.2, 126.9, 123.5, 105.8 and 17.9. Elemental analysis: Anal. Calcd. C, 62.75; H, 4.65; N, 12.91. Found: C, 62.76; H, 4.64; N, 12.92. LCMS: (m/z): C17H15N3O2S: 326.00(M+H)+.

5.2 Antibacterial evaluation

The resistance of biological infections on available drugs has been reported wide worldly; therefore researchers have to focus toward the new antimicrobial drugs with new target [29]. The synthesized compounds were screened in vitro for their antibacterial activity against four referential strains namely, E. coli MTCC 443 and C. violaceum MCC 2216 (Gram-negative), S. aureus MCC 2043 and E. faecalis MTCC 2729 (Gram positive),using the disc diffusion method [30]. Thus, disinfected plates were filled with 20 mL of sterilized Muller Hinton agar medium. Afterwards, 100 mL of particular bacterium which contained of 0.5–106 CFU mL (tantamount to 0.5 McFarland standards) was dispersed on the plates surfaces using a sterile swab. The discs which had been impregnated with (15 µL) the each compound with (25 mg mL−1 in DMSO) and were placed on the agar surface. The disc soaked in the DMSO was used as negative control. The plates were incubated at 37 °C for 24 h, and the diameter of the zones of inhibition was measured in millimetres (mm). The sample test was performed in three replicates. Compounds showing significant zone of inhibition were subjected to minimum inhibitory concentration (MIC). MICs were performed in MH Broth in 96-well microplates by a dilution method. Tantamount to 0.5 McFarland standards, exponential bacterial cultures (1.5 × 108 c.f.u) were obtained, added to wells containing decreasing concentrations of the compounds. The 96-well microplates were incubated at 37 °C overnight and the MIC was determined as the lowest concentration that inhibits the visible growth of the microorganism. The stock solution of the test compound was made with 1 mg mL−1 along with the standard drug streptomycin.

5.3 Fatty acid inhibition study

Fatty acid methyl esters were prepared using Metcalfe method in duplicate from bacterial isolates (100 µL) in the presence of Triheptadecanoin (internal standard); NuChek prep, Elysian, MN, USA). Using gas chromatography with flame ionization detection, four fatty acids were accounted. Individual fatty acids are expressed as percent of total acids in a sample. For all samples, data peaks on chromatograms were examined to ensure peak quality and consistency of retention times. Based on retention time of methyl ester derivatives, fatty acids in sample were recognized.

5.4 Hemolysis assay

Sashidhara et al. [31] suggested the procedure regarding this assay: The human blood was collected in a container of EDTA (2 mg mL−1). The resulting suspension was centrifuged at 800×g for 10 min to separate buffy coat and plasma. Successively, the erythrocytes settled were washed thrice with normal saline (0.9%) and then suspended in saline to obtain 5% erythrocytes suspension. Incubation of the cells was done in 1 h at 37 °C in the presence of test compounds (100 µg mL−1). Once incubation done, the solutions were centrifuged at 800×g for 10 min and then absorbance of the supernatant was measured using UV spectrophotometer at 540 nm. The 2% Triton X-100 (Sigma-Aldrich, St. Louis, USA) were used as positive control. The absorbance recorded for the released haemoglobin was expressed as % of Triton X-100 induced hemolysis. The result was calculated by using the formula below:
$${\text{\% }}\,{\text{Hemolysis}} = \frac{{\left( {{\text{Absorbance}}\,{\text{of}}\,{\text{the}}\,{\text{sample}}} \right) - \left( {{\text{Absorbance}}\,{\text{of}}\,{\text{blank}}} \right)}}{{{\text{Highest}}\,{\text{absorbance}}\,{\text{of}}\,{\text{positive}}\,{\text{control}}}} \times 100$$

5.5 Single crystal X-ray diffraction

The X-ray intensity data for compound 5d is collected at a temperature of 296 K on a Rigaku Saturn724 diffractometer using graphite monochromated Mo-Kα radiation. A complete data set was processed using Crystal Clear [32]. The structure was solved by direct methods and refined by full-matrix least squares method on F2 using SHELXS and SHELXL programs [33, 34]. All the non-hydrogen atoms were revealed in the first difference Fourier map itself. All the hydrogen atoms were positioned geometrically (C–H = 0.93(aromatic)/0.96(methyl) Å, N–H = 0.86 Å) and refined using a riding model with Uiso (H) = 1.2 Ueq (C or N) or 1.5 Ueq(C). After ten cycles of refinement, the final difference Fourier map showed peaks of no chemical significance. The ORTEP and packing diagrams were generated using the software MERCURY [35].

6 Supplementary information for XRD

Crystallographic data for the compounds has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 1845758. Copies of this information may be obtained free of charge via (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44-1223-336033; e-mail:



The authors acknowledge the services of Dr Pritesh Bhat and Vinod Devaraji, Application Scientist in molecular docking and molecular dynamic simulation studies using Schrodinger Software. The authors thank Dr. Suchetha Kumari Professor of Biochemistry, from K. S. Hedge Medical Academy (Nitte Deemed to be University) for her contribution in fatty acid study. The authors are grateful to Dr Vaishali Rai M Assistant Professor Department of Microbiology St. Aloysius College (Autonomous) Mangalore for his contribution in hemolysis assay. One of authors (Nadine Uwabagira) is also thankful to Indian Council for Culture Relations (ICCR) for granting scholarship.

Compliance with ethical standards

Conflict of interest

We declare that there is no conflict of interest.

Human and animals rights

No human or animal participant were involved in this study.

Supplementary material

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Supplementary material 1 (PDF 1011 kb)
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Supplementary material 2 (DOCX 486 kb)
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Supplementary material 3 (DOCX 774 kb)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Nadine Uwabagira
    • 1
  • Balladka K. Sarojini
    • 1
    • 2
    Email author
  • Madan K. Shankar
    • 3
  • Ramesh S. Gani
    • 2
  1. 1.Biochemistry Division, Department of ChemistryMangalore UniversityMangalagangothriIndia
  2. 2.Department of Industrial ChemistryMangalore UniversityMangalagangothriIndia
  3. 3.PURSE LabMangalore UniversityMangalagangothriIndia

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