Studies on aminopyrazoles: Antibacterial activity of some novel pyrazolo[1,5-a]pyrimidines containing sulfonamido moieties

Article abstract of DOI:10.1016/S0014-827X(00)00079-3

Hydrazones 2a-d were prepared from diazotiazation of sulfanilamide or its derivatives followed by coupling with ethyl cyanoacetate. 3-Aminopyrazoles 3a-d were obtained by refluxing of 2a-d with hydrazine hydrate in ethanol. [Bis(methylthio)methylene]malononitrile (4) was reacted with aminopyrazoles 3a-d in refluxing DMF containing triethylamine to yield the novel pyrazolo[1,5-a]pyrimidines 6a-d. The anilino derivatives 8a-h were obtained by fusion of compounds 6a-d with aromatic amines. When compounds 6a,c,d were subjected to the reaction with hydrazine hydrate, the hydrazino derivatives 9a-c were isolated. Also, the aminopyrazoles 3 were reacted with some electrophiles such as arylidenemalononitriles, ethoxymethylene malononitrile and ethyl ethoxymethylene cyanoacetate to yield the novel substituted pyrazolo[1,5-a]pyrimidines 13, 17 and 19, respectively. Structures of the new compounds were established by their elemental analyses and spectral data. Most of these compounds were also tested in vitro for their antibacterial activity against some Gram positive and Gram negative bacteria.

Full text of DOI:10.1016/S0014-827X(00)00079-3

www.elsevier.nl/locate/farmac
Il Farmaco 55 (2000) 596–602
Studies on aminopyrazoles: antibacterial activity of some novel
pyrazolo[1,5-a]pyrimidines containing sulfonamido moieties
M.S.A. El-Gaby *, A.A. Atalla, A.M. Gaber, K.A. Abd Al-Wahab
Department of Chemistry, Faculty of Science, Al-Azhar Uni6ersity at Assiut, Assiut 71524, Egypt
Received 9 February 2000; accepted 31 July 2000
Abstract
Hydrazones 2a–d were prepared from diazotiazation of sulfanilamide or its derivatives followed by coupling with ethyl
cyanoacetate. 3-Aminopyrazoles 3a–d were obtained by refluxing of 2a–d with hydrazine hydrate in ethanol. [Bis(-
methylthio)methylene]malononitrile (4) was reacted with aminopyrazoles 3a–d in refluxing DMF containing triethylamine to yield
the novel pyrazolo[1,5-a]pyrimidines 6a–d. The anilino derivatives 8a–h were obtained by fusion of compounds 6a–d with
aromatic amines. When compounds 6a,c,d were subjected to the reaction with hydrazine hydrate, the hydrazino derivatives 9a–c
were isolated. Also, the aminopyrazoles 3 were reacted with some electrophiles such as arylidenemalononitriles, ethoxymethylene
malononitrile and ethyl ethoxymethylene cyanoacetate to yield the novel substituted pyrazolo[1,5-a]pyrimidines 13, 17 and 19,
respectively. Structures of the new compounds were established by their elemental analyses and spectral data. Most of these
compounds were also tested in vitro for their antibacterial activity against some Gram positive and Gram negative bacteria.
© 2000 Published by Elsevier Science S.A. All rights reserved.
Keywords: Aminopyrazoles; Pyrazolo[1,5-a]pyrimidines; Sulfonamides and antibacterial activity
1. Introduction
aqueous ethanol containing sodium acetate at 0–5°C
yielded the key intermediate hydrazones 2a–d. The
spectral data revealed that these compounds exist in the
hydrazone form 2a–d. Refluxing of compounds 2a–d
with hydrazine hydrate in ethanol furnished the corre-
sponding 3-aminopyrazoles 3a–d in good yields
(Scheme 1). The structures of 3a–d were established on
the basis of elemental analyses and spectral data.
It has been reported that ketene dithioacetals and
related compounds are well known as useful starting
materials for the synthesis of heterocycles [8]. The
behavior of 3a–d towards ketene dithioacetals like
compounds 4 and 7 was investigated. Thus, it has been
found that [bis(methylthio)methylene]malononitrile (4)
[9] reacts with aminopyrazoles 3a–d in refluxing DMF
containing catalytic amounts of triethylamine to yield
the corresponding pyrazolo[1,5-a]pyrimidines (6a–d).
The structure of compounds 6a–d were established on
the basis of their elemental analysis and spectral data.
Thus, the IR spectra of 6a–d revealed characteristic
bands for NH2, NH, CꢀN, NꢁN and SꢁO functional
groups. The 1H NMR spectrum of compound 6a
Pyrazolo[1,5-a]pyrimidines are of considerable chem-
ical and pharmacological importance as purine analogs
[1]. On the other hand, sulfonamides have a variety of
biological activities such as antibacterial [2], insulin
releasing [3], carbonic anhydrase inhibitory [4,5], anti-
inflammatory [6] and antitumor [7] activities. These
findings encourged us to explore the synthesis of pyra-
zolo[1,5-a]pyrimidines containing sulfonamido moieties
in order to examine their antibacterial activity.
2. Chemistry
Diazotiazation of sulfanilamide or its derivatives 1a–
d followed by coupling with ethyl cyanoacetate in
* Corresponding author. Fax: +20-88-325436.
E-mail address: m elgaby@hotmail.com (M.S.A. El-Gaby).
–
0014-827X/00/$ - see front matter © 2000 Published by Elsevier Science S.A. All rights reserved.
PII: S0014-827X(00)00079-3

M.S.A. El-Gaby et al. / Il Farmaco 55 (2000) 596–602
597
showed a signal l=2.80 assignable to the SCH3 group,
a multiplet at l=7.31–8.00 assigned to aromatic pro-
tons and two broad singlets at l=4.80 and 7.10
assignable to two amino groups. The formation of 6
from the reaction of 3 with dithioacetals 4 proceeds via
initial alkylation of the ring nitrogen in 3 to give 5
followed by cyclization [10] to yield the final products
6, (Scheme 2). Fusion of 6a–d with aromatic amines at
150°C furnished the corresponding anilino derivatives
8a–h. Compounds 8a–h were also conveniently synthe-
sized in a one-pot reaction by refluxing the correspond-
ing aminopyrazoles 3a–d with [(arylamino)(methyl-
thio)methylene]malononitriles (7a,b) [9] in DMF con-
taining catalytic amounts of triethylamine. When com-
pounds 6a,c,d were subjected to the reaction with
hydrazine, the hydrazino derivatives 9a–c were isolated
and the dipyrazolo[1,5-a:4%.3%-e]pyrimidines 10 were
eliminated on the basis of spectral data. Thus, the IR
spectra of compounds 9a–c revealed the presence of a
CꢀN band (Scheme 2).
Compounds 3a–c react with arylidenemalononitriles
11 in refluxing DMF catalyzed by pyridine to yield
pyrazolo[1,5-a]pyrimidines 13. The structure of com-
pounds 13 was established on the basis of elemental
analysis and spectral data. The formation of 13 from
the reaction of 3 with 11 is assumed to proceed via
initial Michael addition [11] of the ring nitrogen atom
in 3 to the activated double bond in 11 to yield Michael
adduct 12 which then cyclizes and loses H2 to give 13
(Scheme 3).
Scheme 1.
Scheme 2.

598
M.S.A. El-Gaby et al. / Il Farmaco 55 (2000) 596–602
Scheme 3.
Scheme 4.
The study was extended to investigate the behavior of
3. Experimental
3 with ethoxymethylenemalononitrile and ethyl ethoxy-
methylene cyanoacetate. Thus, when ethoxymethylene
malononitrile 14a was reacted with compounds 3a,d in
refluxing DMF–pyridine furnished the corresponding
pyrazolopyrimidines 17a,b. The formation of 17 pro-
ceeds via intermediate formation 15, which rearranges
to 16 [12] before cyclization into 17 (Scheme 4). On the
other hand, when compounds 3a,d were treated with
ethyl ethoxymethylene cyanoacetate 14 in refluxing pyr-
idine for which two products 18 and 19a,b seemed
possible. Structure 18 was readily ruled out on the basis
of analytical and spectral data. Thus, the IR spectra of
19a,b exhibited absorption bands for CꢀN.
All m.p. values are uncorrected. IR spectra were
measured as KBr pellets on a Shimadzu IR 200 spec-
trophotometer. 1H NMR spectra were recorded in
deuterated chloroform at 200 MHz on a Varian Gemini
NMR spectrometer using tetramethyl-silane as an inter-
nal reference. Elemental analyses were carried out at
the Microanalytical Center of Cairo University. The
characteristics data for prepared compounds are given
in Table 1, analytical results for C, H, N, were within
0.090.1% of the calculated values. The spectral data
are collected in Tables 2 and 3.

M.S.A. El-Gaby et al. / Il Farmaco 55 (2000) 596–602
599
[Bis(methylthio)methylene]malononitrile(4)and[(aryl-
amino)(methylthio)methylene]malononitriles (7a,b)
3.2. 4-[4-(N-substituted)sulfamoyl]-
phenylazo-3-aminopyrazol-5-ones (3a–d)
were obtained according to a reported method [9].
A solution of 2 (0.01 mol) and hydrazine hydrate
(0.02 mol) in ethanol (30 ml) was refuxed for 1–2 h.
The solid product, so formed was collected by filtration
and recrystallized from proper solvent to give 3a–d.
3.1. Ethyl{[4-(N-substituted)sulfamoyl]phenylazo}-
cyanoacetate (2a–d)
Sulfonamide derivatives (0.01 mol) were dissolved in
a mixture of concentrated HCl (4 ml) and water (5 ml)
and cooled to 0°C in an ice bath. A cold aqueous
solution of sodium nitrite (0.01 mol) was then added.
The diazonium salt so obtained was filtered into a
cooled mixture of sodium acetate (5 g) and ethyl
cyanoacetate (0.01 mol) in ethanol. The resulting solid
was washed with water and recrystallized from proper
solvent to give 2a–d.
3.3. 5-Amino-7-methylthio-1,2-dihydro-3-
[4-(N-substituted)sulfamoyl]phenylazo-2-oxo
pyrazolo[1,5-a]pyrimidin-6-carbonitriles (6a–d)
To a suspension of compounds 3 (0.01 mol) and [bis-
(methylsulfanyl)methylidene]malononitrile 4 [9] (0.01
mol) in dimethylformamide (20 ml), three drops of
triethylamine were added. The mixture was refluxed
Table 1
Characteristics of the synthesized compounds
Comp. no.
R
Ar
M.p. (°C)
Yield (%)
Molecular formula (molecular wt.)
2a
2b
2c
2d
3a
3b
3c
3d
6a
6b
6c
6d
8a
8b
8c
8d
8e
8f
8g
8h
9a
9b
9c
13a
13b
13c
13d
13e
13f
13g
13h
13i
17a
17b
19a
19b
H
205 a
272 a
223 a
218 a
290 b
285 c
265 b
260 b
240 c
90 a
96
80
85
87
82
86
76
75
64
62
67
65
72
76
74
71
67
60
72
75
57
60
82
74
72
71
67
64
60
74
76
76
68
67
72
75
C11H12N4O4S (296)
C16H15N5O4S (373)
C15H14N6O4S (374)
C16H16N4O4S (388)
C9H10N6O3S (282)
C14H13N7O3S (359)
C13H12N8O3S (360)
2-Pyridinyl
2-Pyrimidinyl
2-(4-Methyl pyrimidinyl)
H
2-Pyridinyl
2-Pyrimidinyl
2-(4-Methyl pyrimidinyl)
H
2-Pyridinyl
2-Pyrimidinyl
2-(4-Methyl pyrimidinyl)
H
C14H14N8O3S (374)
C14H12N8O3S2 (404)
C19H15N9O3S2 (481)
C18H14N10O3S2 (482)
C19H16N10O3S2 (496)
C20H17N9O3S (463)
C20H17N9O4S (479)
170 a
108 a
150 a
140 a
145 a
142 a
160 a
135 a
140 a
210 a
\300
\300
\300
220 a
265 a
190 a
226 a
242 a
236 a
223 a
198 a
130 a
168 a
190 a
174 a
178 a
C6H4CH3-p
C6H4OCH3-p
C6H4CH3-p
C6H4OCH3-p
C6H4CH3-p
C6H4OCH3-p
C6H4CH3-p
C6H4OCH3-p
H
2-Pyrimidinyl
2-Pyrimidinyl
2-Pyrimidinyl
2-Pyrimidinyl
2-(4-Methyl pyrimidinyl)
2-(4-Methyl pyrimidinyl)
H
2-Pyrimidinyl
2-(4-Methyl pyrimidinyl)
H
C25H19N10O3S (540)
C25H20N10O4S (556)
C24H19N11O3S (541)
C24H19N11O4S (557)
C25H21N11O3S (555)
C25H21N11O4S (571)
C13H12N10O3S (388)
C17H14N12O3S (466)
C18H16N12O3S (480)
C19H13FN8O3S (452)
C20H16N8O3S (448)
C20H16N8O4S (464)
C24H16FN9O3S (529)
C25H19N9O3S (525)
C25H19N9O4S (541)
C23H15FN10O3S (530)
C24H18N10O3S (526)
C24H18N10O4S (542)
C13H10N8O3S (358)
C18H14N10O3S (450)
C13H9N7O4S (359)
C18H13N9O4S (451)
C6H4F-p
H
H
C6H4CH3-p
C6H4OCH3-o
C6H4F-p
C6H4CH3-p
C6H4OCH3-o
C6H4F-p
2-Pyridinyl
2-Pyridinyl
2-Pyridinyl
2-Pyrimidinyl
2-Pyrimidinyl
2-Pyrimidinyl
H
2-(4-Methyl pyrimidinyl)
H
C6H4CH3-p
C6H4OCH3-o
2-(4-Methyl pyrimidinyl)
a From ethanol.
b From DMF.
c From dioxane.

600
M.S.A. El-Gaby et al. / Il Farmaco 55 (2000) 596–602
Table 2
IR spectra of the synthesized compounds
Comp. no.
wNH (NH2)
wCꢀN
wCꢁO
wNꢁN
wSO asy.
wSO sy.
2
2
2a
2b
2c
2d
3a
3b
3c
3d
6a
6b
6c
6d
8a
8b
8c
8d
8e
8f
8g
8h
9a
9b
9c
13a
13b
13c
13d
13e
13f
13g
13h
13I
17a
17b
19a
19b
3450, 3350, 3240
3450, 3250
3480, 3200
2200
2205
2200
2205
1720
1710
1715
1710
1720
1685
1660
1680
1670
1660
1670
1660
1665
1680
1660
1650
1650
1650
1650
1660
1665
1662
1667
1660
1665
1650
1650
1645
1650
1667
1650
1650
1650
1680
1690
1685
1330
1370
1340
1340
1320
1350
1340
1340
1340
1360
1345
1340
1360
1340
1360
1355
1350
1330
1360
1340
1352
1340
1332
1334
1325
1325
1356
1365
1358
1330
1340
1340
1325
1335
1340
1330
1116
1140
1160
1170
1140
1130
1110
1150
1160
1140
1150
1152
1150
1170
1150
1130
1130
1140
1140
1125
1123
1120
1122
1145
1132
1142
1127
1130
1125
1145
1130
1135
1140
1130
1154
1162
3460, 3260
3400, 3300, 3200
3410, 3300, 3200
3450, 3340, 3200
3400, 3320, 3150
3450, 3400, 3250
3460, 3400, 3200
3450, 3400, 3210
3400, 3350, 3100
3450, 3400, 3230
3450, 3400, 3240
3480, 3420, 3250
3460, 3350, 3100
3450, 3400, 3360
3450, 3400, 3230
3400, 3350, 3200
3450, 3410, 3240
3450, 3320
3430, 3350, 3200
3400, 3350, 3200
3460, 3380, 3200
3450, 3400, 3200
3450, 3380, 3230
3430, 3300
3480, 3400, 3220
3400, 3350, 3200
3460, 3400, 3200
3480, 3400
1580
1590
1580
1580
1600
1580
1582
1580
1600
1600
1600
1590
1590
1600
1606
1601
1580
1582
1585
1580
1560
1567
1600
1595
1580
1592
1590
1580
1580
1590
1582
1590
2200
2200
2205
2200
2200
2200
2200
2200
2200
2200
2200
2200
2200
2200
2200
2200
2200
2200
2200
2200
2200
2200
2200
2200
2200
2200
2200
2200
3460, 3400, 3200
3350, 3300
3350, 3200, 3100
3330, 3300, 3100
3350, 3210
for 3 h and then allowed to cool. The solid precipitate
was isolated by suction and recrystallized from the
appropriate solvent to give 6a–d.
Method B: The experimental procedure used for the
synthesis of 6 was carried out except for the use
of [(arylamino)(methylthio)methylene]malononitrile in-
stead of [bis(methylthio)methylene]malononitrile.
3.4. 5-Amino-7-arylamino-1,2-dihydro-3-
[4-(N-substituted)sulfamoyl]phenylazo-2-
oxopyrazolo[1,5-a]pyrimidin-6-carbonitriles (8a–h)
3.5. 5-Amino-7-hydrazino-1,2-dihydro-3-
[4-(N-substituted)sulfamoyl]phenylazo-2-
oxopyrazolo[1,5-a]pyrimidin-6-carbonitriles (9a–c)
Method A: a mixture of 6 (0.01 mol) and the re-
quired aromatic amine (0.01 mol) was fused at 150°C
for 0.5 h, then triturated with ethanol, poured into
water and then acidified with hydrochloric acid. The
solid product, formed was collected by filtration and
recrystallized from the appropriate solvent to give 8a–
h.
Hydrazine hydrate (0.02 mol) was added to a solu-
tion of 6 (0.01 mol) in ethanol (30 ml) and the reaction
mixture was heated under reflux for 3 h. The reaction
mixture was cooled and poured on crushed ice–HCl.
The product was filtered, washed with water and recrys-
tallized from proper solvent to give 9a–c.

M.S.A. El-Gaby et al. / Il Farmaco 55 (2000) 596–602
601
3.7. 7-Amino-3-[4-(N-substituted)sulfamoyl]phenylazo-
1,2-dihydro-2-oxopyrazolo-[1,5-a]pyrimidin-6-
carbonitriles (17a,b)
3.6. 5-Amino-7-aryl-1,2-dihydro-3-[4-(N-substituted)-
sulfamoyl]phenylazo-2-oxo-pyrazolo[1,5-a]pyrimidin-
6-carbonitriles (13a–i)
Equimolar amounts of 3 (0.01 mol) and 11 (0.01
mol) in DMF (20 ml) containing a catalytic amount
of pyridine were heated under reflux for 1 h. The
solid product so obtained was collected by filtration
and recrystallized from proper solvent to give
13a–i.
A suspension of 3 (0.01 mol) in DMF (20 ml) was
treated with 14a (0.01 mol) and two drops of pipe-
ridine. The mixture was heated for 3 h and then left
to cool at room temperature. The solid product ob-
tained was collected by filtration and recrystallized
from proper solvent to give 17a,b.
3.8. 3-[4-(N-substituted)sulfamoyl]phenylazo-2,7-
dioxo-1,2,4,7-tetrahydropyrazolo-[1,5-a]pyrimidin-
6-carbonitriles (19a,b)
Prepared by the same procedure as 17 using 14b
instead of 14a. The solid obtained recrystallized from
proper solvent to give 19a,b.
Table 3
1H NMR spectra of some synthesized compounds
Comp. no.
l (ppm)
2a
1.23 (t, 3H, CH3), 4.00 (q, 2H, OCH2), 7.00 (s,
2H, SO2NH2; exchangeable), 7.20–7.70 (m, 4H,
ArꢂH), 12.50 (s, br, 1H, NH; exchangeable).
1.20 (t, 3H, CH3), 4.10 (q, 2H, OCH2), 6.80 (s,
1H, SO2NH; exchangeable), 6.92–7.80 (m, 8H,
ArꢂH), 12.20 (s, br, 1H, NH; exchangeable).
5.90 (s, br, 2H, NH2; exchangeable), 7.10 (s,
br, 2H, SO2NH2; exchangeable), 7.30–7.70 (m,
5H, ArꢂH+NH), 10.20 (s, br, NH;
4. Preliminary antibacterial screening
2b
3a
The antibacterial activity of the compounds 3c,
6c,d, 8b,f,h, 9c, 13c,f and 19a,b was determined by
the agar diffusion technique [13,14]. The test organ-
isms were Staphylococcus aureus (NCTC 7447), Bacil-
lus subtilis (NCTC 10400), Sarcina sp. (NCTC 1117),
Escherichia coli (NCTC 10416) and Serratia marces-
cens (IMRU 70). The agar media were inoculated
with test organisms and a solution of the tested com-
pound in DMSO (1 mg/ml) was placed separately in
cups (8 mm diameter) in the agar medium. A 0.1%
solution of streptomycin was used as a reference. The
inhibition zones were measured after 24 h incubation.
The results of the antibacterial activity tests are sum-
marized in (Table 4).
Most of the synthesized compounds were found to
possess various antibacterial activity towards all the
microorganisms used. Compounds 3c, 6c, 6d, 8f and
8h, which all contain a pyrimidine moiety, possess
high antibacterial activities towards S. marcescens
(IMRU-70). Compounds 8f, 8h and 9c, which also
contain a pyrimidine moiety possess the highest an-
tibacterial activities towards Sarcina sp. (NCTC-1117).
On the other hand, compound 13f which contains a
pyridine moiety was found to possess the highest an-
tibacterial activity towards S. aureus (NCTC 7447) as
compared to the remaining compounds. Compounds
8b, 13c, 19a and 19b which contain a SO2NH2 group
were weakly active against S. aureus (NCTC 7447).
However, none of the tested compounds showed
superior activity than the reference streptomycin.
exchangeable).
6a
6b
8b
2.80 (s, 3H, SCH3), 4.80 (s, br, 2H, NH2;
exchangeable), 7.10 (s, br, 2H, SO2NH2;
exchangeable), 7.31–8.00 (m, 4H, ArꢂH), 8.91
(s, br, 1H, NH; exchangeable).
2.81 (s, 3H, SCH3), 6.76 (s, br, 2H, NH2;
exchangeable), 7.20 (s, br, 1H, SO2NH;
exchangeable), 7.30–8.01(m, 8H, ArꢂH), 8.61
(s, br, 1H, NH; exchangeable).
3.70 (s, 3H, OCH3), 5.60 (s, br, 2H, NH2;
exchangeable), 6.70 (s, 2H, SO2NH2;
exchangeable), 6.80–7.60 (m, 8H, ArꢂH), 7.80
(s, 1H, NH; exchangeable), 10.10 (s, 1H, NH;
exchangeable).
2.30 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 4.60 (s,
br, 2H, NH2; exchangeable), 6.70–7.20 (m,
10H, ArꢂH), 7.50 (s, br, 1H, SO2NH;
exchangeable), 8.00 (s, br, NH, exchangeable),
10.10 (s, 1H, NH; exchangeable).
3.90 (s, 3H, OCH3), 8.7 (s, br, 2H, NH2;
exchangeable), 6.90 (s, br, 2H, SO2NH2,
exchangeable), 7.00–7.91 (m, 8H, ArꢂH), 8.01
(s, 1H, NH; exchangeable).
2.10 (s, 3H, CH3), 6.50 (s, br, 2H, NH2;
exchangeable), 6.90–7.81(m, 1H, ArꢂH), 8.02
(s, 1H, SO2NH; exchangeable), 8.30 (s, 1H,
NH; exchangeable).
2.30 (s, 3H, CH3), 6.50 (s, br, NH2;
exchangeable), 7.00 (s, br, SO2NH;
exchangeable), 7.10–7.90 (m, 7H, ArꢂH), 8.00
(s, 1H, N H; exchangeable).
8h
13c
13h
17b

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M.S.A. El-Gaby et al. / Il Farmaco 55 (2000) 596–602
Table 4
Antibacterial activity of some synthesized compounds a
Comp. no.
Gram positive
Gram negative
Staphylococcus aureus
Bacillus subtilis
Sarcina sp.
Escherichia coli (NCTC Serratia marcescens
(NCTC 7447)
(NCTC 10400)
(NCTC 1117)
10416)
(IMRU 70)
3c
6c
6d
8b
+
+
+
+
++
+
+
++
++
++
++
+++
+++
++
+++
+++
+++
++
+
+
8f
8h
9c
13c
13f
19a
19b
Streptomycin
++
++
+
+
+++
+
+
+
+
+++
+++
++
++
++
+++
++
++
++
++
+
++
++++
+++
+++
+++
++
++
+
+++
+++
++
+++
++++
+
+
+++
++++
+
++++
++++
a +, moderately sensitive giving a zone of inhibition 9–11 mm; ++, sensitive giving a zone of inhibition 12–14 mm; +++, very sensitive
giving a zone of inhibition 15–18 mm; ++++, very highly sensitive giving a zone of inhibition over 18 mm.
References
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