In silico Approach to Identify Novel Thiazolidin-4-ones Against...

[Full title: In silico Approach to Identify Novel Thiazolidin-4-ones Against Staphylococcus aureus]

[Find the meaning and references behind the names: Rajala, Find, Ways, Range, Nehru, New, Class, India, Scholar, Active, Wild, Saini, Anti, Show, Eye, Mandal, Novel, Original, Data, Major, Few, Patel, Success, Web, Dec, Hit, Plays, Adme, Server, Ghoneim, Chemical, Sure, Role, Alkali, Swiss, Study, Strong, Target, Good, Ones]

Asian Journal of Pharmaceutic s • Oct-Dec 2022 • 16 (4) | 414 In silico Approach to Identify Novel Thiazolidin-4-ones Against Staphylococcus aureus Rajala Srikala 1 , S. Mohanalakshmi 2 1 Research Scholar, Jawaharlal Nehru Technological University Anantapur, Anantapur, Andhra Pradesh, India, 2 Director, Amity Institute of Pharmacy, Amity University, Gwalior, Madhya Pradesh, India Abstract Introduction: The DHFR inhibitors perform a significant role in thymidine synthesis by blocking the DHFR and interference with this pathway inhibits bacterial DNA synthesis. In this article, a molecular docking study followed by in silico pharmacokinetic parameters could be studied as an effective approach to detect newer DHFR inhibitors. Methods: Novel Thiazolidin-4-one derivatives were designed to perform molecular docking studies using Autodock-1.5.6 and identified the hit molecules. The hits were further evaluated for their drug likeliness using the Swiss ADME web server. Results: The binding affinity of the designed ligands towards DHFR was selected based on binding affinities and interaction patterns. Almost all the compounds have good binding affinities in the range of -10.4 to -5.6 and -11.0 to -8.0 compared with that of cognate ligand -7.6 and –7.9 for wild and mutant DHFR, respectively. Conclusion: The results reveal that Thiazolidin-4-ones as DHFR inhibitors and among 56 compounds, except 5 compounds all compounds showing good binding affinities may produce significant anti-staphylococcal activity for further enhancement Keywords: Autodock, DHFR inhibitors, discovery studio, in silico , Swiss ADME Address for correspondence: Rajala Srikala, Jawaharlal Nehru Technological University Anantapur, Anantapur, Andhra Pradesh, India. E-mail: srikala.rajala@gmail.com Received: 28-05-2022 Revised: 13-09-2022 Accepted: 01-10-2022 INTRODUCTION I nfectious diseases are a significant threat worldwide as new microorganism resistance to antibiotics inflates issues concerning the continual utilization of medicament agents in clinical observation. Thus, there is a requirement to develop new medication for the effective treatment of microorganism infections is a major priority. One of the ways enforced to inhibit bacterial pathogens is to target the synthesis pathway of nucleic acids, wherever the DHFR plays a significant role. The aptness of targeting DHFR for combating Staphylococcus aureus has been valid by the drug Trimethoprim, a very powerful anti-staphylococcal agent [1-3] Supported many ligandor structure-based approaches, varied categories of inhibitors are investigated, as alkali analogs [4-6] However, only a few of them inhibit in vitro growth of microorganisms There is a requirement to develop new chemical entities to inhibit the DHFR catalyst. Thiazolidin- 4-one is taken into account as a biologically active scaffold that possesses the majority sorts of biological activities. Thiazolidin-4-ones are with success introduced in numerous classes and evidenced as potential moieties, like thiazolidomycin activity against Streptomyces species, Ralitoline as a potent antiepileptic, Pioglitazone as a hypoglycemic agent, Etozolin as an antihypertensive agent. This variation within the biological response profile has engrossed the eye of many researchers to find this skeleton to its various potentials against many activities [7] Kerru et al ., Patel et al ., Mandal et al ., Saini et al ., Ghoneim and Zordok, and several other additional researchers have connected Thiazolidin-4-ones as antimicrobial agents [8-12] With sure variations, these compounds may generate potent chemical entities against Staphylococci species In this regard, within the current study, we tend to have designed various sets of novel thiazolidin-4-ones bearing aryl and diaryl substitutions at C 2 and N 3 positions, unsubstituted and alkyl radical substitution at the C 5 position and performed in silico analysis of the designed moieties [13] ORIGINAL AR TICLE

[Find the meaning and references behind the names: Mol, Code, Babel, Fig, Unique, File, Polar, Ure, Carbon, Tools, Edo, Acid, Nap, Ray, Open, Table, Non, Pro, General, Fuse, Bank, Pre]

Figure 1: General structure of thiazolidin-4-one Srikala and Mohanalakshmi: Novel Thiazolidin-4-ones Against Staphylococcus aureus Asian Journal of Pharmaceutic s • Oct-Dec 2022 • 16 (4) | 415 MATERIALS AND METHODS Molecular docking Chemical structures of unique thiazolidin-4-one derivatives were proposed using literature. Flexible-ligand docking simulations were executed with AutoDock version 1.5.6. X-ray crystallographic structure of DHFR enzyme was taken from the protein data bank (2 W 9 H and 5 ISQ; [14,15] http:// www.rcsb.org/) with resolution 1.48 Å and 1.90 Å For the preparation of a target protein, crystallographic ligand (Trimethoprim and 3’-(3-(2,4-diamino-6-ethylpyrimidin- 5-yl)pro 2-yn-1-yl)-4’-methoxy-[1,1’-biphenyl]-4- carboxylic acid (UCP 1106)), NAP, EDO, and water molecules were all removed from the original structure. All the pre-processing steps for DHFR protein were executed through AutoDock Tools 1.5.6 program (ADT) [16] ADT program was operated to fuse the non-polar hydrogens into the associated carbon atoms of the receptor and Kollman charges were allocated Ligands were designed using ChemSketch (www.acdlabs com) [ Fig ure 1 and Table 1], and the file formats are converted from .mol to .pdb format using Open Babel [17] Then Table 1: (Continued) Code R R’ R’’ 45 5 M 4 MBP 2-chloropyrimidin-5-yl CH 3 46 5 M 4 MBP 4-hydroxy-5-methylpyrimidin-2-yl H 47 5 M 4 MBP 4-chloropyrimidin-2-yl H 48 5 M 4 MBP 4-chloropyrimidin-2-yl CH 3 49 5 M 4 MBP 2-chloropyrimidin-4-yl H 50 5 M 4 MBP pyrimidin-5-yl H 51 5 M 4 MBP pyrimidin-5-yl CH 3 52 5 M 4 MBP 4-hydroxy-5-methylpyrimidin-2-yl CH 3 53 5 M 4 MBP 4,5,6-trimethylpyrimidin-2-yl H 54 5 M 4 MBP 2-chloropyrimidin-4-yl CH 3 55 5 M 4 MBP pyrimidin-2-yl CH 3 56 5 M 4 MBP 4,5,6-trimethylpyrimidin-2-yl CH 3 2 M 2 MBP - 2-methoxy-2’-methyl-[1,1’-biphenyl]-4-yl; 5 M 2 MBP - 5-methoxy-2’-methyl-[1,1’-biphenyl]-3-yl; 5 M 3 MBP - 5-methoxy-3’-methyl-[1,1’-biphenyl]-3-yl; 5 M 4 MBP - 5-methoxy-4’-methyl-[1,1’-biphenyl]-3-yl Table 1: Structures of designed compounds (1-56) Code R R’ R’’ 01 2 M 2 MBP 4,5,6-trimethylpyrimidin-2-yl H 02 2 M 2 MBP 4,5,6-trimethylpyrimidin-2-yl CH 3 03 2 M 2 MBP 4-hydroxy-5-methylpyrimidin-2-yl H 04 2 M 2 MBP 4-hydroxy-5-methylpyrimidin-2-yl CH 3 05 2 M 2 MBP pyrimidin-2-yl H 06 2 M 2 MBP pyrimidin-2-yl CH 3 07 2 M 2 MBP 4-chloropyrimidin-2-yl H 08 2 M 2 MBP 4-chloropyrimidin-2-yl CH 3 09 2 M 2 MBP 2-chloropyrimidin-4-yl H 10 2 M 2 MBP 2-chloropyrimidin-4-yl CH 3 11 2 M 2 MBP pyrimidin-5-yl H 12 2 M 2 MBP pyrimidin-5-yl CH 3 13 2 M 2 MBP 2-chloropyrimidin-5-yl H 14 2 M 2 MBP 2-chloropyrimidin-5-yl CH 3 15 5 M 2 MBP 4-chloropyrimidin-2-yl CH 3 16 5 M 2 MBP 2-chloropyrimidin-5-yl CH 3 17 5 M 2 MBP 4-hydroxy-5-methylpyrimidin-2-yl H 18 5 M 2 MBP 4-chloropyrimidin-2-yl H 19 5 M 2 MBP 2-chloropyrimidin-5-yl H 20 5 M 2 MBP 2-chloropyrimidin-4-yl CH 3 21 5 M 2 MBP pyrimidin-2-yl CH 3 22 5 M 2 MBP pyrimidin-5-yl CH 3 23 5 M 2 MBP 2-chloropyrimidin-4-yl H 24 5 M 2 MBP pyrimidin-5-yl H 25 5 M 2 MBP 4,5,6-trimethylpyrimidin-2-yl H 26 5 M 2 MBP pyrimidin-2-yl H 27 5 M 2 MBP 4-hydroxy-5-methylpyrimidin-2-yl CH 3 28 5 M 2 MBP 4,5,6-trimethylpyrimidin-2-yl CH 3 29 5 M 3 MBP 4-chloropyrimidin-2-yl CH 3 30 5 M 3 MBP pyrimidin-2-yl H 31 5 M 3 MBP 2-chloropyrimidin-5-yl H 32 5 M 3 MBP 4-hydroxy-5-methylpyrimidin-2-yl H 33 5 M 3 MBP 4,5,6-trimethylpyrimidin-2-yl H 34 5 M 3 MBP 4-chloropyrimidin-2-yl H 35 5 M 3 MBP pyrimidin-5-yl H 36 5 M 3 MBP 2-chloropyrimidin-5-yl CH 3 37 5 M 3 MBP pyrimidin-2-yl CH 3 38 5 M 3 MBP 2-chloropyrimidin-4-yl H 39 5 M 3 MBP pyrimidin-5-yl CH 3 40 5 M 3 MBP 2-chloropyrimidin-4-yl CH 3 41 5 M 3 MBP 4-hydroxy-5-methylpyrimidin-2-yl CH 3 42 5 M 3 MBP 4,5,6-trimethylpyrimidin-2-yl CH 3 43 5 M 4 MBP 2-chloropyrimidin-5-yl H 44 5 M 4 MBP pyrimidin-2-yl H (Contd...)

[Find the meaning and references behind the names: Every, Map, Amino, Rms, Square, Gene, Mash, Maps, Root, Size, Mass, Freedom, Mean, Pose, Grid, Rate, Self, Atom]

Srikala and Mohanalakshmi: Novel Thiazolidin-4-ones Against Staphylococcus aureus Asian Journal of Pharmaceutic s • Oct-Dec 2022 • 16 (4) | 416 non-polar hydrogens, Gasteiger charges, and torsion degrees of freedom were assigned by the ADT program. Lamarckian genetic algorithm (LGA) employed to model the interactions between thiazolidin-4-ones and DHFR active site using 100 GA runs; 27000 maximum generations; a gene mutation rate of 0.02; and a crossover rate of 0.8 were operated for LGA method. Based on the validation study, the cognate (co-crystallo graph ic) ligand was extracted and re-docked into its receptor (self-docking). Validation is performed by comparing the root mean square deviation of the Cartesian coordinates of the atoms of the ligand in the docked pose and crystallographic conformations DHFR was characterized by grid maps in the actual docking procedure. The grids were calculated using the AutoGrid module. The grid included a map for every atom type within the ligand and also a map for electrostatic interactions. The size of the grid was 50 × 50 × 50 Å (distributed in the x, y, and z directions) and it was centered on the center of mass of the catalytic site of DHFR with a spacing of 0.375 Å. Cluster analysis was performed on the docked results concerning RMS tolerance of 2 Å. 2 D and 3 D interactions of the docked ligands were analyzed using Discovery Studio Visualizer-20.1 (https://discover.3 ds.com/ discovery-studio-visualizer-download) In silico pharmacokinetic parameters The in silico drug likeliness and ADME properties of the proposed molecules were determined by using the SwissADME webserver [18-20] In this server, the structure was drawn or the SMILES format of the ligands was incorporated and executed the program to attain the desired results Table 2: (Continued) Code Wild DHFR Binding affinity Mutant DHFR Binding affinity 42 –7.3 –9.4 43 –9.9 –10.8 44 –10.2 –10.1 45 –9.4 –10.6 46 –9.7 –10.2 47 –9.7 –10.1 48 –10.2 –9.5 49 –8.7 –10.7 50 –8.4 –11 51 –8.8 –10.4 52 –9.2 –10 53 –8.8 –10 54 –8.9 –9.8 55 –9.5 –9.2 56 –8 –8.9 Table 2: Binding energies and interacted amino acids for compounds 1-56 with DHFR (2 W 9 H and 5 ISQ) Code Wild DHFR Binding affinity Mutant DHFR Binding affinity Reference −7.6 –7.9 1 –6.5 –8 2 –5.6 –8.4 3 –9.2 –8.3 4 –8.6 –8.5 5 –8.2 –8.4 6 –8.4 –8.7 7 –8.4 –9 8 –8.6 –9.3 9 –8.1 –9.9 10 –8.6 –8.5 11 –7.9 –9.4 12 –8 –9.4 13 –8.1 –9.2 14 –7.5 –9.4 15 –9.5 –10.6 16 –9.3 –10.5 17 –9.5 –9.9 18 –9.2 –10.2 19 –9 –10.3 20 –9.4 –9.8 21 –9.1 –10.1 22 –8.8 –10.2 23 –8.7 –10.2 24 –8.3 –10.6 25 –9.1 –9.5 26 –8.8 –9.8 27 –8.5 –9.1 28 –7.4 –8.5 29 –10.4 –10.9 30 –10.3 –10.2 31 –10 –10.3 32 –9.9 –10.2 33 –9.6 –10.3 34 –9.5 –10.1 35 –9.3 –10.3 36 –9.3 –10.3 37 –8.6 –10.6 38 –8.5 –10.4 39 –8.7 –10.1 40 –8.9 –9.6 41 –8.6 –9.6 (Contd...)

[Find the meaning and references behind the names: Mode, Rose, Violet, Bond, Green]

Srikala and Mohanalakshmi: Novel Thiazolidin-4-ones Against Staphylococcus aureus Asian Journal of Pharmaceutic s • Oct-Dec 2022 • 16 (4) | 417 Figure 2: 2 D interactions of Cognate ligand with active site of DHFR (a) 2 W 9 H and (b) 5 ISQ. Green – H-bond interaction, Rose – Alkyl/Pi-Alkyl interactions, Violet – Pi-Sigma interactions b a Figure 3: 2 D interactions of docked compound 29 with DHFR (a) 2 W 9 H and (b) 5 ISQ b a Figure 4: 3 D structures of best affinity mode of docked compounds (a) Reference with Wild DHFR (b) 29 with Wild DHFR (c) Reference with Mutant DHFR (d) 29 with Mutant DHFR d c b a

[Find the meaning and references behind the names: Log, Bonds]

Srikala and Mohanalakshmi: Novel Thiazolidin-4-ones Against Staphylococcus aureus Asian Journal of Pharmaceutic s • Oct-Dec 2022 • 16 (4) | 418 Table 3: Molecular properties for designed compounds 1-56 Code MW H-bond donors H-bond acceptors Log P Rotatable bonds MR TPSA Ref 290.32 2 5 2.21 5 79.77 105.51 1 419.54 0 4 3.86 4 125.94 80.62 2 433.57 0 4 4.15 4 130.74 80.62 3 407.49 1 5 3.32 4 118.03 100.85 4 421.51 1 5 3.56 4 122.84 100.85 5 377.46 0 4 3.09 4 111.04 80.62 6 391.49 0 4 3.34 4 115.85 80.62 7 411.9 0 4 3.36 4 116.05 80.62 8 425.93 0 4 3.66 4 120.86 80.62 9 411.9 0 4 3.17 4 116.05 80.62 10 425.93 0 4 3.4 4 120.86 80.62 11 377.46 0 4 3.12 4 111.04 80.62 12 391.49 0 4 3.3 4 115.85 80.62 13 411.9 0 4 3.45 4 116.05 80.62 14 425.93 0 4 3.74 4 120.86 80.62 15 425.93 0 4 3.63 4 120.86 80.62 16 425.93 0 4 3.77 4 120.86 80.62 17 407.49 1 5 3.37 4 118.03 100.85 18 411.9 0 4 3.42 4 116.05 80.62 19 411.9 0 4 3.51 4 116.05 80.62 20 425.93 0 4 3.5 4 120.86 80.62 21 391.49 0 4 3.38 4 115.85 80.62 22 391.49 0 4 3.43 4 115.85 80.62 23 411.9 0 4 3.25 4 116.05 80.62 24 377.46 0 4 3.16 4 111.04 80.62 25 419.54 0 4 3.7 4 125.94 80.62 26 377.46 0 4 3.09 4 111.04 80.62 27 421.51 1 5 3.73 4 122.84 100.85 28 433.57 0 4 4.04 4 130.74 80.62 29 425.93 0 4 3.75 4 120.86 80.62 30 377.46 0 4 3.23 4 111.04 80.62 31 411.9 0 4 3.66 4 116.05 80.62 32 407.49 1 5 3.41 4 118.03 100.85 33 419.54 0 4 3.83 4 125.94 80.62 34 411.9 0 4 3.48 4 116.05 80.62 35 377.46 0 4 3.28 4 111.04 80.62 36 425.93 0 4 3.89 4 120.86 80.62 37 391.49 0 4 3.53 4 115.85 80.62 38 411.9 0 4 3.38 4 116.05 80.62 39 391.49 0 4 3.59 4 115.85 80.62 40 425.93 0 4 3.65 4 120.86 80.62 41 421.51 1 5 3.72 4 122.83 100.85 42 433.57 0 4 4.12 4 130.74 80.62 43 411.9 0 4 3.64 4 116.05 80.62 (Contd...)

[Find the meaning and references behind the names: Molar, Area, Weight]

Srikala and Mohanalakshmi: Novel Thiazolidin-4-ones Against Staphylococcus aureus Asian Journal of Pharmaceutic s • Oct-Dec 2022 • 16 (4) | 419 Table 3: (Continued) Code MW H-bond donors H-bond acceptors Log P Rotatable bonds MR TPSA 44 377.46 0 4 3.23 4 111.04 80.62 45 425.93 0 4 3.87 4 120.86 80.62 46 407.49 1 5 3.38 4 118.03 100.85 47 411.9 0 4 3.53 4 116.05 80.62 48 425.93 0 4 3.82 4 120.86 80.62 49 411.9 0 4 3.34 4 116.05 80.62 50 377.46 0 4 3.25 4 111.04 80.62 51 391.49 0 4 3.53 4 115.85 80.62 52 421.51 1 5 3.8 4 122.83 100.85 53 419.54 0 4 3.79 4 125.94 80.62 54 425.93 0 4 3.66 4 120.86 80.62 55 391.49 0 4 3.53 4 115.85 80.62 56 433.57 0 4 4.11 4 130.74 80.62 Recommended values <500 Daltons ≤5 ≤10 ≤5 ≤10 40 to 130 ≤140 Å 2 MW: Molecular weight, MR: Molar refractivity, TPSA: Total polar surface area Table 4: ADME and synthetic accessibility for designed compounds 1-56 Code Aqueous solubility P-gp substrate log Kp (cm/s) Synthetic accessibility Reference Soluble Yes –7.42 2.58 1 Moderately soluble Yes –5.24 3.98 2 Poorly soluble Yes –5.04 4.35 3 Moderately soluble No –5.75 3.89 4 Moderately soluble No –5.55 4.26 5 Moderately soluble No –5.81 3.57 6 Moderately soluble No –5.61 3.94 7 Moderately soluble No –5.33 3.63 8 Poorly soluble No –5.14 4 9 Moderately soluble No –5.33 3.64 10 Poorly soluble No –5.14 4.03 11 Moderately soluble Yes –6.05 3.61 12 Moderately soluble No –5.84 3.97 13 Moderately soluble No –5.57 3.68 14 Moderately soluble No –5.37 4.04 15 Poorly soluble No –5.14 4.04 16 Moderately soluble No –5.37 4.09 17 Moderately soluble No –5.75 3.93 18 Moderately soluble No –5.33 3.67 19 Moderately soluble No –5.57 3.73 20 Poorly soluble No –5.14 4.06 21 Moderately soluble No –5.61 3.98 22 Moderately soluble No –5.84 4.01 23 Moderately soluble No –5.33 3.67 24 Moderately soluble No –6.05 3.66 (Contd...)

[Find the meaning and references behind the names: Ile, Ser, Pocket, Due, Ala, Shown]

Srikala and Mohanalakshmi: Novel Thiazolidin-4-ones Against Staphylococcus aureus Asian Journal of Pharmaceutic s • Oct-Dec 2022 • 16 (4) | 420 Table 4: (Continued) Code Aqueous solubility P-gp substrate log Kp (cm/s) Synthetic accessibility 25 Moderately soluble Yes –5.24 4.02 26 Moderately soluble No –5.81 3.62 27 Moderately soluble No –5.55 4.29 28 Poorly soluble Yes –5.04 4.39 29 Poorly soluble No –5.14 4.01 30 Moderately soluble No –5.81 3.58 31 Moderately soluble No –5.57 3.69 32 Moderately soluble No –5.75 3.9 33 Moderately soluble Yes –5.24 3.98 34 Moderately soluble No –5.33 3.63 35 Moderately soluble No –6.05 3.62 36 Moderately soluble No –5.37 4.05 37 Moderately soluble No –5.61 3.95 38 Moderately soluble No –5.33 3.65 39 Moderately soluble No –5.84 3.97 40 Poorly soluble No –5.14 4.03 41 Moderately soluble No –5.55 4.26 42 Poorly soluble Yes –5.04 4.35 43 Moderately soluble No –5.57 3.7 44 Moderately soluble No –5.81 3.6 45 Moderately soluble No –5.37 4.06 46 Moderately soluble No –5.75 3.91 47 Moderately soluble No –5.33 3.65 48 Poorly soluble No –5.14 4.02 49 Moderately soluble No –5.33 3.66 50 Moderately soluble No –6.05 3.63 51 Moderately soluble No –5.84 3.99 52 Moderately soluble No –5.55 4.28 53 Moderately soluble Yes –5.24 3.99 54 Poorly soluble No –5.14 4.05 55 Moderately soluble No –5.61 3.96 56 Poorly soluble Yes –5.04 4.36 log Kp: Skin permeation RESULTS AND DISCUSSION The docking study of designed thiazolidin-4-ones to the active site of protein was performed by Autodock for calculating the binding affinities of the designed ligands with the protein. The designed molecules were docked into the DHFR (2 W 9 H and 5 ISQ), to determine their DHFR inhibitory activity. All compounds except 1, 2, 14, 28, and 42 had shown a good binding affinity to both wild and mutant DHFR receptors compared to the cognate ligand for anti-staphylococcal activity [Table 2 ]. From Table 1, the interactions are mainly due to the lipophilic factors and hydrogen bonding. The interactions with wild and mutant DHFR are mainly subjugated in the region of ALA 7, ILE 14, and SER 49 residues which are in the active site region [Figure 2 ]. The aryl substitutions are located in the hydrophobic pocket and the amino group is located in the hydrophilic pocket. The compound 29 exhibited hydrogen bonding with ILE 14 (H-bond length 2.52 Å) residue of wild DHFR and hydrogen bonding with ILE 14, SER 49 (H-bond length 2.17 Å and 2.57 Å, respectively) residues of mutant DHFR, which is depicted in Fig ure 3. The best-docked poses of the compounds 29, 30 and 29, 50 for wild and mutant DHFR with significant binding affinities are shown in Fig ure 4 The ADMET properties for the thiazolidin-4-ones 1-56 were determined in silico using the SwissADME webserver of

[Find the meaning and references behind the names: Oliver, Barrier, Sharman, Sharma, Sarver, Singh, Adamson, Putz, Better, Ghanem, Soc, Mini, Ravichandran, Parmar, Rule, Zoubi, Pur, Dose, Mon, Int, Bishara, Goldberg, Poor, Ann, Present, Chem, Rom, Veber, Development, Moorman, Jain, Sree, Mandell, Metab, Romeo, Legnani, Paul, Bhagat, High, Wahlberg, Dupont, Bhat, Yahav, Harris, Tissot, Vaidya, Neuberger, Tirupati, Ghosh, Agrawal, Iannazzo, Chiacchio, Thakur, Severe, Cell, Svensson, Jimeno, Chang, Med, Lipinski, Soni]

Srikala and Mohanalakshmi: Novel Thiazolidin-4-ones Against Staphylococcus aureus Asian Journal of Pharmaceutic s • Oct-Dec 2022 • 16 (4) | 421 the Swiss Institute of Bioinformatics. Molecular weights of the compounds are between 377.46 and 433.57 g.mol -1 . Estimated no. of hydrogen bond donors are in the range of 0–1, hydrogen bond acceptors are in the range of 4–5. LogP, molar refractivity, rotatable bonds, and total polar surface area of the compounds are between 3.09 and 4.15; 111.04 and 130.74; 4; 80.62 and 100.85 Å 2 , respectively. The compounds are in the range of Lipinski’s rule of five and Veber’s rule [Table 3] All the compounds are showing moderate to poor aqueous solubility which indeed results in high gastro-intestinal (GI) absorption. All the compounds are not crossing the bloodbrain barrier. Skin permeation values are found in the range of –6.05 to –5.04 cm/s. 01, 02, 11, 25, 28, 33, 42, 53, and 56 are P-gp substrates which can decrease drug accumulation in multidrug-resistant cells. The details of the ADME properties for compounds 1-56 are shown in Table 4 Besides, synthetic accessibility of the compounds can be predicted using Swiss ADME on a scale of 1-10, that is, very easy to difficult to synthesize. All the designed compounds can be easily synthesized in the laboratory Bioavailability of all 1-56 compounds was found to be 0.55 CONCLUSION The docking study revealed that the thiazolidin-4-ones showed better alignment than the new experimental drugs at the active site by interacting with active site amino acid residues of DHFR (2 W 9 H and 5 ISQ). Thus, the in silico method adopted in the present study helped in identifying the lead molecules to inhibit DHFR. Results observed in the present study demonstrated that some derivatives of the designed thiazolidin-4-ones may exert interesting antistaphylococcal activity. The compounds 29, 30, and 50 have significant DHFR inhibitory activity and are likely to be useful as drugs or after further refinement in the discovery of novel anti-staphylococcal agents ACKNOWLEDGMENTS The authors are grateful to the authorities of Sree Vidyanikethan College of Pharmacy, Tirupati for the facilities REFERENCES 1. Mandell GL, Moorman DR. Treatment of experimental staphylococcal infections: Effect of rifampin alone and in combination on development of rifampin resistance. Antimicrob Agents Chemother 1980;17:658-62 2. Tissot-Dupont H, Gouriet F, Oliver L, Jamme M, Casalta JP, Jimeno MT, et al . High-dose trimethoprimsulfamethoxazole and clindamycin for Staphylococcus aureus endocarditis. Int J Antimicrob Agents 2019;54:143-8 3. Paul M, Bishara J, Yahav D, Goldberg E, Neuberger A, Ghanem-Zoubi N, et al . Trimethoprim-sulfamethoxazole versus vancomycin for severe infections caused by methicillin resistant Staphylococcus aureus : Randomised controlled trial. BMJ 2015;350:h 2219 4. Chiacchio MA, Iannazzo D, Romeo R, Giofrè SV, Legnani L. Pyridine and pyrimidine derivatives as privileged scaffolds in biologically active agents. Curr Med Chem 2019;26:7166-95 5. Wahlberg G, Adamson U, Svensson J. Pyridine nucleotides in glucose metabolism and diabetes: A review. Diabetes Metab Res Rev 2000;16:33-42 6. Prachayasittikul S, Pingaew R, Wora chartcheewan A, Sinthupoom N, Prachayasittikul V, Ruchirawat S, et al . Roles of pyridine and pyrimidine derivatives as privileged scaffolds in anticancer agents. Mini Rev Med Chem 2017;17:869-901 7. Jain AK, Vaidya A, Ravichandran V, Kashaw SK, Agrawal RK. Recent developments and biological activities of thiazolidinone derivatives: A review. Bioorg Med Chem 2012;20:3378-95 8. Kerru N, Gummidi L, Bhaskaruni SV, Maddila SN, Jonnalagadda SB. Ultrasound-assisted synthesis and antibacterial activity of novel 1, 3, 4-thiadiazole-1 H-pyrazol-4-yl-thiazolidin-4-one derivatives. Monatshefte Für Chemie Chem Mon 2020;151:981-90 9. Patel NB, Soni HI, Parmar RB. Significance of microwave irradiation in synthesis of thiazolidin- 4-one bearing pyrimidine analogues: Their in vitro antimicrobial, antituberculosis and antimalarial studies. Curr Microw Chem 2020;7:230-7 10. Mandal MK, Ghosh S, Naesens L, Bhat HR, Singh UP. Facile synthesis, antimicrobial and antiviral evaluation of novel substituted phenyl 1, 3-thiazolidin-4-one sulfonyl derivatives. Bioorg Chem 2021;114:105153 11. Saini N, Sharma A, Thakur VK, Makatsoris C, Dandia A, Bhagat M, et al . Microwave assisted green synthesis of thiazolidin-4-one derivatives: A perspective on potent antiviral and antimicrobial activities. Curr Res Green Sustain Chem 2020;3:100021 12. Ghoneim AA, Zordok WA. An efficient procedure of synthesis, DFT calculation and theoretical investigation of 4‐thiazolidinone fused thiopyrimidine derivatives as antimicrobial agents. Polycycl Aromat Compd 2021;42:1-6 13. Srikala R, Mohanalakshmi S. Molecular docking and in silico pharmacokinetic parameters of substituted thiazolidin-4-ones as anti-tubercular agents. Ann Rom Soc Cell Biol 2021;4:6443-51 14. Heaslet H, Harris M, Fahnoe K, Sarver R, Putz H, Chang J, et al . Structural comparison of chromosomal and exogenous dihydrofolate reductase from Staphylococcus aureus in complex with the potent inhibitor trimethoprim.

[Find the meaning and references behind the names: Reeve, Hutchison, Ferreira, Brain, Sci, Michielin, Tool, Morley, Wright, Rep, Egg, Simple, Daina, Nil, Free, James, Small, Boyle, None]

Srikala and Mohanalakshmi: Novel Thiazolidin-4-ones Against Staphylococcus aureus Asian Journal of Pharmaceutic s • Oct-Dec 2022 • 16 (4) | 422 Proteins 2009;76:706-17 15. Reeve SM, Scocchera E, Ferreira JJ, G-Dayanandan N, Keshipeddy S, Wright DL, et al . Charged propargyllinked antifolates reveal mechanisms of antifolate resistance and inhibit trimethoprim-resistant MRSA strains possessing clinically relevant mutations. J Med Chem 2016;59:6493-500 16. Sanner MF. Python: A programming language for software integration and development. J Mol Graph Model 1999;17:57-61 17. O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open babel: An open chemical toolbox. J Cheminform 2011;3:33 18. Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 2017;7:1-3 19. Daina A, Michielin O, Zoete V. iLOGP: A simple, robust, and efficient description of n-octanol/water partition coefficient for drug design using the GB/SA approach. J Chem Inform Model 2014;54:3284-301 20. Daina A, Zoete V. A boiled‐egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem 2016;11:1117 Source of Support: Nil. Conflicts of Interest: None declared.

Other Health Sciences Concepts:

[back to top]

Discover the significance of concepts within the article: ‘In silico Approach to Identify Novel Thiazolidin-4-ones Against...’. Further sources in the context of Health Sciences might help you critically compare this page with similair documents:

Effective treatment, Significant role, Infectious disease, Bioavailability, Antimicrobial agent, Molecular docking, In-silico approach, ADMET properties, Binding affinity, Lipinski's Rule of Five, Molecular weight, Staphylococcus aureus, Veber's rule, Hydrogen bonding, Chemical structure, Biological activities, Significant threat, Binding Affinities, Aqueous solubility, Molecular docking studies, Green Synthesis, Skin permeation, Discovery Studio, Active site, Docking study, Chemical entities, Protein data bank, Molar refractivity, Binding energies, Bacterial pathogen, Molecular properties, In Silico, Lipinski's rule, Lamarckian genetic algorithm, Target Protein, Rotatable Bonds, Hydrophobic pocket, Log P, Molecular docking study, Drug accumulation, Pyridine derivatives, ADME properties, Trimethoprim, Dihydrofolate reductase, Cluster analysis, Hydrogen bond acceptor, In silico analysis, Nucleic acid, Electrostatic interaction, In silico method, Hydrogen bond donor, Synthetic accessibility, Trimethoprim-Sulfamethoxazole, Anti-staphylococcal activity, Chemsketch, Swiss ADME, Biologically active scaffold, Pharmacokinetic Parameter, Flexible ligand docking, Thiazolidin-4-ones, Interaction pattern, New medication, Drug likeliness, DHFR inhibitor, AutoDock, Gasteiger charges, X-ray crystallographic structure, Open Babel, Staphylococci species, P-gp substrate.