Ddl: D-Ala-D-Ala Ligases
GPCR: G-Protein-Coupled Receptor
IUPAC: The International Union of Pure And Applied Chemistry
Mur A Udp-N-Acetylglucosamine Enolpyruvyltransferase
Mur B Udp-N-Acetylenolpyruvylglucosamine Reductase
Mur C- N-Acetylmuramate L-Alanine Ligase
Mur D- N-Acetylmuramoyl-L-Alanine D-Glutamate Ligase
Mur E - N-Acetylmuramoyl-L-Alanyl-D-Glutamate Meso-Diaminopimelate Ligase
PASS: Prediction Of Activity Spectra For Biologically Active Substances.
PDB ID-Protein Data Bank-Identification
QSAR: Quantitative Structure Activity Relationship
Rtob: Rotatable Bonds
SAR: Structure Activity Relationship
SD File: Structure Data File
SMILES: Simplified Molecular-Input Line-Entry System
TPSA: Topological Polar Surface Area
UDP : Uridine Diphosphate
The literature is enriched with excellent antimicrobial activity for compounds containing the 2,5-substituted 1,3,4-oxadiazole core [9-11]. Oliveira and co-workers reported synthesis and anti-staphylococcal activity of 1, 3, 4-oxadiazolines against strains of S.aureus, resistant to methicillin and amino glycosides and that encode efflux proteins (multidrug drugs resistant—MDR more active than the standard drug chloramphenicol [12]. The antibacterial and antifungal activity of 2-(5-amino-1,3,4-oxadiazol-2-yl)-4-bromophenol and 5-(3,5-dibromophenyl)- 1,3,4-oxadiazol-2-amine were investigated against gram-positive bacteria, gram-negative bacteria and fungal species approximately equal to the standard drugs of treatment streptomycin and Griseofulvin [13]. 2,5-disubstituted 1,3,4 oxadiazoles were reported as potent antibacterial and antifungal agents [14](Figure 1).
Despite of the development of several new antimicrobial agents, their use has been clinically limited due to bacterial resistance and pharmacokinetic insufficiencies [15]. The aim of the research was to target the biosynthetic pathway of cytoplasmic peptidoglycan, which is currently gaining much interest as a target site for antibacterial therapy and provides good prospects for discovering selective bacterial inhibitors [16]. Therefore, it prompted us to design the new molecules in such a way that the basic pharmacophoric scaffolds were conjugated with each other, sulfonamide moiety at 2nd position of 1,3,4-oxadiazol ring and phenyl ring at position 5, altered by varying substituents on phenyl ring. These compounds were predicted molecular properties and drug likeness scores, compared the effect of different substitutions in the pharmacophore on the drug likeness properties. Molecular docking studies of the compounds on Mur enzymes were conducted for ensuring the possibility of mechanism of action.
Figure 1: Design of new compounds by conjugation of sulfonamide and 1,3, 4-oxadiazole moieties
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The docking process involves the prediction of ligand conformation and orientation (or posing) within a targeted binding site. In general, there are two aims of docking studies: accurate structural modeling and correct prediction of activity by the identification of molecular features responsible for specific biological recognition, or the prediction of compound modifications that improve potency [19].
The structural analogues have been designed in such a way that it will show more drug likeness score than the prototype molecule but having the same pharmacophore essential for the activity. A series of ten 4-amino-N-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl] substituted benzene-1-sulfonamides were designed and their chemical structures were drawn using Marvin sketch.
Different substituents such as electron donating (chloro, isopropyl, tert-butyl), electron releasing (hydroxyl, methoxy, nitro) etc were substituted on the benzene ring to study their effect on the predicted properties and also biological activities.
The list of designed analogues with drug likeness scores, and other molecular properties have been listed below. The position of substituent on benzene ring was modified in these designed molecules to get increased drug likeness score. Table 1 gives the information about different substituted compounds and table 2 indicates the nomenclature generated using soft ware chemicalize.org (Table 1, Table 2).
Compound |
R |
1. |
H |
2. |
4-OH |
3. |
4-Cl |
4. |
4-NH2 |
5. |
4-OH,3-CH3 |
6. |
4-CH(CH3)2 |
7. |
4-C(CH3)3 |
8. |
4-N(CH3)2 |
9. |
4-NO2 |
10. |
3,4,5-(OCH3)3 |
S.No |
R |
Nomenclature |
1 |
H |
IUPAC: 4-Amino-N-[(5-Phenyl-1,3,4-Oxadiazol-2-L)Methyl]Benzene-1-Sulfonamide |
2 |
4-OH |
IUPAC: 4-Amino-N-{[5-(4-Hydroxyphenyl)-1,3,4-Oxadiazol-2-Yl]Methyl}Benzene-1-Sulfonamide |
3 |
4-Cl |
SMILES: NC1=CC=C(C=C1)S(=O)(=O)NCC1=NN=C(O1)C1=CC=C(CL)C=C1 |
4 |
4-NH2 |
IUPAC: 4-Amino-N-{[5-(4-Aminophenyl)-1,3,4-Oxadiazol-2-Yl]Methyl}Benzene-1-Sulfonamide |
5 |
4-OH, |
IUPAC: 4-Amino-N-{[5-(4-Hydroxy-3-Methoxyphenyl)-1,3,4-Oxadiazol-2-Yl]Methyl}Benzene-1-Sulfonamide |
6 |
4-CH(CH3)2 |
IUPAC: 4-Amino-N-({5-[4-(Propan-2-Yl)Phenyl]-1,3,4-Oxadiazol-2-Yl}Methyl)Benzene-1-Sulfonamide |
7 |
4-C(CH3)3 |
IUPAC: 4-Amino-N-{[5-(4-Tert-Butylphenyl)-1,3,4-Oxadiazol-2-Yl]Methyl}Benzene-1-Sulfonamide |
8 |
4-N(CH3)2 |
IUPAC: 4-Amino-N-({5-[4-(Dimethylamino)Phenyl]-1,3,4-Oxadiazol-2-Yl}Methyl)Benzene-1-Sulfonamide |
9 |
4-NO2 |
IUPAC: 4-Amino-N-{[5-(4-Nitrophenyl)-1,3,4-Oxadiazol-2-Yl]Methyl}Benzene-1-Sulfonamide |
10 |
3,4,5-(OCH3)3 |
IUPAC: 4-Amino-N-{[5-(3,4,5-Trimethoxyphenyl)-1,3,4-Oxadiazol-2-Yl]Methyl}Benzene-1-Sulfonamide |
Absorption is defined as the process involved in getting a drug from its dosage form into the body and the ability to predict the percent oral absorption is primary goal in the design, optimization, and selection of potential candidates in the development of oral drugs. Topological Polar surface area (TPSA) is another key property that has been linked to bioavailability and it was found that passively absorbed molecules with a TPSA more than 140 are thought to have low oral availability [21]. TPSA obtained for the tested compounds were below 140 indicating their good oral bioavailability. Thus these results predicted the good drug likeliness, solubility, permeability and oral bioavailability of compounds. No compound violated the Lipinski rule of five (Table 3, Table 4, Table 5, Table 6).
S.NO |
R |
Molecular Formula |
Molecular weight |
Log P |
TPSA |
SASA |
1 |
H |
C15H14N4O3S |
330.362 |
0.78 |
111.11 |
436.55 |
2 |
4-OH |
C15H14N4O4S |
346.361 |
0.47 |
131.34 |
447.81 |
3 |
4-Cl |
C15H13ClN4O3S |
364.807 |
1.38 |
111.11 |
452.77 |
4 |
4-NH2 |
C15H15N5O3S |
345.376 |
-0.05 |
137.13 |
451.37 |
5 |
4-OH,3-OCH3 |
C16H16N4O5S |
76.387 |
0.32 |
140.57 |
495.57 |
6 |
4-CH(CH3)2 |
C25H23N3O5 |
372.441 |
2.02 |
111.11 |
528.98 |
7 |
4-C(CH3)3 |
C26H25N3O5 |
386.468 |
2.32 |
111.11 |
564.79 |
8 |
4-N(CH3)2 |
C16H16N4O5S |
376.387 |
0.32 |
140.57 |
495.57 |
9 |
4-NO2 |
C15H13M.N5O5S |
375.359 |
0.72 |
156.93 |
476.76 |
10 |
3,4,5-(OCH3)3 |
C18H20N4O6S |
420.44 |
0.3 |
138.8 |
580.24 |
TPSA - Topological Polar surface area
SASA- Solvent Accessible Surface Area
S.NO |
R |
Lipinski rule of five |
Bio- |
Ghose |
Lead likeness |
Mugge |
Veber |
1 |
H |
Yes |
Yes |
Yes |
Yes |
Yes |
Yes |
2 |
4-OH |
Yes |
Yes |
Yes |
No |
Yes |
Yes |
3 |
4-Cl |
Yes |
Yes |
Yes |
Yes |
Yes |
Yes |
4 |
4-NH2 |
Yes |
Yes |
Yes |
Yes |
Yes |
Yes |
5 |
4-OH,3-OCH3 |
Yes |
Yes |
Yes |
Yes |
Yes |
No |
6 |
4-CH(CH3)2 |
Yes |
Yes |
Yes |
Yes |
Yes |
Yes |
7 |
4-C(CH3)3 |
Yes |
Yes |
No |
No |
Yes |
Yes |
8 |
4-N(CH3)2 |
Yes |
Yes |
Yes |
Yes |
Yes |
Yes |
9 |
4-NO2 |
Yes |
Yes |
Yes |
Yes |
No |
No |
10 |
3,4,5-(OCH3)3 |
Yes |
Yes |
Yes |
Yes |
Yes |
Yes |
S.No |
R |
nON |
nOHNH |
N violations |
nrotob |
Volume |
Mi Logp |
n Atoms |
1 |
H |
7 |
3 |
0 |
5 |
272.04 |
0.903 |
23 |
2 |
4-OH |
8 |
4 |
0 |
5 |
280.058 |
0.424 |
24 |
3 |
4-Cl |
7 |
3 |
0 |
5 |
285.576 |
1.581 |
24 |
4 |
4-NH2 |
8 |
5 |
0 |
5 |
283.329 |
0.021 |
24 |
5 |
4-OH,3-OCH3 |
9 |
4 |
0 |
6 |
305.604 |
0.243 |
26 |
6 |
4-CH(CH3)2 |
7 |
3 |
0 |
6 |
321.99 |
2.416 |
26 |
7 |
4-C(CH3)3 |
7 |
3 |
0 |
6 |
338.227 |
2.61 |
27 |
8 |
4-N(CH3)2 |
8 |
3 |
0 |
6 |
317.946 |
1.006 |
26 |
9 |
4-NO2 |
10 |
3 |
0 |
6 |
295.374 |
0.862 |
26 |
10 |
3,4,5-(OCH3)3 |
10 |
3 |
0 |
8 |
348.677 |
0.535 |
29 |
S.No |
R |
No of HBA |
No of HBD |
Mol Log p |
Mol Log s |
Mol PSA (A2) |
Mol volume (A3) |
No of stereo centres |
1 |
H |
6 |
3 |
1.7 |
-3.71(in Log(moles/L) 64.84 (in mg/L) |
92.98 A2 |
274.16 A3 |
0 |
2 |
4-OH |
7 |
4 |
1.44 |
-3.56(in Log(moles/L)94.63 (in mg/L) |
110.60 A2 |
284.70 A3 |
0 |
3 |
4-Cl |
6 |
3 |
1.6 |
-3.86(in Log(moles/L)94.63 (in mg/L) |
111.06A2 |
264.16 A3 |
0 |
4 |
4-NH2 |
6 |
5 |
1.2 |
-3.88(inLog(moles/L)) 45.80 (in mg/L) |
113.79 A2 |
281.58 A3 |
0 |
5 |
4-OH,3-OCH3 |
8 |
4 |
1.4 |
-3.83(inLog(moles/L)) 55.73 (in mg/L) |
117.16 A2 |
317.35 A3 |
0 |
6 |
4-CH(CH3)2 |
6 |
3 |
2.82 |
-5.18(inLog(moles/L)) 2.43 (in mg/L) |
92.98 A2 |
327.14 A3 |
0 |
7 |
4-C(CH3)3 |
6 |
3 |
3.31 |
-5.84(inLog(moles/L)) 0.56 (in mg/L) |
92.98 A2 |
358.69 A3 |
0 |
8 |
4-N(CH3)2 |
6 |
3 |
1.82 |
-4.28(inLog(moles/L)) 19.73 (in mg/L) |
95.79 A2 |
323.64 A3 |
0 |
9 |
4-NO2 |
8 |
3 |
1.37 |
-4.80(inLog(moles/L)) 6.00 (in mg/L) |
126.37 A2 |
299.07 A3 |
0 |
10 |
3,4,5-(OCH3)3 |
9 |
3 |
1.73 |
-3.87(inLog(moles/L)) 56.23 (in mg/L) |
115.96 A2 |
369.19 A3 |
0 |
S.No |
R |
GPCR |
Ion Channel Modulator |
Kinase Inhibitor |
Nuclear Receptor Ligand |
Protease Inhibitor |
Enzyme Inhibitor |
1 |
H |
-0.18 |
-0.4 |
-0.12 |
-0.58 |
0.06 |
-0.07 |
2 |
4-OH |
-0.13 |
-0.34 |
-0.08 |
-0.4 |
0.09 |
-0.02 |
3 |
4-Cl |
-0.17 |
-0.39 |
-0.14 |
-0.57 |
0.03 |
-0.11 |
4 |
4-NH2 |
-0.17 |
-0.38 |
-0.12 |
-0.54 |
0.07 |
-0.07 |
5 |
4-OH,3-OCH3 |
-0.18 |
-0.39 |
-0.07 |
-0.47 |
-0.02 |
-0.05 |
6 |
4-CH(CH3)2 |
-0.16 |
-0.37 |
-0.17 |
-0.45 |
0.07 |
0.07 |
7 |
4-C(CH3)3 |
-0.12 |
-0.29 |
-0.12 |
-0.38 |
0.07 |
0.06 |
8 |
4-N(CH3)2 |
-0.15 |
-0.37 |
-0.09 |
-0.48 |
-0.06 |
-0.08 |
9 |
4-NO2 |
-0.3 |
-0.4 |
-0.26 |
-0.6 |
0.06 |
-0.17 |
10 |
3,4,5-(OCH3)3 |
-0.21 |
-0.4 |
-0.11 |
-0.56 |
-0.04 |
-0.11 |
S.No |
R |
Druglikeness score |
1 |
H |
0.41 |
2 |
4-OH |
0.24 |
3 |
4-Cl |
0.33 |
4 |
4-NH2 |
0. 50 |
5 |
4-OH,3-OCH3 |
0.74 |
6 |
4-CH(CH3)2 |
0.93 |
7 |
4-C(CH3)3 |
0.83 |
8 |
4-N(CH3)2 |
0.48 |
9 |
4-NO2 |
0.36 |
10 |
3,4,5-(OCH3)3 |
0.74 |
Table 9 indicates the docking scores, binding energies and compared with the standard. All the compounds exhibited good binding energies, of which the propyl and t-butyl substituted phenyl ring containing compounds showed stronger interactions.
The detailed interaction of active compounds with Mur A, Mur C and Mur E are given in tables 10, 11 and 12 respectively. Most of the interactions of the compounds with amino acids at active site of the enzymes were due to hydrogen bonds, van der Waals and hydrophobic attractions. Compounds 6 [ΔG=-9.8(Kcal/mol)] and compound 9 [ΔG= -9.5(Kcal/mol)] were found to have good interactions at active site of Mur A enzyme than the standard Mur A inhibitor, Fosfomycin [ΔG= -4.8(Kcal/mol)] (Figure 4). The nitro group increased its efficiency or conformation of compounds towards active interaction. Schonbrunn et al reported similar type of interaction of the fluorescence probe 8-anilino-1-naphthalene sulfonate (ANS) with the antibiotic target MurA [25].
Of all the compounds, compound 6 and compound 9 with isopropyl substitution exhibited the highest scores against all the three Mur enzymes. Compound 7 showed good binding interactions with Mur C and Mur E. The Mur E enzyme of Mur pathway of Mycobacterium tuberculosis is an attractive drug target as it is unique to bacteria and is absent in mammalian cells [26].
This indicates the high specificity and good interactions of the compounds at binding pockets of these Mur enzymes. Docking studies were also conducted on Alpha amylase PDB ID: 3BC9 and Dihydropteroate synthase PDB ID:1ad4, but the compounds exhibited only mild interactions. Thus the compounds were found to be selective towards Mur enzymes (Table 9, Table 10, Table11, Table 12) (Figure 4, Figure 5, Figure 6).
S.No |
R |
||||||
Targets and Estimated binding energy ΔG(Kcal/mol) a |
|||||||
UDP-N |
UDP-N |
UDP-N |
Alpha PDB ID:3BC9 |
Dihydro |
|||
1 |
H |
-9 |
-9.2 |
-9.3 |
-7.5 |
-6.6 |
|
2 |
4-OH |
-9.1 |
-9.1 |
-9.2 |
-7.7 |
-6.4 |
|
3 |
4-Cl |
-9.3 |
-9.1 |
-8.3 |
-7.5 |
-6.9 |
|
4 |
4-NH2 |
-9.2 |
-9.1 |
-8.2 |
-7.6 |
-6.8 |
|
5 |
4-OH, |
-9.1 |
-9.1 |
-9.3 |
-7.5 |
-7 |
|
6 |
4-CH(CH3)2 |
-9.8 |
-9.7 |
-9.8 |
-7.9 |
-6.8 |
|
7 |
4-C(CH3)3 |
-8.8 |
-9.6 |
-9.7 |
-7.8 |
-6.6 |
|
8 |
4-N(CH3)2 |
-9 |
-9 |
-9.5 |
-7.6 |
-6.4 |
|
9 |
4-NO2 |
-9.5 |
-9.5 |
-9.5 |
-7.7 |
-6.9 |
|
10 |
3,4,5-(OCH3)3 |
-8.7 |
-9.1 |
-8.3 |
-7.3 |
-6.8 |
|
11 |
Standard |
-4.8 |
-5.2 |
-5.2 |
|
||
Sulfadiazine -4.7 |
Compound |
Hydrogen bond interactions |
Other interactions |
Fosfomycin |
|
van der Waals interactions of methyl group with Leu124A and Arg120A |
|
|
|
Compound 6 |
|
Hydrophobic aromatic pockets-(His125B, Pro303A, Pro293A) |
Compound 9 |
|
van der Waals interactions -(Gly164A,Val163A,Thr304A) |
Compound |
Hydrogen bond interactions |
Other interactions |
Phosphinate |
- |
van der Waals interactions of methyl group with Thr 120B,Gly123B,Gly342B and Arg321B, Aromatic interactions with His 286B |
Compound 6 |
|
Hydrophobic aromatic pockets-( Tyr341B, His122B,His343B, His286B) |
Compound 7 |
|
van der Waals interactions -( Lys 124B, Gly123B, Gly342B,Gly347B,Val250B, Thr125B, Thr126B) |
Compound |
Hydrogen bond interactions |
Other interactions |
Phosphinate |
|
Hydrophobic aromatic pockets(Tyr311D), van der Waals interactions of methyl group with Ser370D, Ser123D, Leu 346D and Thr127D |
Compound 6 |
|
Hydrophobic aromatic pockets-(Tyr 311D and Tyr 361D) |
|
|
|
Compound 7 |
|
van der Waals interactions -(Ser370D, Ser123D,Leu346D, Thr127D and Arg345D ) |
Docking studies further supported the biological activities. The results indicated the possible inhibitory activity towards the Mur enzymes. The results also indicate the selectivity towards Mur A, Mur C, & Mur E enzymes. Of all the compounds, compound 6 and compound 9 with isopropyl substitution exhibited the highest scores against all the three Mur enzymes. Compound 7 showed good binding interactions with Mur C and Mur E. Further research in this approach may be extended to decrease the in vitro evaluation on these enzymes. In addition, the synthesis of these compounds was also observed to be feasible. Thus this study will be promising in finding novel antimicrobial agents with the Mur enzyme inhibitory activity (or) peptidoglycan synthesis inhibitory activity and therapeutic potential as novel anti-TB drugs.
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