Design, synthesis and biological evaluation of spiropyrimidinetriones oxazolidinone derivatives as antibacterial agents

Article abstract of DOI:10.1016/j.bmcl.2018.02.055

Gram-positive bacteria are among the most common human pathogens associated with clinical infections which range from mild skin infections to sepsis. Resistance towards existing class of drugs by Gram-positive bacteria including methicillin resistant Stap

Full text of DOI:10.1016/j.bmcl.2018.02.055

Accepted Manuscript
Design, Synthesis and Biological Evaluation of Spiropyrimidinetriones Oxazo-
lidinone Derivatives as Antibacterial Agents.
Asher M. Siddiqui, Jitendra A. Sattigeri, Kalim Javed, Syed Shafi, M. Shamim,
Smita Singhal, Zubbair M. Malik
PII:
S0960-894X(18)30164-1
https://doi.org/10.1016/j.bmcl.2018.02.055
BMCL 25651
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 August 2017
7 January 2018
27 February 2018
Please cite this article as: Siddiqui, A.M., Sattigeri, J.A., Javed, K., Shafi, S., Shamim, M., Singhal, S., Malik, Z.M.,
Design, Synthesis and Biological Evaluation of Spiropyrimidinetriones Oxazolidinone Derivatives as Antibacterial
Agents., Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.02.055
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Design, Synthesis and Biological Evaluation
of Spiropyrimidinetriones Oxazolidinone
Derivatives as Antibacterial Agents.
Leave this area blank for abstract info.
Asher M Siddiquia,b, JitendraA Sattigeria, Kalim
b
b
b
a

Javed , Syed Shafi , Shamim M ,Smita Singhal
Zubbair M Malikc
aDaiichi Sankyo India Pharma Pvt. Ltd., Gurgaon, Haryana 122015, India
bDepartment of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi 110062, India
cCentre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
F
O
O
F
O
O
N
N
N
N
O
NH
OH
O
O
HN
O
NH
B Ring A Ring
C Ring
C5 side chain
B Ring
C5 side chain
A Ring
O
30n
Linezolid
MICs: 0.25 -8 µg/mL
 Corresponding author; e-mail: mohd.asher@gmail.com, kjaved@jamiahamdard.ac.in
1 |

Bioorganic & Medicinal Chemistry Letters
Design, Synthesis and Biological Evaluation of Spiropyrimidinetriones
Oxazolidinone Derivatives as Antibacterial Agents.
Asher M Siddiquia,b, Jitendra A Sattigeria, Kalim Javedb, Syed Shafib, Shamim Mb, Smita
Singhala, Zubbair M Malikc
a Daiichi Sankyo India Pharma Pvt. Ltd., Gurgaon, Haryana 122015, India
b Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New
Delhi 110062, India
c Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi
110025, India
Corresponding author: e-mail: mohd.asher@gmail.com, kjaved@jamiahamdard.ac.in
Abstract
Gram-positive bacteria are among the most common human pathogens associated with
clinical infections which range from mild skin infections to sepsis. Resistance towards existing class
of drugs by Gram-positive bacteria including methicillin resistant Staphylococcus aureus (MRSA),
Staphylococcus epidermidis (MRSE) and vancomycin resistant enterococci (VRE) is a growing
concern. There is an urgent need to discover new antibiotics which are active against resistant strains
of Gram positive bacteria. We report herein a novel class of spiropyrimidinetrione oxazolidinone
derivatives as novel antibacterial agents. Key step towards the synthesis of title compounds involved
the use of tert-amino reaction with [1,5]-hydride shift leading to the new C-C bond formation.
Compound 30n has demonstrated potent antibacterial activity against a panel of Gram-positive
microbial strains including MRSA, MRSE, and LNZ and vancomycin resistant strains of E.faecalis.
Further, molecular docking studies suggest that 30n has binding mode similar to that of LNZ in 50S
RNA ribosome.
Keywords: spiropyrimidinetrione, oxazolidinone, [1,5]-hydride shift, drug resistance.
2 |

The emergence of antibacterial resistance to existing antibiotics is posing a serious concern in
hospital settings and community1-4. Infections caused by multidrug-resistant Gram-positive bacteria
represent a major public health burden, not just in terms of morbidity and mortality, but also in terms
of increased financial burden on exchequer5-7. In recent decades, the discovery and development of
new antibiotics have slowed dramatically as scientific barriers to drug discovery; regulatory
challenges and diminishing returns on investment have led major drug companies to scale back or
abandon their antibiotic research. Consequently, the antibiotic discovery—which peaked in the
1950s—has dropped precipitously resulting in a lack of new antibiotics coming to the market8,9.
Treatment of infections caused by Gram-positive bacteria including Methicillin Resistant
Staphylococcus aureus10,11 (MRSA), Methicillin Resistant Staphylococcus epidermidis12 (MRSE) and
vancomycin resistant enterococci13(VRE) [E. faecalis and E. faecium] is increasingly becoming a big
challenge to health care professionals.
Linezolid (LNZ) 1 (Figure 1), an oxazolidinone class of synthetic antibiotic, was introduced into
the clinic around 20 years14,15 back for treating serious infections caused by Gram positive bacteria
such as S. aureus, S. epidermis and VRE16. Unfortunately, the resistance to LNZ started to appear soon
after its implementation for therapeutic use with the rate of resistance being high especially among
Enterococci and Staphylococcus epidermidis strains17,18. The most common mechanism by which
these pathogens develop resistance to LNZ is by manifesting G2576T/U mutation in the 23S rRNA
sub-unit. The second mechanism of resistance involves the plasmid-encoded cfr gene, an enzyme with
23S rRNA methyltransferase activity, which confers a pan-resistant phenotype involving
chloramphenicol, clindamycin and LZD19.
Figure 1: Linezolid
O
F
O
N
N
O
1
HN
O
C Ring
B Ring A Ring
C5 side chain
The most common approach to overcome antibacterial resistance is the modification of existing
classes of antibacterial agents to provide new analogues with improved attributes20. Since its
discovery, a number of second generation oxazolidinones (eg. 2&3, Figure 2) have been reported21-22
.
Additionally, a number of conformationally restricted oxazolidinone analogues23-24 (e.g. 4&5, Figure
2) having potent activity against Gram positive bacteria have also been reported. Recently,
3 |

25-26
AstraZeneca and Pfizer disclosed compounds 6 & 7 (Figure 3)
containing unique
Spiropyrimidinetrione (tetracyclic) structural framework which exhibited potent antibacterial activity.
Figure 2: Oxazolidinone based potent antibacterials.
O
F
O
F
N
N
N
O
O
N
N
N
N
O
O
N
N
P
N
ONa
N
HN
ONa
2
3
O
Tedizolid
Trius/Merck
Radezolid
Phase II (Melinta Therapeutics)
O
O
O
O
N
N
N
NC
N
O
O
HN
HN
O
O
4
5
Figure 3: Recently reported spiropyrimidinetriones based antibacterials
H
N
O
O
H
N
O
O
O2N
NH
N
O
O
NH
O
N
N
O
H
O
N
F
O
H
F
O
6
7
AstraZeneca
Pfizer
Herein, we report the design and synthesis of novel spiropyrimidinetriones 23a-d (Type I) and 30a-
s (Type II) as potential antibacterial agents (Figure 4). The key design aspect involved combining the
structural features of oxazolidinone and spiropyrimidinetriones class of antibacterial compounds.
Molecular framework of LNZ can be divided into A-ring (oxazolidinone), B-ring (phenyl), and C-ring
(morpholine), and a C-5 acylaminomethyl side chain on the A-ring27-28(Figure 1). In Type I class, ring
B and C were replaced by a new spiropyrimidinetrione moiety while keeping the oxazolidinone ring
A constant. While in Type II class of molecules, only ring C was replaced with the
4 |

Spiropyrimidinetrione moiety while keeping rings A and B constant. A key reaction in the synthesis
of this class of compounds was via tert-amino effect reaction (T-amino reaction)29 involving a[1, 5]-
hydride shift (Scheme 1) thus providing a novel methodology30-32 to construct pharmaceutically
relevant tetrahydroquinoline skeleton33.
Figure 4: Spiropyrimidinetrione oxazolidinone derivatives
O
N
F
O
N
O
O
O
N
O
N
O
O
HN
HN
A
N
H
HN
O
HN
O
O
O
O
N
H
O
A Ring
C5 side chain
B Ring A Ring
Type II
C5 side
chain
Type I
23a
(Representative eg)
30a
(Representative eg)
Scheme 1: Reaction mechanism of tert-amino effect
E
E
E
H
E
-
-
H
5
E
E
6
6
5
6
E
5
5
E
6
4
3
H
4
3
[1,5]-hydride shift
4
H
4
3
1
3
1
2 N+
2 N+ R`
1
2N
R`
R`
1
2 N
R`
R
R
R
R
8
9
10
11
The synthesis of Type I compounds 23a-d was initiated from the aldehyde 12 following standard
synthetic protocol. Thus, 16 was obtained in an overall yield of 75% in 4 steps. The compound 16 was
converted to oxazolidinone 17 by standard protocol34. Sequential functional group transformations led
to the formation of key intermediate 21 in 4 steps in an overall yield of 74%. Usual acetal
deprotection protocol afforded the aldehydes 22a-b. Heating intermediates 22a-b with barbituric acid
under microwave condition at 120ºC for 30 min led to the formation of 23a-d in 80-90% yield via T-
amino reaction (Scheme 2).
5 |

Scheme 2: Synthesis of Type I derivatives 23a-d
Reagents and conditions: (a) PTSA, ethylene glycol, toluene, reflux 3h, 85%; (b) Morpholine,
K2CO3, DMF, 70ºC, 4h, 90% ; (c) H2, Pd-C, MeOH, rt, 4h, 82%; (d)benzylchloroformate, aqueous
NaHCO3, acetone, 0ºC-rt, 5h, 90% ; (e) n-BuLi, (R)-glycidyl butyrate, THF, -78ºC - RT, 70%; (f)
MsCl, Et3N, DCM,0ºC-rt, 4h, 90%; (g) NaN3, DMF, 70ºC, 10h, 75%; (h) Ph3P, THF:H2O (3:1), RT-
50ºC, 6h, 70%; (i) (CH3CO)2O, Et3N, DCM, 0ºC -RT, 2h , 60%; (j) 1N. HCl, THF, 50ºC, 2h, 70%; (k)
n-BuOH, barbituric acid/pyrazolidine-3,5-dione, microwave, 120ºC, 30 min, 80-90%.
O
O
O
O2N
O2N
O2N
O
O
H
c
a
b
F
F
N
O
12
13
14
Y
Y
O
N
O
N
O
N
X
O
O
e
O
N
N
j
O
H
O
O
O
O
O
15 : X=NH2
16 : X=NHCBZ
22a; Y=OH
22b; Y=NHAc
17: Y=OH,
18: Y=OMs,
19: Y=N3,
d
f
g
h
i
20: Y=NH2 ,
21: Y=NHAc
Y
k
O
N
A
A = Barbituric acid (BA),
Pyrazolidine-3 5-dione (PD)
Y = OH, NHAc
tert-amino
reaction
O
N
O
23a-d*
*for structure details please refer to Table 01
6 |

Synthesis of Type II compounds 30a-s was initiated from aldehyde 24a-c35using standard organic
transformations. Thus, intermediates24a-c were converted into their corresponding borate esters25a-c
by Suzuki reaction. Palladium catalysed C-C coupling between 25a-c and 26a-b34 afforded 27a-f in
up to 65% yields (Scheme 3). Deprotection of BOC from intermediate 27a-c yielded free amines 28a-
c in up to 70% yield. Free amines were converted into corresponding amides 29a-f (60-75% yield),
carbamates 29g-j (65-75% yield) and sulphonamides 29k-l (70-80% yield) by standard derivatization
protocols. These advanced intermediates 29a-l were then converted to final compounds 30a-l via T-
amino reaction under microwave conditions by heating with barbituric acid for 30 min at 120ºC
(Scheme 4). Hydroxyl derivatives 30m-o were synthesized from intermediate 27d-f. Thus, TBS group
was deprotected by TBAF to afford intermediate 28d-f. Final compounds 30m-o were synthesized via
T-amino reaction using barbituric acid as the electron withdrawing group under microwave conditions
(75-90% yield). Likewise, derivatives 30p-q were synthesized from the corresponding intermediates
28f & 29c via T-amino reaction with pyrazolidine-3,5-dione as the participating electron withdrawing
group. Intermediates 28a & 28d on reaction with dimethylmalonate gave the corresponding
Knovenagel condensation products 29m-n, which on T-amino reaction using Gd(OTf)3 (lewis acid)36
afforded 30r-s (70-80%yield, Scheme 5).
7 |

Scheme 3: Synthesis of key intermediates 27a-f.
Reagents and conditons: (a) bis(pinacolato)diboron, KOAc, Pd(dppf)Cl2, dioxane, 80ºC, 4h; 50-60%
(b) Pd(dppf)Cl2, CsCO3, DMF/H2O, 80ºC, 6h, 50-65%
R
O
N
O
N
O
B
Br
O
b, 26
O
N
H
a
H
O
N
O
H
X
X
F
n
n
24 a-c
25 a-c
27 a-f
X
n
27a: X=O, n= 1, R=NHBOC
24a: X=O, n= 1
24b: X=CH, n= 1
24c: X=CH, n= 0
25a: X=O, n= 1
25b: X=CH, n= 1
25c: X=CH, n= 0
27b: X=CH, n= 1, R=NHBOC
27c: X=CH, n= 0, R=NHBOC
27d: X=O, n= 1, R=OTBS
27e: X=CH, n= 1, R=OTBS
27f: X=CH, n= 0, R=OTBS
R
N
Br
O
F
O
26a: R=NHBOC
26b: R=OTBS
8 |

Scheme 4: Synthesis of Type II compounds 30a-l
Reagents and Conditions: (a) dioxane 4.0 M HCl, MeOH, RT, 12h, 50-70%; (b)R1-COCl, TEA,
DCM, 0ºC-RT, 2h (R1=Me, Et, CF3), 60-75%; (c) R2-CO2Cl, TEA, DCM, 0ºC-RT, 2h (R2=Me, Et),
65-75%; (d) MeSO2Cl, TEA, DCM, 0ºC-RT, 2h, 70-80%;(e) n-BuOH, barbituric acid,microwave,
120ºC, 30 min, 75-90%;
R
H2N
O
N
O
N
O
N
O
N
O
O
H
a
H
F
F
X
X
n
n
27 a-c
28 a-c
28a: X=O, n= 1,
28b: X=CH, n= 1,
28c: X=CH, n= 0,
27a: X=O, n= 1, R=NHBOC
27b: X=CH, n= 1, R=NHBOC
27c: X=CH, n= 0, R=NHBOC
b
c
d
R2
O
R1
O
O
O
MeO2SHN
NH
NH
O
O
N
N
N
O
N
O
H
O
O
O
O
H
H
F
F
F
N
X
n
N
X
X
n
n
29a: X=O, n= 1, R1=Me
29b: X=CH, n= 1, R1=Me
29c: X=CH, n= 0, R1=Me
29d: X=O, n= 1, R1=Et
29e: X=CH, n= 0, R1=Et
29f: X=CH, n= 0, R1=CF3
29g: X=O, n= 1, R2=Me
29h: X=CH, n= 0, R2=Me
29i: X=O, n= 1, R2=Et
29j: X=CH, n= 0, R2=Et
29k: X=O, n= 1
29l: X=CH, n= 0
R
e
e
e
O
H
N
N
O
O
O
NH
F
O
N
X
n
30a-l*
R=NHCOR1, NHCO2R2,NHSO2Me
R1=Me, Et, CF3 R2=Me, Et
X=O,CH
n=0,1
*for structure details please refer to Table 02
9 |

Scheme 5: Synthesis of Type II compounds 30m-s
(a) TBAF, THF, 12h 70-85%; (b) n-BuOH, barbituric acid, microwave, 120ºC, 30 min,75-
90%; (c) n-BuOH, pyrazolidine-3,5-dione, microwave, 120ºC, 30 min,75-85%; (d)
Dimethylmalonate, piperidine, AcOH, toluene, reflux, 6h, 60-70%; (e) ACN, Gd(OTf)3, RT,
3h, 70-80%.
R
HO
HO
O
O
H
N
N
N
O
O
O
N
N
O
O
N
O
O
O
H
NH
a
b
H
F
F
O
F
N
X
X
X
n
n
n
28d: X=O, n= 1
28e: X=CH, n= 1
28f: X=CH, n= 0
30m: X=O, n= 1
30n: X=CH, n= 1
30o: X=CH, n= 0
27d: X=O, n= 1, R=OTBS
27e: X=CH, n= 1, R=OTBS
27f: X=CH, n= 0, R=OTBS
R
O
N
H
O
N
O
c
NH
28f, 29c
F
O
N
30p: R=OH
30q: R=NHAc
R
R
O
O
O
N
N
CO2Me
H
MeO2C
CO2Me
CO2Me
O
d
e
28a, 28d
F
N
F
N
O
O
29m: R=OH
29n: R=NHAc
30r: R=OH
30s: R=NHAc
Antimicrobial activity of compounds 23a-d was tested against a panel of Gram positive bacterial
strains including S. aureus ATCC 29213, MRSA 562, MRSA DB-00026, LNZR(LNZ resistant) S.
aureus ATCC 13709, S. epidermidis ATCC 12228, MRSE ATCC 35984 and LNZRS.
epidermidis1117174. Compounds 23a-d did not elicit any antimicrobial activity (MIC > 32 µg/mL)
against this panel of Gram positive bacterial strains (Table 1).
10 |

Table 1: MICs (µg/mL) of Type I compounds 23a-d.
Y
O
N
A
O
O
N
23a-d
A
Y
MICs(µg/mL)
23
a
BA
BA
PD
PD
NHAc
OH
>32
>32
>32
>32
b
c
NHAc
OH
d
BA-Barbituric acid
PD-Pyrazolidine-3 5-dione
Interestingly, compound 30a belonging to Type II class exhibited antibacterial activity comparable
to LNZ against the tested panel of Gram-positive pathogens (Table 2). Extensive three-point
modification around the structure 30a was performed (Figure 5). Morpholine, pyrrolidine, and
piperidine derivatives were synthesized in the tertiary amine portion. Barbituric acid, pyrazolidine-3
5-dione, and dimethyl malonate were utilised as electron withdrawing groups. Amides, carbamates,
sulphonamides, and hydroxyl groups were used as substituents on C5 oxazolidinone side chain. We
prepared a total of 19 new compounds by the multistep reactions (Scheme 3,4,5) for this SAR study
(Table 2). From amongst all the compounds 30b, 30c, 30h & 30n were found to be the most potent.
These four potent compounds were further profiled against a panel of LNZR and vancomycin resistant
enterococci strains (Table 3). These compounds exhibited moderate to good in-vitro antibacterial
activity against the tested pathogens. In particular, 30n showed appreciable activity against the LNZ
and vancomycin resistant enterococci strains.
Based on these results it was possible to deduce some preliminary SAR. First, Methylcarbamates
(30g) and acetamide (30a) were found to exhibit superior activity than other morpholine derivatives
(30d, 30i, 30k, 30m). Second, barbituric acid derivatives (30a, 30c) showed better antibacterial
activity profile than dimethyl malonate(30s) and pyrazolidine-3 5-dione(30q). Third, pyrrolidine (30c,
11 |

30o) and piperidine (30b, 30n) derivatives were found to exhibit better antibacterial profile than the
morpholine derivative (30a, 30m).
Table 2: MICs (µg/mL) of Type II compounds30 a-s.
R
O
N
O
A
F
N
X
n
MICs (µg/mL)
S.aureus
S.aureus
MRSE
ATCC
35984
S.epidermidis
1117174
(LNZR)
MRSA
S.epidermidis
MRSA
30
A
n
X
R
ATCC
29213
ATCC 13709
Smith (LNZR)
562
ATCC 12228
DB-00026
a
b
c
d
e
f
BA
BA
BA
BA
BA
BA
BA
BA
BA
BA
BA
BA
BA
BA
BA
PD
1
1
0
1
0
0
1
0
1
0
1
0
1
1
0
0
0
1
1
O
NHCOMe
NHCOMe
NHCOMe
NHCOEt
NHCOEt
NHCOCF3
NHCO2Me
NHCO2Me
NHCO2Et
NHCO2Et
NHSO2Me
NHSO2Me
OH
4
4
8
32
4
2
2
4
8
8
4
2
8
8
16
8
4
2
2
2
8
8
4
2
2
32
CH
CH
O
2
<1
2
2
16
<1
<1
4
>32
32
2
2
16
8
4
16
8
>32
32
32
CH
CH
O
16
32
4
4
4
32
8
16
8
32
4
32
g
h
i
4
>32
>32
>32
>32
>32
>32
32
2
32
CH
O
2
2
4
2
32
16
8
8
16
8
8
32
j
CH
O
4
8
>32
>32
32
k
l
32
16
8
32
8
32
16
8
32
4
CH
O
m
n
o
p
q
r
s
4
2
32
CH
CH
CH
CH
O
OH
4
2
4
16
<1
<1
<1
4
32
OH
4
2
8
32
32
OH
4
2
8
32
32
PD
NHCOMe
OH
8
8
8
>32
>32
>32
>32
>32
>32
32
DM
DM
16
8
8
16
16
2
8
O
NHCOMe
4
4
Linezolid
2
2
2
>32
BA-Barbituric acid, DM-Dimethyl malonate,
PD-Pyrazolidine-3,5-dione
12 |

Figure 5: SAR of the synthesized spiropyrimidinetrione oxazolidinone derivatives.
O
OMe
OMe
N
O
O
N
O
Acetamides
N
methylcarbamate and
hydroxyl derivatives
were found to be potent
(MIC ≤ 2mg/mL)*
O
O
O
O
N
O
N
O
N
O
N
O
N
O
N
O
N
O
O
N
O
F
Barbituric acid
O
N
O
derivatives showed
good activity (1-2
mg/mL)*
30a
Pyrrolidine and piperidine
derivatives were found to be
more potent (MIC ≤ 2 mg/mL)*
N
F
O
F
N
N
O
N
S
O
O
F
than corresponding morpholine
derivatives
N
N
O
NH2
OH
* MICs in µg/mL against MRSA 562 strains
Table 3: MICs (µg/mL) of selected Type II compounds against enterococci.
MICs ( µg/mL)
E.faecalis
29212 ATCC
LNZR
E.faecalis
ATCC
29212
E.faecalis
ATCC 51299
E.faecalis
ATCC 19434
E.faecium
R1 VRE
E.faecium
E.faecium
31/132 VRE
30
303 LNZR
b
1
4
2
2
2
8
2
2
2
1
16
16
>32
8
2
c
2
4
2
2
2
h
n
8
16
2
16
2
8
16
2
1
0.25
4
Linezolid
Vancomycin
4
>32
2
2
>32
2
2
>32
0.5
0.5
>32
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Computational studies have become a very prominent tool in drug discovery37. In order to
understand the potency of the synthesized compounds and guide the further structure activity
relationship, molecular docking studies were performed in relation with LNZ. For the purpose of this
study, crystal structure of 50S ribosome unit of E.coli (PDB ID: 3CPW) was used.
The key interaction of LNZ is that of oxazolidinone ring A. The oxazolidinone ring along with C5
acylacetamide has good shape complimentary with ribosome. Fluorophenyl ring B is involved in the
typical aromatic shifted π stacking interaction. The morpholine ring apparently does not make
significant interaction with the ribosome. This has been substantiated with the fact that many different
functional groups have been substituted without appreciable loss in activity38.Docking studies with
30n was then performed using 50S ribosome unit of E.coli (PDB ID: 3CPW). The OH attached to the
oxazolidinone ring makes a hydrogen bond with base portion of G2646 (estimated bond length 3.18
A). Oxygen of the barbituric acid also shows hydrogen bond with G2540 (estimated bond length 2.94
A). Spiropyrimidinetriones moiety is stabilised through hydrophobic interaction with C2487, U2541,
A2486 and G2102. The aromatic fluorophenyl ring proximal to oxazolidinone is stabilised by A2099,
A2100 and A2538 (Figure 6). We also performed an overlay of LNZ and 30n and observed that both
bind in the same region (Figure 7). Interestingly, spiropyrimidinetriones moiety (barbituric acid)
played a key role in addition to the oxazolidinone ring.
Figure 6: Molecular docking studies of compound 30n
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Figure 7: Overlay of 30n and Linezolid.
In summary, several novel oxazolidinone type antibacterial bearing a unique spiropyrimidinetriones
moiety were synthesized and evaluated for their antibacterial properties. Most of the Type II
synthesized compounds exhibited in-vitro antibacterial activity (MIC range 1-8µg/mL) and several
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compounds 30b, 30c, 30h & 30n showed potent activity against multidrug resistant pathogens (MIC
range 0.25-2µg/mL). Compound 30n in particular exhibited potency similar to Linezolid with activity
on Linezolid and Vancomycin resistant strains. The detailed evaluation of this compound is ongoing
and would be the subject matter of future communications.
Acknowledgments
AMS, JAS acknowledge DAIICHI SANKYO INDIA PHARMA LTD for providing the appropriate
facilities to accomplish the work.
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