Antimycobacterial activity of novel hydrazide-hydrazone derivatives with 2H-chromene and coumarin scaffold

Article abstract of DOI:10.1016/j.bmcl.2016.11.071

This study reports the synthesis of new 2H-chromene or coumarin based acylhydrazones, which were evaluated for their in vitro antimycobacterial activity against reference strain Mycobacterium tuberculosis H37Rv and compared to the first-line antituberculo

Full text of DOI:10.1016/j.bmcl.2016.11.071

Accepted Manuscript
Antimycobacterial activity of novel hydrazide-hydrazone derivatives with 2H-
chromene and coumarin scaffold
Violina T. Angelova, Violeta Valcheva, Nikolay G. Vassilev, Rosen Buyukliev,
Georgi Momekov, Ivan Dimitrov, Luciano Saso, Mirjana Djukic, Boris
Shivachev
PII:
S0960-894X(16)31236-7
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.11.071
BMCL 24466
Reference:
Bioorganic & Medicinal Chemistry Letters
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Revised Date:
Accepted Date:
2 September 2016
19 November 2016
23 November 2016
Please cite this article as: Angelova, V.T., Valcheva, V., Vassilev, N.G., Buyukliev, R., Momekov, G., Dimitrov,
I., Saso, L., Djukic, M., Shivachev, B., Antimycobacterial activity of novel hydrazide-hydrazone derivatives with
2H-chromene and coumarin scaffold, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/
10.1016/j.bmcl.2016.11.071
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Antimycobacterial activity of novel hydrazide-hydrazone derivatives
with 2H-chromene and coumarin scaffold
Violina T. Angelovaa*, Violeta Valchevab, Nikolay G. Vassilevc, Rosen
Buyuklieva, Georgi Momekovd, Ivan Dimitrova, Luciano Sasoe, Mirjana Djukicf,
Boris Shivachevg
aDepartment of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 2, Dunav St.,
1000 Sofia, Bulgaria
bInstitute of Microbiology, Bulgarian Academy of Sciences, 26, Acad. G. Bonchev St., 1113
Sofia, Bulgaria
cLaboratory of Nuclear Magnetic Resonance, Institute of Organic Chemistry with Centre of
Phytochemistry, Bulgarian Academy of Sciences, 9, Acad. G. Bonchev St., 1113 Sofia,
Bulgaria
dLaboratory of Experimental Chemotherapy, Department of Pharmacology, Pharmacotherapy
and Toxicology, Faculty of Pharmacy, Medical University-Sofia, 2, Dunav St., 1000 Sofia
Bulgaria
eDepartment of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University, P.le
Aldo Moro 5, 00185, Rome, Italy
fDepartment for Toxicology, Faculty of Pharmacy, University of Belgrade, 450, Vojvode
Stepe, St., 11221 Belgrade, Serbia
gBulgarian Academy of Sciences, Institute of Mineralogy and Crystallography, 107, Acad. G.
Bonchev St., 1113 Sofia, Bulgaria
* Corresponding author: (Violina T. Angelova)
E-mail addresses: violina@pharmfac.net; violina_stoyanova@abv.bg.
Medical University of Sofia,
2 Dunav str., Sofia 1000, BULGARIA,
Tel: +359 2 9236 586
1

Abstract
This study reports the synthesis of new 2H-chromene or coumarin based acylhydrazones,
which were evaluated for their in vitro antimycobacterial activity against reference strain
Mycobacterium tuberculosis H37Rv and compared to the first-line antituberculosis drugs,
isoniazid (INH) and ethambutol (EMB). The most active compounds 7m (MIC 0.13 M), 7o
(MIC 0.15 M) and 7k (MIC 0.17 M) demonstrated antimycobacterial activity at
submicromolar concentration level and remarkably minimal associated cytotoxicity in the
human embryonic kidney cell line HEK-293T. Structure-activity relationship for this class of
compounds has been established.
Keywords: Antitmycobacterial activity, 2H-Chromene, Coumarin, Cytotoxicity, Hydrazide-
hydrazone.
Despite notable progress in the treatment of mycobacterial infections, tuberculosis
(TB) is still a public health concern worldwide.1,2 The dramatic increase in number of cases of
multidrug-resistant (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB)3-5
require development of novel low toxic compounds with improved efficacy6-8 Current
treatment of TB with first and second line drugs require a minimum six months of therapy to
prevent relapse. This long-term chemotherapy certainly increases the risk of drug resistance.
Although isoniazid (INH) is still the most effective antituberculosis drug, recommended by
WHO, it has two major drawbacks which need to be overcomed: hepatotoxicity and its
deactivation via the genetically polymorphic N-arylaminoacetyltransferases (NATs). Indeed
hydrazones, isoniazid derivatives wherein N2 is blocked towards acetylation by NATs,
2

appeared to be more effective and less hepatotoxic than isoniazid.9-12 Various classes of
pyridine, pyrimidine, coumarin, quinoline, benzoxazole, indole, purine, pyrrole, furan,
benzofuran, triazoles etc. based hydrazones9,10,12-16 have been evaluated for their
antimycobacterial potential. Also, 2H-chromenes, coumarins and their derivatives have
gained great therapeutic importance for the discovery of novel antimycobacterial
compounds.17-24 Keri et al. (2015)25 have emphasized the strategic place of coumarin
derivatives in medicinal chemistry particularly on their antituberculosis effect.
Therefore, we focused on the synthesis of 2H-chromene or coumarin compounds with
various substituted hydrazide-hydrazone pharmacophore attached to the 3rd position in the
chromene ring. The antimycobacterial activity of the synthesized compounds against
Mycobacterium tuberculosis H37Rv strain and the toxicity against human embryonal kidney
cell line HEK-293T were evaluated.
The synthesis of 2H-chromane and coumarin based hydrazones is presented in Scheme
1. Compounts 3a-c were prepared from the condensation of salicylaldehyde 1 and α,β-
unsaturated aldehydes 2a-c under base-promoted conditions.26 For the preparation of 2H-
chromene-3-carbaldehyde 3a and 2-methyl-2H-chromene-3-carbaldehyde 3b we applied the
synthetic strategy of Azizmohammadi et al.,27 while the synthesis of 2-phenyl-2H-chromene-
3-carbaldehyde 3c was performed according to Córdova et al.,28,29 with pyrrolidine as a
catalyst and benzoic acid as an additive in toluene. The synthesis of the hydrazide-hydrazones
7a-q and 8a-f involved equimolar condensation of 2H-chromene-3-carbaldehyde 3a-c or 4-
chlorocoumarin-3-carbaldehyde 4 with appropriate hydrazides 6a-f in abs. ethanol, at room
temperature (Scheme 1).
3

Scheme 1. Synthetic route for 2H-chromene based hydrazones 7a-q and coumarin based
hydrazone 8a-e; *hydrazone derivatives 7l-k and 8a-c have been described elsewhere.30
o
Conditions: (a) K2CO3, 1,4-dioxane, reflux 2 h; (b) pyridine, benzoic acid, toluene, 25 C, 24
h,29 (c) POCl3, DMF, 60 oC; (d) abs. EtOH, r.t., 15-30 min.
The reaction progress was monitored by thin layer chromatography (TLC). The
1
13
proposed structures are confirmed from FTIR, H NMR, C NMR, 2D (1H–1H COSY, 1H–
13C COSY, HMBC and NOESY) and HR-MS spectral techniques. The novel hydrazone
derivatives 7a-q and 8a-e were obtained as a single E geometrical isomer and the observed
duplication pattern in DMSO was due to the presence of syn/anti amide conformers.
30,31,32,33,34 Configuration (E) and a synperiplanar conformation of the compounds was proved
by NOESY spectrum, measured in DMSO-d6 (Supplementary, Fig. S1, Fig S2). Additionaly,
4

the configuration of the C=N double bond in structures 7i (with low activity) and 7k (with
high activity) was confirmed by X-ray diffraction crystallography ((Fig. 1), Supplementary,
Fig. S1, Fig S2, Fig. S3, Fig. S4, Table S2, Table S3).
Figure 1. ORTEP view of the molecular structure of a) 7i and b) 7k.
The synthesized compounds 7a-q and 8a-e were evaluated in vitro against M.
tuberculosis H37Rv, using the Canetti method.35 Isoniazid and ethambutol were used as
controls. The results of the in vitro antimycobacterial screening are summarized in Table 1.
The established antimycobacterial activity of the tested series prompted us to evaluate the
cytotoxic potential of the promising leads (i.e. compounds that show activity at
submicromolar concentrations), thus determining the selectivity (SI) of the antiproliferative
effects (Table 1.). The cytotoxicity of the selected compounds was assessed against the human
embryonal kidney cell line 293-T, after 72 h of continuous exposure.
5

Table 1. Antimycobacterial activity and cytotoxicity of the compounds 7a-q and 8a-f.
c
№
Compd.
7a
Structure
MICb
(M)
6.39
IC50
(M)
ND
SId
-
Log Pa
1
3.55
2
6.48
36.04
--
3.24
7b
3
4
5
7.03
0.74
22.10
47.32
ND
-
63.94
-
3.35
2.76
3.58
7c
7d
7e
> 6.12
6
6.20
ND
-
3.24
7f
7
8
9
> 6.70
0.18
ND
-
117.83
-
3.31
2.84
3.23
7g
7h
7ie
21.21
23.33
6.84
10
11
7je
48.77
76.32
76.20
2.76
2.49
0.64
0.17
7ke
448.94
6

12
13
14
15
16
17
> 5.14
0.13
13.18
90.66
ND
-
697.38
-
4.11
3.94
4.23
3.85
3.81
2.97
7l
7m
7n
7o
7p
7q
> 5.54
0.15
11.91
30.87
30.18
79.4
1.34
-
56.94
0.53
18
19
20
21
8ae
8be
8ce
8d
6.12
5.83
6.10
1.45
28.56
33.07
12.56
26.15
3.56
3.15
3.05
3.42
-
-
-
22
30.18
45.04
2.85
8e
0.67
Isoniazidf
EMB_2HClf
1.45
7.64
-
-
-
-
7

b
alog P was calculated by MDL QSAR software; Antimycobacterial activity towards a
reference strain of Mycobacterium tuberculosis H37Rv, MIC (M) was defined as the lowest
c
concentration resulting in a complete inhibition of the bacterial growth and reproduction; In
d
vitro cytotoxicity towards human embryonal kidney cell line 293T, IC50 (M); Selectivity
e
index, SI ratio = IC50/MIC) by the MTT assay; Prepared by a procedure previously reported;
fIsoniazid (reference compound) and EMB_2HCl (ethambutol dihydrochloride) - reference
compounds; ND - not determined.
The majority of the tested compounds with high antimycobacterial activity (7d, 7h, 7j,
7k, 7m, 7o, 7p, and 8e) caused a 50 % cell growth inhibition within the tested concentration
range (12.5–100 μM); 7h and 7o displayed high cytotoxicity; the other compounds (7j ,7k,
7m, 7p, 7q and 8e) were less toxic to human cells; and 7m showed marginal cytotoxicity.
Thus, regarding the selective inhibition (Selectivity index, SI) of mycobacteria, compounds
7m (SI=697.38), 7k (SI=448.94) and 7h (SI=117.83) could be considered as promising hybrid
antituberculosis agents.
The structure-activity relationship of compounds 7a-q and 8a-e with respect to their
antimycobacterial activity could be summarized as follows:
a) Chromene derivatives with strong charge donation (electron donating group) and
delocalization in the hydrazide moiety in 2-furyl 7d, 7h, 7o, isonicotinoyl 7k and 5-(4-
methyl-1,2,3-tidiazinyl) 7q, or 4-methoxyphenyl 7m and 4-hydroxyphenyl 7j fragments
exhibited excellent activity against M. tuberculosis H37Rv with MICs in the
submicromolar range. 2-Phenyl-2H-chromene derivatives 7m and 7o with MIC of 0.13
and M 0.15 M, respectively, differ only in a benzene ring (p-methoxyphenyl, 2-furyl
substituents), demonstrated the highest activity. Among the tested hydrazones, 7m showed
the highest antimycobacterial effect and exhibited low cytotoxicity, indicating a favorable
selectivity index, SI=697;
8

b) The substitution of the H-atom at the 2nd position in 2H-chromene moiety of hydrazones
7b and 7d, with a methyl substituent in compounds 7f and 7h and with an phenyl group in
the case of 7m and 7o led to a significant increase in the antimycobacterial activity, which
was not observed in hydrazones with a 4-chlorophenyl moiety 7a, 7e, 7l and 2-thienyl-
substituted hydrazones 7c, 7g and 7n. Notably, the substitution of the 2-furyl and
methoxyphenyl moiety in the hydrazides with 2-thienyl or 4-chlorophenyl moiety resulted
in a lower activity; fluorophenyl substitution 7p and 8e led to activity improvement
compared to chlorophenyl substitution 7l.
c) 2-Methylchromene derivatives containing 4-hydroxyphenyl and 4-pyridyl moieties 7j and
7k exhibited MICs of 0.64 M and 0.17 M, respectively, but the activity of coumarin
containing hydrazones 8b and 8c with the same substituents in the aromatic ring were less
affected (MIC= 5.83, MIC= 6.10 , respectively);
d) Except for the 5-(4-methyl-1,2,3-thiadiazole)-substituted coumarin derivative 8e and the
4-fluorophenyl substituted coumarin 8d which exhibited good activity with potency equal
to that of isoniazid, all other hydrazones with coumarin scaffold 8a-c demonstrated
antimycobacterial potency lower than that of INH and MIC values ranging from 5.83 to
6.12 µM.
e) All tested hydrazones appeared more lipophilic with logP values considerably higher than
INH itself (logP = 0.06). We observed correlation between the antimycobacterial potency
and LogP values within each set of compounds (with the same chromene ring, but
different substituents in the aromatic rings I, II, III and IV, Table 1). The hydroxyl and
methoxy groups at para position in the aromatic ring, as well as 2-furyl- and 4-pyridyl-
moieties were able to act as a hydrogen bond acceptor and decrease log P values of the
compounds, which may be is important for their inhibitory activity against M. tuberculosis
H37Rv.
9

SAR analysis revealed that the antimycobacterial activity of the synthesized
compounds does not depend only on their lipophilic characteristics. Activation of the
hydrazide moiety by electrondonating groups seems to be also essential in the
pharmacodynamics of these compounds. Evidently, coumarin and/or 2H-chromene moieties
acts as a scaffold and that the substituents at 2nd, and 3rd positions in chromene ring and
principally substituents in the hydrazide moiety provide target specificity in each of the tested
series (I, II, III, IV).
In summary, a series of new hybrid hydrazones bearing 2H-chromene or coumarin
moieties were synthesized by means of a classic procedure with satisfactory yields and their
structures were fully supported by spectral data (IR, NMR, MS) and X-ray analisis. Twenty
two hydrazones were tested in vitro for antimycobacterial activity (against M. tuberculosis
H37Rv) and compared to reference first-line drugs isoniazid and ethambutol. Significantly
improved activity with MICs the in micro- to submicromolar concentration range was
observed by varying the substituents in hydrazone moiety and in the chromene nucleus. Some
of the new compounds, 7d, 7h, 7j, 7k, 7m, 7o, and 7q with log P values ranging from 2.49 to
3.94 demonstrated considerably higher antimycobacterial potency than INH. Among the
tested hydrazones 7m has proven to be the most effective compound against M. Tuberculosis
H37Rv (MIC=0.13 μM). Its antimycobacterial and cytotoxicity equieffective concentrations
vary 700-fold, indicating a favorable selectivity index. Thus, this hydrazide-hydrazone class
potentially defines a promising new candidate series for further investigations.
Acknowledgments
10

This study was supported by the National Research Fund of Bulgaria (projects UNA-17/2005
and DRNF- 02/13/2009). We gratefully appreciate the help of Yulian Voynikov with mass
spectrometry.
Supplementary Material
Supplementary data (experimental procedures, characterization of final compounds and
biological assays protocols) associated with this article can be found, in the online version,
at…
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13

Figure Captions
Scheme 1. Synthetic route for 2H-chromene based hydrazones 7a-q and coumarin based
hydrazone 8a-e; *hydrazone derivatives 7l-k and 8a-c have been described elsewhere.29
o
Conditions: (a) K2CO3, 1,4-dioxane, reflux 2 h; (b) pyridine, benzoic acid, toluene, 25 C, 24
h, (c) POCl3, DMF, 60 oC; (d) abs. EtOH, r.t., 15-30 min.
Figure 1. ORTEP view of the molecular structure of a) 7i and b) 7k, atomic displacement
parameters are at 50 % probability, H atoms are shown as spheres with arbitrary radii.
Figure 2. Superposition of the molecules of 7i (in green) and 7k.
Table 1. Antimycobacterial activity and cytotoxicity of the compounds 7a-q and 8a-f.
alog P was calculated by MDL QSAR software; bAntimycobacterial activity towards reference
strain of Mycobacterium tuberculosis H37Rv, MIC (M) was defined as the minimum
concentration of the compound required to inhibit bacterial growth completely (0 % growth);
cIn vitro cytotoxicity towards human embryonal kidney cell line 293 T, IC50 (M);
e
dSelectivity index, SI ratio = IC50/MIC) by the MTT assay; Prepared by a procedure
f
previously reported; Isoniazid (reference compound) and EMB_2HCl (ethambutol
dihydrochloride) - reference compounds; ND - not determined.
Figure 3. Schematic representation of the proposed mechanisms compared with mechanism of
action of isoniazid and hydrazone derivatives
14

Highlights
1.
2.
3.
4.
22 (16 new) hydrazides-hydrazones were evaluate for antimycobacterial activity
8 new hydrazides-hydrazones exhibited activity better than isoniazid
3 hydrazones with favorable selectivity index are promising for further investigations
Structure-activity relationship for this class of compounds has been established.
15

Graphical abstract
16