Design, synthesis, antimycobacterial activity and molecular docking studies of novel 3- (N-substituted glycinamido) benzoic acid analogues as anti tubercular agents

Article abstract of DOI:10.1016/j.bmcl.2020.127603

We have recently identified mycolic acid methyl transferase (MmaA1) enzyme inhibitors as potential antitubercular agents using in silico modelling techniques. In continuation of that study, we synthesised a series of novel 3-(N-substituted glycinamido) benzoic acid derivatives with an aim to optimise the lead molecule. The newly synthesised compounds were evaluated for their in vitro antimycobacterial activity against M. tuberculosis H₃₇Rv. Among these, 5 compounds A3, A4, A5, A6 and A10 exhibited most potent activity with an MIC value of 1.6 μg/ml. Further molecular docking studies were carried out to investigate the binding mode of the ligands with MmaA1 protein. The docking studies revealed that the ligands made strong interactions with the catalytic site residues TRP30, TYR 32, GLY 71, TRP 74, GLY 76, ALA 77 and GLU 136 of MmaA1 protein. Druglikeness and leadlikeness properties of the compounds were also studied using computational tools. The results of in silico and in vitro studies indicate that these novel compounds are propitious leads for tuberculosis therapy.

Full text of DOI:10.1016/j.bmcl.2020.127603

Journal Pre-proofs
Design, synthesis, antimycobacterial activity and molecular docking studies of
novel 3- (N-substituted glycinamido) benzoic acid analogues as anti tubercu‐
lar agents
Hymavathi Veeravarapu, Mohan Tirumalasetty, Sony Priya Kurati, Umarani
Wunnava, Murali Krishna Kumar Muthyala
PII:
S0960-894X(20)30714-9
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127603
BMCL 127603
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Bioorganic & Medicinal Chemistry Letters
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30 September 2020
3 October 2020
Please cite this article as: Veeravarapu, H., Tirumalasetty, M., Priya Kurati, S., Wunnava, U., Krishna Kumar
Muthyala, M., Design, synthesis, antimycobacterial activity and molecular docking studies of novel 3- (N-
substituted glycinamido) benzoic acid analogues as anti tubercular agents, Bioorganic & Medicinal Chemistry
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Design, synthesis, antimycobacterial activity and molecular docking studies of novel
3- (N-substituted glycinamido) benzoic acid analogues as anti tubercular agents
Hymavathi Veeravarapu, Mohan Tirumalasetty, Sony Priya Kurati, Umarani Wunnava and
Murali Krishna Kumar Muthyala*
Pharmaceutical Chemistry Research Lab, AU College of Pharmaceutical Sciences, Andhra
University, Visakhapatnam, India.
*Corresponding author address:
Dr. M. Murali Krishna Kumar
Pharmaceutical Chemistry Research Laboratory
AU College of Pharmaceutical Sciences
Andhra University
Visakhapatnam – 530003
Andhra Pradesh, INDIA
Email ID: drmmkau@gmail.com
1

Abstract
We have recently identified mycolic acid methyl transferase (MmaA1) enzyme
inhibitors as potential antitubercular agents using in silico modelling techniques. In
continuation of that study, we synthesised a series of novel 3- (N-substituted glycinamido)
benzoic acid derivatives with an aim to optimise the lead molecule. The newly synthesised
compounds were evaluated for their in vitro antimycobacterial activity against M.
tuberculosis H37Rv. Among these, 5 compounds A3, A4, A5, A6 and A10 exhibited most
potent activity with an MIC value of 1.6 μg/ml. Further molecular docking studies were
carried out to investigate the binding mode of the ligands with MmaA1 protein. The docking
studies revealed that the ligands made strong interactions with the catalytic site residues
TRP30, TYR 32, GLY 71, TRP 74, GLY 76, ALA 77 and GLU 136 of MmaA1 protein.
Druglikeness and leadlikeness properties of the compounds were also studied using
computational tools. The results of in silico and in vitro studies indicate that these novel
compounds are propitious leads for tuberculosis therapy.
Keywords
Tuberculosis; 3- (N-substituted glycinamido) benzoic acid; methyl transferases; MABA
assay; molecular docking
2

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis is
distinguished by its lipid rich cell wall. It contains a complex structure of covalently linked
peptidoglycan, arabinogalactan and mycolic acids1-3. Mycolic acids are very long chain (C40-
C60) fatty acids which often carry substitutions like alcohol, ether and cyclopropyl groups.4,5
These substitutions bring about necessary functional changes in mycolic acids, including
maintenance of cell wall rigidity, physical strength of cell wall and virulence6,7.
Mycolic acid methyl transferases belong to the mycolic acid cyclopropane synthases
family and are involved in the synthesis of methoxy mycolic acids. Mycolic acid methyl
transferase (MmaA1) belongs to a gene cluster that encodes four closely related methyl
transferases (MmaA1-4) that introduce post synthetic modifications in the meromycolate
chain of mycobacteria8. The methyl transferases share a common cofactor, S-adenosyl
methionine (SAM). These SAM dependent enzymes bring about post synthetic modifications
and unsaturations in the synthesis of mycolic acids9,10. MmaA1 protein is required for the
synthesis of trans and keto mycolic acids in the mycobacteria. The MmaA1 protein converts
cis-olefin oxygenated precursors of mycolates to trans-olefins with an adjacent methyl branch
to form trans mycolic acids. Increased trans mycolic acid synthesis leads to increased cell
wall rigidity, increased drug resistance and altered colony morphology.
Our research group has recently reported the identification of 3-(2-
morpholinoacetamido)-N-(3,4-dihydro-4-oxoquinazolin-7-yl)benzamide and its intermediates
as inhibitors of MmaA1 protein using structure-based drug design studies.11 This molecule
exhibited an activity of 100 µg/ml, whereas the intermediate compound 3-(2-
chloroacetamido) benzoic acid or 3-(N-substituted glycinamido) benzoic acid exhibited an
MIC of 25 µg/ml against M. tuberculosis H37Rv. With an aim to optimize the structure
further, we proceeded to synthesise the derivatives of 3-(N-substituted glycinamido) benzoic
3

acid (Fig 1). The synthesised compounds were screened for in vitro anti TB activity along
with molecular docking studies and in silico ADME studies. The results of our study are
discussed here in this publication.
Fig.1: Design of scaffold for synthesis of 3-(N-substituted glycinamido)
benzoic acid derivatives
The retrosynthetic analysis (scheme 1) of the chosen scaffold has given us simple and
easily accessible starting materials. Here, Schotten Baumann reaction of 3-amino benzoic
acid with chloroacetyl chloride has given us the first starting material 3-(2-chloroacetamido)
benzoic acid. This, then undergoes nucleophilic substitution reaction with corresponding
amine to realize the target compound.
4

O
O
Cl
H2N
Cl
NH
OH
O
O
N
O
O
HN
OH
Scheme 1: Retrosynthetic route of 3-(2-chloroacetamido)
benzoic acid
The synthesis of 3-(N-substituted glycinamido) benzoic acid derivatives was brought
about by two different procedures resulting in excellent yields (70-95%). The synthesis of
aliphatic amine substituted 3- (N-substituted glycinamido) benzoic acid derivatives is given
in Scheme 2. The synthetic procedure for aromatic amine substituted 3-(N-substituted
glycinamido) benzoic acid derivatives is given in Scheme 3. The detailed procedures for the
synthesis are given in the supplementary information.
Scheme 2: Synthesis of aliphatic amine substituted of 3- (N-substituted
glycinamido) benzoic acid derivatives and their yields
5

Scheme 3: Synthesis of aromatic amine substituted derivatives of
3- (N-substituted glycinamido) benzoic acid and their yields
The newly synthesised compounds were evaluated against H37Rv for their anti-TB
activity using MABA assay 12,13. The results showed the compounds A3-A6 and A10 to have
the highest anti-TB activity with an MIC of 1.6 μg/ml (fig 2). They are more than twice as
potent as the standard drugs Pyrazinamide (MIC = 3.12 μg/ml), Ciprofloxacin (MIC= 3.12
μg/ml) and Streptomycin (MIC= 6.25 μg/ml).
The compounds obtained from aliphatic amines have shown better activity than those
obtained from aromatic amines. Here, replacement of morpholine (A1) with piperidine (A5)
significantly improved potency from MIC 25 μg/ml to 1.6 μg/ml. In case of anilines,
presence of halogens improved bioactivity in the order 2,4-di F > 4-Br > 4-Cl. In contrast,
presence of electron donating groups on aromatic ring, significantly reduced the potency.
This suggests that the scaffold 3- (N-substituted glycinamido) benzoic acid is very important
6

for activity and further substitutions of the scaffold with aliphatic heterocyclic groups and
substituted aromatic amine groups help in enhancing its activity.
Fig 2: MABA assay results of the compounds A1-A14
14
Further, molecular docking studies were performed using PyRx15 at the active site
of the MmaA1 protein with all the 14 synthesised molecules to understand the binding mode
of the ligands towards the MmaA1 protein. Docking was carried out using AutoDock Vina16
module in PyRx. The ligand input files were prepared using OpenBabel17. OpenBabel was
used to convert ligands to Sybyl Mol2 format, the input format for PyRx. The ligands were
subject to minimisation for 200 steps using Steepest descent method with a step size of 0.02
and 20 steps of Conjugate gradient minimisation in Chimera18.
For the docking study, regular protocol i.e., considering the protein structure rigid and
ligands flexible was implemented. A total of 9 conformations were generated for each docked
pose of the ligand. The output files are evaluated by visual inspection of the docking
conformations and binding affinity. The active site information was taken from our previous
study.11 The active site residues of the MmaA1 protein are ASP 19, TRP 30, TYR 32, GLY
71, TRP 74, GLY 76, ALA 77 and PHE 135 which were predicted from CASTp19, SiteMap20
7

and protein-ligand docking using PatchDock21 with S-adenosyl-N-decyl-aminoethyl
(SADAE). SADAE is a potent bi-substrate inhibitor of M. tuberculosis mycolic acid methyl
transferases.22 S-adenosyl-N-decyl-aminoethyl (SADAE) is a molecule in which the amino
acid moiety of S-adenosyl methionine is substituted by a lipid chain. The adenosine moiety of
SADAE replaces the cofactor, S-adenosyl methionine (SAM) and the lipid chain is deeply
buried in the hydrophobic environment created by the residues lining the substrate-binding
pocket. Therefore, docking of the MmaA1 protein was carried out with SADAE and all the
designed molecules to ascertain whether they bind at the same active site and occupy similar
conformation as that of SADAE.
The docking results were prioritised based on their binding affinity. Analysis of the
docking results show that the ligands A1- A14 bind with the predicted active site residues,
i.e., TRP 30, VAL 31, TYR 32, GLY 71, TRP 74, GLY 76, ALA 77 and PHE 135 of
MmaA1 protein. The active site of MmaA1 protein is lined by non-polar hydrophobic amino
acids, i.e., TYR, TRP, GLY, VAL and PHE. Hence the active site is buried inside the protein
core and occupies a large volume which is divided into co-factor binding site and
hydrophobic binding site. The ligand A4 is the highest scoring ligand with a binding affinity
of -9.9 kcal/mol. It binds at the SAM (co-factor) binding site in the active site of the protein.
It is involved in hydrogen bond interactions with the residues TRP 30 and TYR 74 and pi-pi
interactions with TYR 32 of MmaA1 protein which is shown in figures 3(a) and (b).
8

Fig 3(a): Docking interactions of ligand A4 with the residues of MmaA1protein at the
active site. The ligand A4 is represented as blue colour ball and stick model
and the protein is represented as grey colour cartoon, the active site residues
of the MmaA1 protein interacting with the ligand as grey colour ball and
sticks.
(b): 2-D view of the interactions of A4 with the active site residues of MmaA1
protein
The docked complex of SADAE with MmaA1 protein shows that SADAE sits both in
the co-factor binding (SAM binding site) site and the putative substrate binding pocket. All
the ligands show similar conformation at the active site of the MmaA1 protein which is
represented in figure 4.
Fig. 4: Binding mode of all the compounds at the active site of MmaA1 protein along
with SADAE. The right side figure shows the magnified view at the active site of
9

MmaA1 protein. The figure shows the ligands are aligned to the adenine moiety of
SADAE. SADAE is represented as blue color ball and stick model, the ligands
A1-A14 are represented in green color ball and stick model.
Fig 5. Alignment of the docked compounds at the active site of MmaA1 protein shown in
surface representation. SADAE is represented as blue color ball and stick model and the
compounds A1-A14 shown as red color ball and stick model.
The docked complexes of A1-A14 show that they occupy the cofactor binding site
replacing the adenosine moiety of the SAM similar to SADAE (fig 5). Therefore, the
alignment of the molecules with SADAE was studied and it revealed that they are aligned to
the adenosine moiety of SADAE, resulting in the opening of the hydrophobic tunnel in the
active site. Figure 6(a) shows the alignment of the top ranked ligand A4 with SADAE in the
active site, indicating that A4 occupies only the SAM binding site whereas SADAE has an
extended conformation into the hydrophobic site due to its lipid moiety. While the docked
conformation of ligand A4 shows that the hydrophobic site is in open conformation while it is
occupying only the SAM binding site, represented in figure 6(b). The hydrogen bonding and
pi-pi interactions with the residues TRP 30, TYR 32, TRP 74 might be responsible for the
opening of the hydrophobic tunnel in the active site. But here, in this study we were
10

interested only in the binding interactions and activity of the designed molecules. The active
site dynamics of the protein are beyond the scope of present study.
Fig. 6(a): Docked conformation of the top-ranking ligand 3-(2-(4-phenyl piperazin-1-yl)
acetamido) benzoic acid (A4) and SADAE in the active site of the MmaA1 protein.
A4 is represented as blue colour ball and stick model and SADAE is represented as
red colour ball and stick model.
(b): Conformation of the top-ranking ligand 3-(2-(4-phenylpiperazin-1-yl)
acetamido) benzoic acid (A4) without SADAE at the active site of MmaA1 protein.
From the docking analysis of the ligands, A4 (∆G = -9.9 kcal/mol), A10 (∆G = -9.4
kcal/mol) and A7 (∆G = -7.1 kcal/mol), (Table 2 in supplementary information) it is evident
that the binding site residues TRP 30, TYR 32, TRP 74 appear to play a crucial role in ligand
binding affinity and contribute to higher docking scores (∆G value). In the docking poses it is
observed that, the poses obtained at receptor site (co-factor site) showed the best score among
the docked conformers. In case of ligand A4, it showed a dock score of -9.9 kcal/mol when
bound at the receptor site and a ∆G value of -8.5 kcal/mol when bound away from the active
site pocket (supplementary data).
11

The carboxylic acid group in the benzoic acid moiety of the 3-(N- substituted
glycinamido benzoic acid) appears to be important for binding with the MmaA1 protein.
Especially, when the C=O group is involved in H-bond interactions with the residues TRP 30
and TRP 74 and pi-pi interactions with TRP 32 of the MmaA1 protein the binding affinity
(∆G) is higher (>9) but when it interacts with other residues such VAL 31, CYS 72, GLY 75,
GLY 76 and ALA 77 the binding affinity (∆G) is found to be lower. In case of aromatic
amine substituted derivatives the benzene ring (aromatic moiety) is involved in pi-pi
interactions with VAL 31 and TYR 32 which is favourable for increased binding affinity
(∆G).
Further docking analysis has shown the parent compound (3-(2-
morpholinoacetamido)-N-(1, 4-dihydro-4-oxoquinazolin-6-yl) benzamide) has a binding
affinity of -10.7 Kcal/mol, whereas the scaffold (3-(2-chloroacetamido) benzoic acid) has
-7.4 Kcal/mol. Substituting the chloro group with the different substituents led to varying
values of binding affinity. For ex. substituting the chloro group with phenyl piperazine, 2,4-
difluoro aniline, aniline, 4-chloroaniline, p-toluidine and benzyl piperazine showed higher
docking scores (>9). Whereas substituents like piperidine, pyrrolidine, di-ethyl amine and
morpholine resulted in lower docking scores (fig 7). This shows that the substituting the
chloro group with bulkier groups and substituted aromatic groups results in good binding
affinity with the protein. This supports that the presence of bulkier groups is essential for
good binding affinity when compared to smaller substituents.
12

Fig 7: Binding energitics of the ligands with MmaA1 protein at the
active site. The active site residues of the protein are shown as
green colour sticks. The ∆G values for the different ligands are
given.
Compounds with undesirable properties and poor ADMET (Absorption, Distribution,
Metabolism, Excretion and Toxicity) profiles are responsible for clinical failures at later
stages of drug discovery23-25. Identifying and eliminating potentially toxic molecules at early
stages is therefore very essential26. ADMET properties for the compounds were predicted
using molinspiration27, PreADMET28 and SwissADME.29 All the important ADME
parameters like leadlikeness, druglikeness, blood brain permeation (BBB), GI absorption and
CYP inhibition30-32 were predicted. The number of rotatable bonds (<10), low polar surface
area (<140 Å2) and fewer H-bond donors and acceptors are important predictors for oral
bioavailability.33 The results show that the compounds are well absorbed and do not permeate
through BBB which is a very essential prerequisite for any drug/lead like compound. The
results show all the ligands have drug like properties and A1, A3-A5, A7, A8, A10 - A13
have lead like properties. (details given in Supplementary data)
In summary, novel 3- (N-substituted glycinamido) benzoic acid derivatives were
synthesised and evaluated for their anti-TB activity. Five compounds A3, A4, A5, A6 and
13

A10 exhibited excellent anti-TB activity of MIC 1.6 μg/ml against M. tuberculosis H37Rv.
Molecular docking was carried out to understand the molecular interactions of the molecules
with the MmaA1 protein which revealed the residues TRP 30, VAL 31, TYR 32, GLY 71,
TRP 74, GLY 76, ALA 77 and PHE 135 of MmaA1 protein to have important hydrogen
bonding interactions and pi-pi interactions with the ligands resulting in good docking scores
ranging from -9.9 to -7.1. The in silico ADMET results have shown the compounds A1, A3-
A5, A7, A8, A10 - A13 to have druglikeness and leadlikeness properties. Our study resulted
in identification of derivatives of 3- (N-substituted glycinamido) benzoic acid as a new class
of MmaA1 enzyme inhibitors.
14

Acknowledgements
The author HV acknowledges Department of Science and Technology (DST), Government of
India for financial support under the Women Scientist Scheme (WOS-A) vide reference no.
SR/WOS-A/CS-1031/2014.
The authors HV, MT, SPK, UW and MMK acknowledge The Principal, AU College of
Pharmaceutical Sciences, Andhra University, Visakhapatnam, India, for providing the
facilities to carry out this work.
The authors HV, MT, SPK, UW and MMK thank The Director, NMR Research Centre,
Andhra University, Visakhapatnam, India for providing the spectral data.
Conflict of interest
The authors declare that they have no conflict of interest.
15

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Design, synthesis, antimycobacterial activity and molecular docking studies of novel
3-(N-substituted glycinamido) benzoic acid analogues as anti tubercular agents
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Design, synthesis, antimycobacterial activity and molecular docking studies of novel
3-(N-substituted glycinamido) benzoic acid analogues as anti tubercular agents
 Novel derivatives of 3-(N-substituted glycinamido) benzoic acid have been
synthesised using various aliphatic and aromatic amines
 The synthesised compounds exhibited potent antimycobacterial activity carried out
using MABA assay
 Molecular docking studies revealed important binding interactions of the compounds
within the active site of the MmaA1 protein
 in silico ADMET studies aided in identifying promisable lead compounds
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