Exploration of diphenylalkyloxadiazoles as novel cardiac myosin activator

Article abstract of DOI:10.1016/j.bmcl.2018.06.031

To explore novel cardiac myosin activator, a series of diphenylalkyl substituted 1,3,4-oxadiazoles and 1,2,4-oxadiazoles have been prepared and tested for cardiac myosin ATPase activation in vitro. In all cases, three carbon spacer between the oxadiazole core and one of the phenyl ring was considered crucial. In case of 1,3,4-oxadiazole, zero to two carbon spacer between oxadiazole core and other phenyl ring are favorable. Phenyl ring can be replaced by cyclohexyl moiety. In case of 1,2,4-oxadiazole, zero or one carbon spacer between the oxadiazole and other phenyl ring are favorable. Introduction of hydrogen bonding donor (NH) group at the 2^nd position of the 1,3,4-oxadiazole enhances the activity. Substitutions on either of the phenyl rings or change of phenyl ring to other heterocycle are not tolerated for both the oxadiazoles. The prepared oxadiazoles showed selective activation for cardiac muscle over smooth and skeleton muscles.

Full text of DOI:10.1016/j.bmcl.2018.06.031

Accepted Manuscript
Exploration of diphenylalkyloxadiazoles as novel cardiac myosin activator
Manoj Manickam, Pulla Reddy Boggu, Thanigaimalai Pillaiyar, Niti Sharma,
Hitesh B. Jalani, Eeda Venkateswararao, Sang-Hun Jung
PII:
S0960-894X(18)30520-1
https://doi.org/10.1016/j.bmcl.2018.06.031
BMCL 25912
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 April 2018
14 June 2018
15 June 2018
Please cite this article as: Manickam, M., Reddy Boggu, P., Pillaiyar, T., Sharma, N., Jalani, H.B., Venkateswararao,
E., Jung, S-H., Exploration of diphenylalkyloxadiazoles as novel cardiac myosin activator, Bioorganic & Medicinal
Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.06.031
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Exploration of diphenylalkyloxadiazoles as novel cardiac myosin activator
Manoj Manickam, Pulla Reddy Boggu, Thanigaimalai Pillaiyar, Niti Sharma, Hitesh B. Jalani,
Eeda Venkateswararao, Sang-Hun Jung*
College of Pharmacy and Institute of Drug Research and Development, Chungnam National
University, Daejeon 34134, Republic of Korea
Abstract
To explore novel cardiac myosin activator, a series of diphenylalkyl substituted 1,3,4-
oxadiazoles and 1,2,4-oxadiazoles have been prepared and tested for cardiac myosin ATPase
activation in vitro. In all cases, three carbon spacer between the oxadiazole core and one of the
phenyl ring was considered crucial. In case of 1,3,4-oxadiazole, zero to two carbon spacer
between oxadiazole core and other phenyl ring are favorable. Phenyl ring can be replaced by
cyclohexyl moiety. In case of 1,2,4-oxadiazole, zero or one carbon spacer between the
oxadiazole and other phenyl ring are favorable. Introduction of hydrogen bonding donor (NH)
group at the 2nd position of the 1,3,4-oxadiazole enhances the activity. Substitutions on either of
the phenyl rings or change of phenyl ring to other heterocycle are not tolerated for both the
oxadiazoles. The prepared oxadiazoles showed selective activation for cardiac muscle over
smooth and skeleton muscles.
Keywords: Cardiac myosin activator, 1,3,4-oxadiazoles, 1,2,4-oxadiazoles.
*Corresponding author: jungshh@cnu.ac.kr. Tel.; +82 42 821 5939; Fax +82 42 823 6566;
Present address: College of Pharmacy and Institute of Drug Research and development,
Chungnam National University, Daejeon 34134, Korea

Heart failure (HF) affects at least 26 million people worldwide and is increasing in prevalence.1,2
In 2013, HF was the most common cause of death worldwide (15% of deaths worldwide).3 The
health expenditures for controlling HF are considerable and will increase dramatically with an
ageing population.4,5 Despite the significant advances in therapies and prevention of HF,
mortality and morbidity are still high and quality of life of HF patients are very poor.6
Decreased systolic function is a central factor in the pathogenesis of heart failure.7,8 Acutely
decompensated chronic heart failure concerns about 70% of patients with acute heart failure
syndromes,9 and at least half the patients with heart failure have low ejection fraction (40% or
less),10 thus leading to systolic heart failure.11 Systolic dysfunction is better characterized as a
decrease in cardiac contractility that can be measured by a reduction in the left ventricular
ejection fraction.12-14 Safe medical therapy to improve cardiac function of heart failure patients
with reduced ejection fraction is still challenging.15 Most current therapies are focused on
blockade of neurohormonal activation using inhibitors of the renin-angiotensin pathway, β-
adrenergic blockers, and aldosterone antagonists and do not improve the contractile function of
the heart.16,17
Currently available inotropes such as adrenergic receptor agonists, phosphodiesterase inhibitors
and calcium sensitizers are used in the treatment of systolic heart failure. Unfortunately, these
drugs have adverse effects such as, increased intracellular concentrations of calcium and cAMP,
contributing to increased heart rate, hypotension, and mortality.18-21 To address these limitations
cardiac myosin activators are being developed, which directly work at the level of the cardiac
sarcomere activating the actin-myosin cross-bridges, the smallest force-producing unit involved
in the contraction mechanism.15,22-25 The selective cardiac myosin activator, omecamtiv mecarbil

(OM), is currently undergoing clinical trials.26 Unlike prior agents that increased intracellular
cAMP and calcium and decrease ejection time, OM increased myocardial contraction and stroke
volume without increasing oxygen consumption, thereby increasing myocardial efficiency.27,28
Although OM is currently undergoing clinical trials, a broader range of drugs that can improve
cardiac function is urgently required.
Recently our group discovered flexible 3-phenylpropyl urea scaffold as novel cardiac myosin
activator with good cardiac myosin ATPase activation in vitro and in vivo.29 For example, 1-
benzyl-3-(3-phenylpropyl)urea (1, cardiac myosin ATPase activation (CMA) at 10 M = 53.3%;
fractional shortening (FS) = 30.04%; ejection fraction (EF) = 18.27%) and 1-phenethyl-3-(3-
phenylpropyl)urea (2, CMA at 10 M = 51.1%; FS = 18.90%; EF = 12.15%) showed potent
activity (Figure 1). Further, the lead compounds 1 and 2 were optimized to improve the activity
and found 3 (CMA at 10 M = 91.6% FS = 17.62%; EF = 11.55%), 4 (CMA at 10 M = 52.3%
FS = 38.96%; EF = 24.19%) and 5 (CMA at 10 M = 47.6% FS = 23.19%; EF = 15.47%) as
novel cardiac myosin activators (Figure 1).30
In continuation, the present work aim to investigate possible isosteric replacement of the urea
scaffold. Hence, oxadiazoles (1,3,4-oxadiazoles and 1,2,4-oxadiazoles) have been designed and
synthesized as selective cardiac myosin activators for the treatment of systolic heart failure
(Figure 2).

Figure 1. Novel urea analogs as cardiac myosin activator
Figure 2. Isosteric replacement of urea with oxadiazoles for novel cardiac myosin activator

Scheme 1 represents the synthesis of compounds 6a-q. The reaction of various carboxylic esters
9a-n with hydrazine hydrate in presence of catalytic amount of pyridine in ethanol under reflux
condition yielded the hydrazide intermediate 10a-n. The reaction of 10a-n with the acid
chlorides 12a-c derived from the corresponding carboxylic acids 11a-c afforded the dihydrazide
intermediates 13a-q in good yield. The intermediates 13a-q on cyclodehydration reaction in
presence of refluxing phosphorous oxychloride yielded 1,3,4-oxadiazoles 6a-q. The N,N-
dimethylsulfonamido substituted carboxylic esters 9o and 9f were synthesized from 9a and 9b by
chlorosulfonation at para position to give 14a and 14b followed by the treatment of N,N-
dimethylamine, respectively. The hydrolysis of 9o with LiOH/H2O yielded 11c.
Scheme 1. Preparation of 1,3,4-oxadiazoles 6a-q. Reagents and conditions; a) NH2NH2.H2O,
pyridine, EtOH, reflux, 10 h b) SOCl2, DCM, reflux, 3 h; c) TEA, DCM, 0 °C, 2 h; d) POCl3,
reflux, 3 h; e) ClSO3H, DCM, 0 °C to RT, 3 h; f) NH(CH3)2.HCl, NaHCO3, THF, 40 °C, 5 h; g)
LiOH, H2O THF, RT, 3 h; , n, m of 6a-q are denoted in Table 1.

Scheme 2 represents the synthesis of compounds 7a-f. The hydrazide intermediate 10d,k,l,n
prepared earlier in scheme 1 was reacted with the corresponding isocyanate 15a-c in acetonitrile
as solvent afforded the key intermediate 16a-f which on cyclodehydration reaction in presence of
POCl3 furnished the final compounds 7a-f.
Scheme 2. Preparation of compounds 7a-f. Reagents and conditions; a) acetonitrile, RT, 8 h; b)
POCl3, reflux, 3 h; , n, m of 7a-f are denoted in Table 1.
The preparation of compounds 8a-f is depicted in Scheme 3. The nitrile compounds 17a-d was
reacted with hydroxylamine in ethanol at reflux temperature to afford the N-hydroxyimidamide
intermediate 18a-d. The carboxylic acid 11a-c was reacted with carbodimidazole for 0.5 h to get
the activated intermediate 19a-c which was further reacted with appropriate 18a-d at ambient
temperature for 3 h to get the corresponding intermediate 20a-f. Without isolation, 20a-f was
cyclized with carbodimidazole at 120 °C using DMF as solvent to yield 1,2,4-oxadiazoles 8a-f.

Scheme 3. Preparation of compounds 8a-f. Reagents and conditions; a) NH2OH.HCl, TEA,
EtOH, reflux, 20 h; b) CDI (1.1 eq), DMF, RT, 0.5 h; c) RT, 3 h; d) CDI (1.1 eq), DMF, 120 °C,
8 h; , n, m of 8a-f are denoted in Table 1.
In the sarcomere, force generation is directly coupled to ATP hydrolysis by myosin ATPase.
Actin stimulated ATPase activity was assayed spectrophotometrically using sarcomere assay31
with modifications. Compounds that activate the sarcomere were identified by measuring %
increase in myosin ATPase activity at 10 µM. The results are shown in Table 1. Compound
specificity with respect to muscle type was evaluated by comparing the effect of the compound
on actin stimulated ATPase activity of a panel of myosin isoforms including cardiac (bovine (10
µM)),31 skeletal (rabbit (100 µM))32,33 and smooth muscle (chicken gizzard (100 µM))34,35 at a
single dose of the compound. Omecamtiv mecarbil was used as positive control for cardiac
myosin ATPase activity and (-)-blebbistatin was used as a negative control for measurement of
skeletal or smooth muscle myosin ATPase activity.36 The results are shown in Table 2.

In on our previous report,29 urea derivatives 1 (cardiac myosin ATPase activation (CMA) at 10
M = 53.3% fractional shortening (FS) = 30.04%; ejection fraction (EF) = 18.27%) and 2 (CMA
at 10 M = 51.1% FS = 18.90%; EF = 12.15%) showed excellent in vitro and in vivo activity and
were taken as lead compounds (Fig.1). In the next report we optimized the lead ureas 1 and 2 and
found more potent urea analogs 3 (CMA at 10 M = 91.6% FS = 17.62%; EF = 11.55%), 4
(CMA at 10 M = 52.3% FS = 38.96%; EF = 24.19%) and 5 (CMA at 10 M = 47.6% FS =
23.19%; EF = 15.47%) (Fig.1).30 In continuation, the present work was undertaken to find
possible isosteric replacement of the urea scaffold. In this regard, 1,3,4-oxadiazoles, 1,2,4-
oxadiazoles and 2-aminooxadiazoles were taken as possible isosteres and structure activity
relationships were established on them to find novel scaffold as cardiac myosin activator.
Table 1. Cardiac myosin activation of 1,3,4-oxadiazoles (6a-q), 1,2,4-oxadiazoles (7a-f) and 2-
amino-1,3,4-oxadiazoles (8a-f)
ATPase
activity %
at (10µM)
Comp. No.
n
m
R
CLogP
3
2
1
0
2
1
1
1
1
1
H
H
H
H
H
2.5
4.084
3.555
3.176
3.437
3.213
6a
6b
6c
6d
6e
51.0
62.9
59.2
38.7

2
1
H
33.6
2.750
6f
2
1
1
1
H
H
58.9
16.1
4.787
3.064
6g
6h
1
0
1
1
H
H
4.2
3.549
3.509
6i
6j
37.3
0
0
0
0
1
1
1
1
H
H
40.2
22.5
11.9
30.8
3.222
1.875
2.632
1.330
6k
6l
SO2NMe2
H
6m
6n
0
0
0
0
0
0
0
2
1
2
1
2
0
1
H
H
H
H
H
H
H
11.2
15.9
8.6
1.859
2.138
2.666
4.125
4.654
3.746
3.907
6o
6p
6q
7a
7b
7c
7d
50.5
32.8
35.2
41.7
0
0
1
1
H
H
33.0
22.9
2.546
2.849
7e
7f
1
1
H
66.3
4.076
8a

0
0
1
2
H
H
60.7
35.9
4.337
4.866
8b
8c
1
0
0
1
1
1
H
H
18.4
46.8
37.2
3.964
4.086
3.532
8d
8e
8f
SO2NMe2
56.5
3.266
STD
Omecamtiv mecarbil (OM)
In the first set of experiment (Table 1), 1,3,4-oxadiazole derivatives 6a-q were prepared as
isostere of urea scaffold. The idea of fixing three carbon spacer from the central scaffold (1,3,4-
oxadiazole) to one side of the phenyl ring was taken from our previous reports.29,30 Keeping this
in mind, the carbon chain from 1,3,4-oxadiazole to one side of the phenyl ring were fixed as
three, whereas the carbon chain to other phenyl ring were sequentially varied from three to zero
as mentioned in 6a (n = 3, m = 1, CMA at 10 M = 2.5%), 6b (n = 2, m = 1, CMA at 10 M =
51.0%), 6c (n = 1, m = 1, CMA at 10 M = 62.9%) and 6d (n = 0, m = 1, CMA at 10 M =
59.2%). These results prove that the two, one and zero carbon spacer between 1,3,4-oxadiazole
and the phenyl ring on other side show good activity which is similar to that of the potent urea
analogs 1, 2, 4, 5 as well as OM (CMA at 10 M = 56.5%). The promising substituents on
phenyl ring of the urea scaffold were also picked up from our earlier report30 to establish a
defined structure activity relationship of 1,3,4-oxadiazoles. The substitution of 3,4-dimethoxy
and 4-N,N-dimethylsulfonamide on the phenyl ring of oxadiazole with two carbon spacer as
demonstrated in 6e (n = 2, m = 1, CMA at 10 M = 38.7%) and 6f (n = 2, m = 1, CMA at 10 M

= 33.6%) respectively, decreased the activity compared to 6b. By changing the phenyl ring to
hydrophobic cyclohexyl group as shown in compound 6g (n = 2, CMA at 10 M = 58.9%)
fetched a good activity in spite of its higher CLogP value, 4.787. Next the substituents such as
3,4-dimethoxy and 4-fluoro on phenyl ring of oxadiazole with one carbon spacer as shown in 6h
(n = 1, m = 1, CMA at 10 M = 16.1%) and 6i (n = 1, m = 1, CMA at 10 M = 4.2%) abolished
the activity compared to 6c. The substituent like 4-methoxy, 3,4-dimethoxy and 4-sulfonamido
on the phenyl ring directly attached to the oxadiazole as demonstrated in 6j (n = 0, m = 1, CMA
at 10 M = 37.3%), 6k (n = 0, m = 1, CMA at 10 M = 40.2%) and 6l (n = 0, m = 1, CMA at 10
M = 22.5%) respectively, did not increase the activity as compared to the parent compound 6d.
On the other hand, the N,N-dimethylsulfonamide substitution on para position of the other
phenyl ring of 6d as shown in 6m (n = 0, m = 1, CMA at 10 M = 11.9%) also showed weak
ATPase activity compared to 6d or 1-5 or OM. All the above facts clearly say the substitutions
on either of the phenyl ring of the oxadiazole scaffold exhibit adverse effect on cardiac myosin
ATPase activity. The change of phenyl ring of 6d with other heterocycles which could improve
the water solubility29 such as 4-tetrahydropyranyl or 4-pyridyl as represented in examples 6n (n
= 0, m = 1, CMA at 10 M = 30.8%, CLogP = 1.330) and 6p (n = 0, m = 1, CMA at 10 M =
15.9%, CLogP = 2.138) showed decrement in the activity. Increment in carbon chain of 6n and
6p from three carbon spacer to four carbon spacer from oxadiazole to other side of the phenyl
ring as shown in compounds 6o (n = 0, m = 2, CMA at 10 M = 11.2%, CLogP = 1.859) and 6q
(n = 0, m = 2, CMA at 10 M = 8.6%, CLogP = 2.666) further decreased the activity. These
examples once again prove that the three carbon spacer is the optimum length from the
oxadiazole to one side of the phenyl ring.

The insertion of hydrogen bonding donor characteristics or the bioisosteric replacement of the
CH group with NH in 1,3,4-oxadiazole scaffold led us to design 2-amino-1,3,4-oxadiazoles 7a-f.
The initial design of 2-amino-1,3,4-oxadiazole separated with three carbon spacer to the phenyl
ring on one side and directly attached to the phenyl ring on the other side as shown in 7a (n = 0,
m = 1, CMA at 10 M = 50.5%) maintained the activity similar to that of 6d. Next by increasing
the three carbon spacer in 7a to four carbon spacer as shown in 7b (n = 0, m = 2, CMA at 10 M
= 32.8%) led to poor activity. On the other hand the decrement of the carbon chain to two as
represented in 7c (n = 0, m = 0, CMA at 10 M = 35.2%) which is the isostere of 6d was also
detrimental. The above results made us to fix three carbon spacer from the amino function of the
1,3,4-oxadiazole scaffold to one of the phenyl ring keeping the other phenyl ring directly
attached to 1,3,4-oxadiazole. The substitution of 3,4-dimethoxy and sulfonamide groups on the
phenyl ring directly attached to 1,3,4-oxadiazole as shown in 7d (n = 0, m = 1, CMA at 10 M =
41.7%) and 7e (n = 0, m = 1, CMA at 10 M = 33.0%) also did not increase the ATPase activity
compared to 7a. Finally, the change of the phenyl ring directly attached to oxadiazole of 7a with
pyridine ring or the isosteric replacement of CH group of 6q with NH as shown in 7f (n = 0, m =
1, CMA at 10 M = 22.9%) even though increased the activity compared to 6q the activity is far
deprived to 7a or 6d or OM. These results prove that substitution on the phenyl ring or change of
phenyl ring with other heterocycle is not favorable for the activity provided the insertion of
hydrogen bonding donor characteristics or the bioisosteric replacement of the CH group with NH
in 1,3,4-oxadiazole scaffold maintained the activity.
In the next set of experiment (Table 1), 1,2,4-oxadiazoles were prepared as isostere of urea
scaffold. Three carbon spacer were fixed as optimum distance from 1,2,4-oxadiazole to one of
the phenyl ring whereas the spacer to the other phenyl ring were changed to one carbon and zero

carbon as shown in compounds 8a (n = 1, m = 1, CMA at 10 M = 66.3%) and 8b (n = 0, m = 1,
CMA at 10 M = 60.7%) respectively. Both the compounds showed good activity. On the other
hand, increasing the three carbon spacer to four carbon spacer in compound 8b as demonstrated
in compound 8c (n = 0, m = 2, CMA at 10 M = 35.9%) showed decrement in activity. The
above result showed the optimum distance from 1,2,4-oxadiazole to one of the phenyl ring is
three and other phenyl ring can be maintained one or zero. Next the 3,4-dimethoxy substitution
was introduced on one side of the phenyl ring with one or zero carbon spacer to the oxadiazole as
demonstrated in compounds 8d (n = 1, m = 1, CMA at 10 M = 18.4%) and 8e (n = 0, m = 1,
CMA at 10 M = 46.8%). These also did not increase the activity compared to that of the parent
compounds 8a and 8b respectively. The substitution of N,N-dimethylsulfonamide group on the
para position of the phenyl ring of 8b with three carbon spacer as shown in compound 8f (n = 0,
m = 1, CMA at 10 M = 37.2%) also decreased the activity. The above facts show the
substitution pattern on either of the phenyl rings is not favorable for the ATPase activity.
The potent compounds 6b-d, 6g, 7a, 8a and 8b and were analyzed for their selectivity in cardiac
myosins over skeletal and smooth myosins (Table 2). None of the compound showed significant
activity for myosin ATPase using skeletal and smooth myosin S1. Thus, from these results it is
evident that these oxadiazole derivatives are selective activator for cardiac myosin S1.
Table 2. Selectivity study in myosins
ATPase % activity
Skeletal
myosin
(at 100 µM) (at 100 µM)
Smooth
myosin
Compound No.
Cardiac myosin at
10 µM 5 µM 1 µM
EC50
(µM)

51.0
62.9
59.2
58.9
50.5
66.3
60.7
56.5
45.3
60.2
55.2
53.1
42.6
60.3
56.4
49.9
29.7
33.5
32.5
30.0
28.4
34.1
31.9
31.2
4.50
3.06
3.27
3.48
5.25
3.02
3.18
3.35
˗ 3.1
1.8
4.1
˗ 3.9
˗ 3.7
4.5
6b
6c
˗ 2.5
˗ 2.7
1.9
6d
6g
2.3
7a
3.3
4.2
8a
8b
˗ 5.3
2.2
˗ 2.4
˗ 3.8
˗ 37.3
Omecamtiv mecarbil
˗ 54.1
(˗)Blebbistatin
------
In conclusion, novel 1,3,4 (or 1,2,4)-oxadiazoles with flexible diphenylalkyl groups were
explored as selective cardiac myosin activator. The structure activity relationship study (Figure
3) demonstrated that oxadiazoles could be a good isostere of urea for finding novel cardiac
myosin activator.
Figure 3. SAR of oxadiazoles as a selective cardiac myosin activator

In all cases, three carbon spacer between the oxadiazole scaffold and one of the phenyl ring is
considered crucial. In case of 1,3,4-oxadiazole, two carbon spacer or one carbon spacer or no
carbon spacer between the oxadiazole and other phenyl ring viz., 2-phenethyl-5-(3-
phenylpropyl)-1,3,4-oxadiazole (6b, n = 2, m = 1, CMA at 10 M = 51.0%), 2-benzyl-5-(3-
phenylpropyl)-1,3,4-oxadiazole (6c, n = 1, m = 1, CMA at 10 M = 62.9%), 2-phenyl-5-(3-
phenylpropyl)-1,3,4-oxadiazole (6d, n = 0, m = 1, CMA at 10 M = 59.2%) are favorable.
Phenyl ring can be replaced by cyclohexyl moiety viz., 2-(2-cyclohexylethyl)-5-(3-
phenylpropyl)-1,3,4-oxadiazole (6g, n = 2, m = 1, CMA at 10 M = 58.9%). Introduction of
hydrogen bonding donor (NH) group at the 2nd position of the 1,3,4-oxadiazole or the
bioisosteric replacement of the CH group with NH in 1,3,4-oxadiazole scaffold, viz., 5-phenyl-N-
(3-phenylpropyl)-1,3,4-oxadiazol-2-amine (7a, n = 0, m = 1, CMA at 10 M = 50.5%)
maintained the activity. Substitutions on either of the phenyl rings or change of phenyl ring to
other heterocycle are not tolerated for both the 1,3,4-oxadiazoles. In case of 1,2,4-oxadiazole,
one carbon spacer or no carbon spacer between the oxadiazole and other phenyl ring viz., 3-
benzyl-5-(3-phenylpropyl)-1,2,4-oxadiazole (8a, n = 1, m = 1, CMA at 10 M = 66.3%), 3-
phenyl-5-(3-phenylpropyl)-1,2,4-oxadiazole (8b, n = 0, m = 1, CMA at 10 M = 60.7%) are
favorable. The prepared oxadiazoles showed selective activation for cardiac muscle over smooth
and skeleton muscles suggesting that oxadiazoles are reliable isostere of urea function of
diphenylalkylurea leads29,30 reported as cardiac myosin activator. Efforts are to be made to
further take the oxadiazoles to the next level and find more potent drug candidate.
Acknowledgment

This work was supported by Priority Research Centers Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology
(2009-0093815).
Supplementary data
The detailed experimental part of this article can be found in the Supplementary data.
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Graphical Abstract:
Exploration of diphenylalkyloxadiazoles as novel cardiac myosin activator

Highlights
 The diphenylalkyl oxadiazoles were identified as novel cardiac myosin ATPase activator.
 Three carbon spacer between oxadiazole core and one of the phenyl ring is crucial.


Introduction of NH group at the 2nd position of the 1,3,4-oxadiazole is favored.
These oxadiazoles are selective activators for cardiac myosin.