A study of antituberculosis activities and crystal structures of (E)-2-[2-(arylidene)hydrazinyl] pyrimidine and (E)-N1-(arylidene)pyrimidine-2-carbohydrazide derivatives

Z. Naturforsch. 2020; 75(12)b: 1011–1028

Alessandra C. Pinheiro, Thaís C. M. Nogueira, Cristiane França da Costa, Cristina Lourenço,

John N. Low, James L. Wardell*, Solange M. S. V. Wardell and Marcus V. N. de Souza

A study of antituberculosis activities and crystal

structures of (E)-2-[2-(arylidene)hydrazinyl]

1

pyrimidine and (E)-N -(arylidene)pyrimidine-

2-carbohydrazide derivatives

https://doi.org/10.1515/znb-2020-0108

Received June 10, 2020; accepted October 20, 2020;

published online November 24, 2020

Keywords: anti-TB; (E)-2-[2-(arylidene)hydrazinyl]pyrim-

idines; (E)-N -(arylidene)pyrimidine-2-carbohydazides;

X-ray crystallography; π interactions.

1

Abstract: A study of the anti-tuberculosis activity against

Mycobacterium tuberculosis ATTC 27294 and an X-ray struc-

tural determination of (E)-2-[2-(arylidene)hydrazinyl]pyrimi-

1

Introduction

1

dine, 1, and (E)-N -(arylidene)pyrimidine-2-carbohydazide,

The pyrimidine moiety (Figure 1) is found in many com-

pounds associated with a wide spectrum of biological ac-

tivities [1, 2], including antineoplastic [3–6], antibacterial

2, derivatives are presented. The effect of the substituents

in the aryl moiety on the antituberculosis (anti-TB) activ-

ities of 1 and 2 is compared with that of other heteroaryl

hydrazonyl and acylhydrazonyl derivatives. The biological

activities of 1 do not depend on the coordinating ability

of the substituted aryl group: in 2, the most effective

aryl group is 5-nitrofuranyl. The structure determinations

of (E)-2-((2-(pyrimidin-2-yl)hydrazono)methyl)-phenol,

[

7, 8], antimalarial [9], antiviral [10] and anti-inﬂammatory

11], antimicrobial and anti-oxidant [12], leishmanial

13, 14] agents. The potential of arylhydrazone derivatives,

especially of nitrogen heteroaromatics, as biological

agents has been extensively studied [15–18]. Over the

recent past, the de Souza group has investigated the bio-

logical activity of a series of such compounds, including

anticancer [19–23], antiparasitic [24], antileishmanial

(E)-N′-(2,5-dihydroxybenzylidene)pyrimidine-2-carbohydrazide

and of the hydrate of (E)-N′-(2-hydroxy-4-methylbenzylidene)

pyrimidine-2-carbohydrazide, and a literature search of

related structures in the CCDC data base, allowed an ex-

amination of the more important interactions, including

the occurrence of X–Y⋯π interactions.

[

25–27] and anti-tuberculosis (TB) agents [28–35]. The

crystal structures of such compounds have also attracted

our interest [20, 21, 36–41].

Compounds combining the pyrimidin-2-yl moiety and

the hydrazonyl functionality have not been excluded from

the general interest in arylhydrazone derivatives, and such

compounds have been involved in studies on docking with

enzymes [42], antimicrobial activity [43, 44], anticancer

[

45, 46] and antileishmanial agents [25–27].

*

Corresponding author: James L. Wardell, Fundação Oswaldo Cruz,

Some of us recently reported on the anti-leishmanial

activity of a series of hydrazone andacylhydrazone

derivatives, built from pyrimidin-2-ylhydrazine and

Instituto de Tecnologia em Fármacos - Farmanguinhos, 21041-250, Rio

de Janeiro, RJ, Brazil; and Department of Chemistry, University of

Aberdeen, Meston Walk, Old Aberdeen, AB24 3UE, Scotland, UK,

E-mail: j.wardell@abdn.ac.uk

Alessandra C. Pinheiro, Thaís C. M. Nogueira, Cristiane França da

Costa and Marcus V. N. de Souza, Fundação Oswaldo Cruz, Instituto

de Tecnologia em Fármacos - Farmanguinhos, 21041-250, Rio de

Janeiro, RJ, Brazil

2

-pyridinoic acid, respectively [25]. In continuation of our

biological activity studies of nitrogen-containing hetero-

arene hydrazones and acylhydrazones, we have tested the

pyrimidin-2-yl-hydrazone and -acylhydrazone derivatives

in an anti-TB study (Scheme 1).

Tuberculosis is a mycobacterial infection, transmitted

through the air and mainly affecting the lungs. It has been

considered a global health emergency by the World Health

Organization(WHO)duetotheadventofmultidrug-resistant

tuberculosis (MDR-TB) and extensively drug-resistant

Cristina Lourenço, Departamento de Bacteriologia, Fundação

Oswaldo Cruz, Instituto Nacional de Infectologia Evandro Chagas,

2

1045-900, Manguinhos, Rio de Janeiro, Brazil

John N. Low, Department of Chemistry, University of Aberdeen,

Meston Walk, Old Aberdeen, AB24 3UE, Scotland, UK

Solange M. S. V. Wardell, CHEMSOL, 1 Harcourt Road, Aberdeen AB15

5NY, Scotland, UK

1

012

A.C. Pinheiro et al.: A study of antituberculosis activities and crystal structures

1

2

3 hits were found. The only structures of the pyrimidin-

-yl-acylhydrazone derivatives that have been reported

are the two discussed in this article.

2

Experimental

2

.1 General

Figure 1: Chemical structure of pyrimidine.

The pyrimidin-2-ylhydrazone and -acylhydrazone deriva-

tives were prepared as previously reported (Scheme 1).

All compounds had m.p.s, NMR and IR spectra and mass

spectrometric data as previously reported [25].

tuberculosis (XDR-TB) strains. Multidrug-resistant tubercu-

losis (MDR-TB) refers to organisms that are resistant to the

first-line drugs isoniazid andrifampin, andisresponsible for

about 3.3% of all new cases every year. Extensively drug-

resistant tuberculosis (XDR-TB), confirmed in more than 58

countries, is resistant to main first and second line anti-TB 2.2 Anti-mycobacterial activity

drugs and is the biggest challenge in the treatment of this

disease [47, 48].

We now wish to report on our findings of the anti-TB were assessed against Mycobacterium tuberculosis ATTC

activities of a series of pyrimidin-2-yl-hydrazone, 1, and 27294 using the micro plate Alamar Blue assay (MABA) [50].

acylhydrazone, 2, derivatives (Scheme 1), and compare This methodology is nontoxic, uses a thermally stable re-

The anti-mycobacterial activities of compounds 1 and 2

-

the activities with those found in earlier studies of other agent and shows good correlation with proportional and

heteroaryl-hydrazone, and -acylhydrazone, derivatives. BACTEC radiometric methods [51, 52]. The method is

We also report on the crystal structures of three derivatives described as follows: sterile deionized water (200 mL) was

used in this study, namely (E)-2-((2-(pyrimidin-2-yl)hydra- added to all outer-perimeter wells of 96 sterile well plates

zono)methyl)phenol (1a), (E)-N′-(2,5-dihydroxybenzylidene) (Falcon, 3072: Becton Dickin). Each of the96 plates received

pyrimidine-2-carbohydrazide (2d) and the hydrate of 100 mL of Middlebrook 7H9 broth (Difco laboratories,

2

e, (E)-N′-(2-hydroxy-4-methylbenzylidene)pyrimidine- Detroit, MI, USA) and successive dilutions of the tested

2

-carbohydrazide, 2e⋅(H O). A search of the CCDC data compound were added directly to the plate. The ﬁnal drug

2

−1

base on 29th April 2020 [49] indicated that very few concentrations tested were 0.01–20.0 mg mL . Plates were

structures of pyrimidin-2-yl-hydrazones and -acylhy- covered and sealed with paraﬁlm and incubated at T = 37 °C

drazones have been reported, certainly in comparison to for ﬁve days. A freshly prepared 1:1 mixture of Alamar Blue

other nitrogen-containing heteroaryl-NH–N=CH-aryl (Accumed International, Westlake, Ohio) reagent and 10%

and -heteroaryl-CO–NH–N=CH-aryl compounds: indeed tween 80 (total volume: 25 mL) was added to the plate and

for the substructure {2–(C—C=N–NH)-pyrimidine} only incubated for 24 h. A blue colouration in the well was

1

a

b

i

1c

1

d

e

f

g

h

i

1

2

a

b

c

ii, iii, iv

2d

2

e

f

g

h

i

Scheme 1: Reagents: i: RCHO, 25 °C; ii MeOH,

SO Cl , 25 °C, 24 h; iii: H NNH · H O (80%),

2

EtOH, 25 °C, 3 h; iv: RCHO, 25 °C, 1–24 h.

A.C. Pinheiro et al.: A study of antituberculosis activities and crystal structures

1013

interpreted as no bacterial growth, and a pink colouration the program SHELXL-97 [54]. The hydroxy hydrogen atom,

was scored as growth. The minimal inhibition concentra- the hydrogen attached to N3 and the two hydrogens of the

tion (MIC) was deﬁned as the lowest drug concentration, water molecule were placed in calculated positions, but

which prevented a colour change from blue to pink.

then fully reﬁned. All other hydrogen atoms were placed in

calculated positions. SHELXL-97 [54] and PLATON [55] were

used in the calculation of the molecular geometries. The

programs ORTEP-3 for Windows [56] and MERCURY [57] were

used in the preparation of the Figures. Crystallographic

details are listed in Table 1.

2.3 Experimental crystallography

Data for compounds was obtained with Mo radiation

λ = 0.71073 Å) at T = 100 K at the NRC crystallographic

service, based at the University of Southampton. Data

(

collection, data reduction and unit cell reﬁnement were 3 Results and discussion

achieved with CRYSALISPRO 1.171.39.9 g [53]. Correction for

absorption was achieved by CRYSALISPRO 1.171.39.9 g [53]. 3.1 General

An empirical absorption correction using spherical har-

monics, implemented in the SCALE3 ABSPACK scaling al- All the compounds were recrystallised samples, prepared

1

gorithm, was applied. The structures were solved by Direct as published [25], and were found to have identical H and

1

3

Methods using SHELXS-97 [54] and fully reﬁned by means of

C NMR and IR spectra and mass spectrometric data as

Table : Crystallographic data.

Compound

a

d

e·(H O)



Empirical formula

Formula weight

Temperature, K

Wavelength λ, Å

Crystal system

Space group

Unit cell dimensions

a, Å

C



H



N



O

C



H



N



O



C



H



N

 

O

.

()

.

monoclinic

P /n

.

()

.

monoclinic

P /c

.

()

.

monoclinic

P /n



.()

.()

.()

.()

.()



.()

.()

.()

.()

.()



.()

.()

.()

.()

.()



b, Å

c, Å

β, deg



Volume, Å

Z

−



Density (calcd.), Mg m

.

.

.



Crystal size, mm

. × . × .

.



. × . × .

.



. × . × .

.



Absorption coeff., mm⁻

F(), e



θ Range data coll., deg

Index ranges

.–.

− ≤ h ≤ 

.–.

− ≤ h ≤ 

− ≤ k ≤ 

− ≤ l ≤ 



.–.

− ≤ h ≤ 

− ≤ k ≤ 

− ≤ l ≤ 



−

 ≤ k ≤ 

 ≤ l ≤ 

Reﬂections collected

Reﬂections unique









R

int

.

.

.

.

.

.

Completeness, %

Absorption correction

Transm. max./min.

Reﬁnement method

Data/parameters

Semi-empirical from equivalents

./.

Full-matrix least-squares on F

./.

./.



/

.

/

.

/

.



Goodness-of-ﬁt (F )

Final R



/wR



[I >  σ(I)]

(all data)

./.

./.

n/a

./−.



./.

./.

n/a

./−.



./.

./.

n/a

./−.







Extinction coefﬁcient

Largest diff. peak/hole, e Å⁻

CCDC No.



1

014

A.C. Pinheiro et al.: A study of antituberculosis activities and crystal structures

previously reported. The samples of compounds 1a, 2d and reactivities of 1b and 1c, [MIC ca. 100 μm], and to the

e used in the X-ray crystallographic study were all further unreactive compound 1e [MIC > 500 μm]. 1f showed a

recrystallized from the same batch of methanol.

2

slightly increased activity over that of ethambutol. The

higher reactivity of 1f, compared to the other 2-hydroxyl

substituted compounds, is of interest as a signiﬁcant role

of hydrazones in many biological studies is considered to

be that of a di- or poly-dentate chelator, and thereby a

potential remover of vital metals from participating in

the development of the disease. With its electron with-

drawing nitro group, 1f has a reduced chelating ability

than any of the other 2-hydroxyphenyl derivatives used

in the study. There is evidence that hydrazones built

from heteroarylhydrazines and aldehydes, with suitably

o-sited donor groups, such as salicylaldehyde and pyri-

dine-2-carbaldehyde derivatives, are effective chelating

agents for metals [34, 58, 59]: for metal complexes

formed from tridentate hydrazones derived from pyr-

amidin-2-ylhydrazine see references [45, 60–65]. The

conclusion that the ability of these pyrimidyl hydrazones

is not based solely on their chelating potential is

conﬁrmed by the poor activity of the pyridin-2-yl sub-

stituent 1g.

3

.2 Anti-mycobacterial activity

The anti-mycobacterial in-vitro activities of compounds 1

and 2 were tested against M. tuberculosis H37Rv strain

(ATCC 27294) (Table 2). The biological results, expressed as

MIC (μM), for compounds 1 and 2 are listed in Table 2, along

with data on the mutagenicity/tumorigenicity and c log P

values. Also listed are the results of using the standard

drugs ethambutol and isonicotinic acid hydrazide.

3

.2.1 Hydrazone study

In the hydrazone study, the 2-hydroxyphenyl derivatives

a–1f exhibited a signiﬁcant range of activities from the

1

most reactive 1f with a MIC value of 12 μM to signiﬁcant

Table : The in-vitro activity of compounds  and  against Myco-

bacterium tuberculosis HRv strain (ATCC , susceptible to

ethambutol).

The heteroaryl derivative 2-(2-((5-nitrofuran-2-yl)

methylene)hydrazonyl)pyrimidine), 1h, exhibited a low

activity [MIC = 429 μm], while the other heteroaryl deriva-

tive 2-(2-((5-nitrothien-2-yl)methylene)hydrazonyl)pyrimi-

dine) (11) was non-active. However, hydrazones derived

from 5-nitrofuran-2-yl and thieny-2-yl carbaldehydes

have shown good activities in other anti-TB studies,

e.g., in the study of 7-chloro-4-quinolinylhydrazone

b

Compound Aryl group

MIC Mutagenic/

c log P

a

(

µM)

tumorigenic

(

a) Hydrazones



a

b

c

d

e

f

g

h

i

-HO-phenylOH

 None/none

 High/none

 None/none

 None/none

.

.

,-(HO)

,-(HO)

,-(HO)



-phenyl



phenyl



-phenyl

-HO- -Me-phenyl

-HO--O N-phenyl

Pyridin--yl

> None/none

 None/none

> Low/none

 High/high

> None/none

. derivatives against M. tuberculosis H37Rv [30]. Speciﬁc



.

.

.

.

nitro-substituted ﬁve-membered ring heteroaromatics,

in particular MEGAZOL, 5-(1-methyl-5-nitroimidazol-2-yl)-

-O

–



N-furan--yl

N-thien--yl

1

,3,4-thiadiazol-2-amine) [66] and BENZNIDAZOLE,



c

N-benzyl-2-(2-nitroimidazol-1-yl)acetamide [67, 68] have

shown good activities as antiparasitic agents. The mecha-

nism of action of these compounds is based on their

ready reduction to radical intermediates using a ﬂavine-

based enzyme, present in the intracellular media. A

radical-based mechanism could also apply with these anti-

TB active nitro-heteroaryl compounds. That the 5-nitro-

EMB

INH

.

.

–

d

–

a

Compound Aryl group

MIC Mutagenic/

µM) tumorigenic

c log P

(

b) Acylhydrazones



a

b

c

d

e

f

g

h

i

-HO-phenylH

,-(HO) -phenyl

,-(HO)-phenyl

,-(HO) -phenyl

-HO- -Me-phenyl

-HO--O N-phenyl

pyridine--yl

> None/none

> High/none

> None/none

 None/none

 None/none

> Low/none

 High/high

.

.



. 2-hydroxyphenyl derivative 1f possesses the best activity of

. all the 2-hydroxyphenyl derivatives studied here could also



.

.

.

.

.

be related to redox potentials [35].



As mentioned earlier, the same set of pyrimidin-

2-ylhydrazones was used in the recent study against pro-

-O



N-furan--yl

N-thien--yl

mastigotes and Leishmania amazonensis-GFP amasti-

gotes, as well as murine macrophages [25]. Here the com-

pound with the best response was the pyridin-2-yl

derivative; indeed most of the compounds studied had

good activities. This clearly suggests that a different



 None/none

a

The minimal inhibition concentration (MIC), which prevented the

b

colour change from blue to pink, Calculated using Data Warrior

program [], EMB = ethambutol, and INH = isonicotinic acid

hydrazide.

c

d

A.C. Pinheiro et al.: A study of antituberculosis activities and crystal structures

1015

mechanism applies here, compared to that in the anti-TB (Table 3). Pharmacokinetic studies have indicated that a

situation.

good balance between permeability and aqueous solubility

for a drug is indicated by a logP value between 0 and 3. The

value found for the most active compound of this study, 1f,

falls within this range, being 0.261. Other compounds that

3

.2.2 Acylhydrazone study

The most active acylhydrazones studied were 2h and 2i. have outstanding activity are the heteroaromatic de-

The pyridine-2-yl, 2g, and the 2-hydroxyphenyl de- rivatives 2h and 2i: the log P values, 0.146 and 0.103, for

rivatives, 2a–2f, were at best moderately active, so again these compounds also fall within the ideal range, but the

here a chelating role for the compounds seems not to have values suggest that the compounds will be slightly more

a major impact.

water soluble. The toxicities of the compounds 1 and 2

The same general reactivity sequence of substituents were also determined using the Data Warrior program [70]

as found in the current study was reported in a larger (Table 2). The most promising compound in each series,

study against M. tuberculosis H37Rv involving 2-(aryl- compounds 1f and 2i, were found to be non-mutagenic and

CH=N–NHCOCH )-thienes, having phenyl or heteroaryl non-tumorigenic.

2

moieties [69]: here the most active compounds were the

5‐nitrothien‐2‐yl and 5‐nitrofuran‐2‐yl derivatives, with MIC

values of 8.5 and 9.0 μm, respectively. Moderately active

compounds were the pyridin‐2‐yl, and 2‐ and 4‐hydrox-

yphenyl derivatives, with MIC values between 170 and

3

.3 Crystallography

3.3.1 General

4

08 μm, while the compounds were phenyl derivatives

with MeO, F, Cl, Br, CN, and O N substituents and the

heteroaryl compounds (furan‐2‐yl, thien‐2‐yl, pyrrol‐2‐yl,

imidazol‐2‐yl, pyridin‐3‐yl, and pyridin‐4‐yl) were inactive

2

Recrystallization of compounds, 1a and 2d, from moist

methanol at room temperature produced anhydrous

crystals, while that for 2e generated the monohydrate – all

from the same batch of methanol. Reﬁnements of 1a and

[

69]. In a further study using 2-(heteroaryl)-CH=N–NHCO)

pyrazine derivatives, the 5-nitrofuran-2-yl derivative was

found to be the most active compound (and non-cytotoxic)

2

e⋅(H O) proceeded most satisfactorily, but not that of 2d.

2

As mentioned below and shown in Table 3, these are

nearly planar π systems which allows for close packing

with formation of stacks, or at least dimers, either with

molecules in parallel or anti-parallel orientations. As the

linker groups contain nitrogen donors (and oxygen do-

nors for acylhydazones) and an C=N group, there is scope

for π interactions between the layers in the stack,

including of course π⋯π as well as C=O⋯π, N–H⋯π and

C=N⋯π interactions, etc., depending on the offsets be-

[

29] among a number of 5-membered and 6-membered

heteroaryl groups. Notably, the pyridin-2-yl derivative was

non-active. Thus some degree of consistency regarding the

effect of the 5-nitrofuranyl group as the aryl unit in

R-CONH–N=CH-aryl compounds is obtained.

3

.2.3 Lipophilicities and toxicities

The lipophilicities of 1 and 2, expressed as logP values, tween successive molecules in successive layers of the

were determined using the Data Warrior program [70] stack.

a

Table : Selected bond lengths.

Compound

a) Hydrazones

C–N

N–N

N–N

C–C

(



a

.()

.()–

.()

.()

.()–

.()

.(]

.()–

.()

.()

.()–

.()

Range of values found

for related compounds [, –]

Compound

b) Acylhydrazones

C–C

C–O

C–N

N–N

N–C

C–C

(



d

.()

.()

.()

.()

.()

.()

.()

.()

.()

.()

.()

.()

e⋅(H



O)

a

Standard bond lengths, Å: C–C ., C=C ., C–N ., C=N ., N–N ., N=N ., C–O ., C=O . [].

1

016

A.C. Pinheiro et al.: A study of antituberculosis activities and crystal structures

3.3.2 Compound 1a

pertains with the π ⋯π interaction. The last sub-structure

A

to mention is the chevron-type arrangement produced from

The atom arrangement and numbering scheme and a side- the C13–H13⋯π interactions and C14–H14⋯O12 hydrogen

on view of the conformation of compound 1a are shown in bonds (Figure 3d). The C14–H14⋯O12 hydrogen bonds

Figure 2a: the intramolecular hydrogen bond, O12– generate C(5) chains.

H12⋯N4, is drawn as a dashed line. The molecule is

The hydroxyl group is thus involved in the intra-

slightly distorted from planarity as indicated by the inter- molecular hydrogen bond with N4 and in two intermolec-

planar angles. The interplanar angles indicate that the ular C5–H5⋯O12 and C14–H14⋯O12 hydrogen bonds. All

successive rotations of the linkers and rings occur in the four nitrogen atoms are involved in several interactions,

same sense: the consequence of that is the overall slight but in the case of N4, the only interaction is the intra-

curvature of the molecules as illustrated in Figure 2a. As molecular O12–H12⋯N4 interaction. Overall, compound

shown in Table 3, a comparison of the measured bond 1A has a two-dimensional structure.

lengths in the linker chain with standard bond lengths

indicates delocalisation [71]. Also included in Table 3 are

3.3.3 Compound 2d

the equivalent bond lengths in related published structures

64, 72–76]: there are only small ranges for each bond

length despite some variation in the compounds in terms of

substituents, solvation and protonation.

The intermolecular interactions in compound 1a

are N–H⋯N and C–H⋯O hydrogen bonds and π⋯π and

[

The resolution of the structure of compound 2d was not

perfect as indicated by the high R and R values of 0.094

1

int

and 0.116, respectively: the ellipsoids were also fairly dis-

torted. However, the CIF check indicated no A or B alerts.

As attempts to gain better crystals failed and the fact that

no related structure of an unhydrated pyrimidin-2-yl acyl

hydrazone was in the CCDC data base, we still feel it is

useful to elaborate on some of the structural details.

Figure 2b shows the atom arrangements and

numbering scheme of the compound. The arrangement

about the –C(O)NH–N=C- fragment is (E)_C_O_N_H/(E)_N₌_C

C–H⋯π interactions (Table 4). Pairs of the classical

2

hydrogen bonds, N3–H3⋯N1, generate dimers with R (8)

rings [77]. Such dimers are linked into zig–zag chains by

pairs of weaker C5–H5⋯O12 and C4–H4⋯H2 hydrogen

bonds (Figure 3a and b). A side-on view of a chain indicates

its slight undulating nature (Figure 3b). The connections by

the C5–H5⋯O12 and C4–H4⋯H2 hydrogen bonds to the

dimers with the N3–H3⋯N1 connectivity produce one

[

69, 78]. The intramolecular hydrogen bonds, O12–

H12⋯N4 and N3–H3⋯N2, are drawn as dashed lines. The

2

R (6) ring and two R (12) rings. The chains, illustrated in molecule has a very slight S-shape, as indicated by the

2

Figure 3a, are linked into sheets by π ⋯π / π ⋯π and interplanar angles. Further details are summarized in

A

B

A

π ⋯π interactions (Figure 3c). The former interactions are Table 3.

A

stronger as indicated by the smaller offsets and shorter

The intermolecular interactions in compound 2d as

indicated by PLATON are O–H⋯O, C–H⋯N and C–H⋯O

Cg⋯Cg distances (Table 4). Molecules with π ⋯π /π ⋯π

B

A

B

interactions are lined up antiparallel. A similar situation hydrogen bonds and C8=O8⋯π interactions (Table 4).

Figure 2: Atom numbering schemes and

atom arrangements.

A.C. Pinheiro et al.: A study of antituberculosis activities and crystal structures

1017

Table : Geometric parameters (Å, deg) for intra- and intermolecular interactions.

Compound

D–H⋯A

D–H

H⋯A

D⋯A

D–H⋯A

(

a) Intramolecular hydrogen bonds





a

d

e·(H

O–H⋯N

N–H⋯N

O–H⋯N

N–H⋯N

.()

.()

.()

.()

.()

.()

.()

.()

.()

.()

.()

.()

.()

.()

.()

()

()

.()

()



O)



O–H⋯N

Compound

D–H⋯A

D–H

H⋯A

D⋯A

D–H⋯A

Symmetry code

(

b) Intermolecular hydrogen bonds





a

d

N–H⋯N

C–H⋯N

.()

.

.()

.

.()

.()

.()

.()

.()

.()

.()

.()

.()

.()

.()

.()

.()

.()



 − x,  − y, –z

 − x,  − y, –z

C–H⋯O

C–H⋯O

O–H⋯O

C–H⋯O

C–H⋯O

C–H⋯O

C–H⋯N

OW–H⋯N

OW–H⋯N

N–H⋯OW

C–H⋯O

.

.()

.

.()

.

.

.

.()

.

.

.

.

.()

.()

.()

.





½ − x, –½ + y, ½ − z

− + x, ½ − y, −½ + z

 + x, –y, ½ + z

 − x, –½ + y, ½ − z

½ − x, –½ + y, ½ − z

x, y, z

()





d



e·(H



O)

()

()

.()



x, y, z

–½ − x, –½ + y, ½ − z

a

Compound

Y–X⋯Cg

X⋯Cg

X

perp

γ

Y–X⋯Cg

Y⋯Cg

Symmetry code

a

(

c) Y–X⋯π interactions





a

d

e·(H

C–H⋯Cg

C–O⋯ Cg

C–HA⋯ Cg

C–O⋯ Cg

.–()

.()

.

.

.

.

.

.

.

.



.()



.()

.()

.()

x, ½ − y, ½ + z

x, y, z

 + x, y, z



O)



.()

.

.()

.()

Cg(I)⋯Cg(J)

d) π⋯π interactions

Cg⋯Cg

α

β

γ

CgIperp

CgJperp

Symmetry code

(



a

Cg()⋯Cg()

Cg()⋯Cg()

.()

.()

.()

.()

.

.

.

.

.()

.()

.()

.()

–x,  − y, –z

 − x,  − y, –z

a

Cg(I) and Cg() = centres of gravities of pyridinyl and phenyl rings of the quinoline ring, respectively; α = dihedral angle between planes I and J

(

deg); β = angle Cg(I) → Cg(J) (deg); γ = angle between Cg(I) → Cg(J) vector and normal to plane J (deg); Cg–Cg = distance between ring Centroids

Å); Cg–Iperp = perpendicular distance of Cg(I) on ring J (Å).

Molecules of the acylhydrazone are linked into columns by the π interaction, as above, and the two C–H⋯O hydrogen

2

combinations of O15–H15⋯O8₍_c_a_r_b_o_n_y_l₎, C16–H16⋯O8₍_c_a_r_b_o_n_y_l₎

,

bonds forming the R (6) ring. The C8=O8⋯π interactions

3

^C⁷^–^H⁷^⋯^O¹²⁽hydroxy) and C13–H13⋯N2 hydrogen bonds:

alternating molecules in the columns are positioned anti-

parallel. Such columns are further linked into sheets by

^C⁵^–^H⁵^⋯^O¹⁵⁽hydroxy) hydrogen bonds (Figure 4a): alternating

molecules in layers of the sheet are inverted. The sheets are

occur between acylhydrazone molecules in different layers

as shown in Figure 4c: in such an arrangement, the N3–H3

moiety is situated above a phenyl ring, resulting in a T

shaped arrangement for the N3–H3⋯π interaction (with

d(H–Cg ) = 3.44 Å and ∠N–H⋯Cg = 77° (Figure 4d)

B

2

composed of a series of rings with the symbols R (11), R (13), [79–81].

2

3

4

R (6), and R (18). Another view, looking down the b axis, a

The hydroxyl group on C12 is involved in a intra-

portion of the twisted, undulating sheet is shown in Figure 4b. molecular O12–H12⋯N4 hydrogen bond and in two inter-

The sheets are linked into a three-dimensional array by molecular C–H⋯O hydrogen bonds, while the hydroxyl

carbonyl⋯π (C8=O8⋯π) interactions, an example of the group on C15 plays a lesser role being solely involved in

interaction is shown in Figure 4c. The carbonyl oxygen linking the chains into sheets. In contrast to the hydrazonyl

atom is thus involved in three intermolecular interactions, compound 1a the nitrogen atom N2 in the pyridinyl ring is

1

018

A.C. Pinheiro et al.: A study of antituberculosis activities and crystal structures

Figure 3: Compound 1a.

a) Part of a chain of molecules formed from C5–H5⋯O12, C4–H4⋯N2, C5–H5⋯O12 and C4–H4⋯N2 hydrogen bonds, (b) a side-on view

showing the slight undulating nature of the chain, (c) part of a 2-dimensional array of molecules formed from linking the chains, shown in

Fig.5a, by π ⋯π and also π ⋯π interactions, (d) a chevron-type arrangement produced from the C13–H13⋯π interactions and C14–

(

A

B

A

H14⋯O12 hydrogen bonds, (e) packing of molecules looking down the b axis: differently coloured molecules indicate different operations.

not involved in intermolecular interactions, but is utilized Figure 2c: the intramolecular hydrogen bonds, O12–

in the intramolecular hydrogen bond with the ortho hy- H12⋯N4 and N3–H3⋯N2, are drawn as dashed lines. The

droxyl group on C12. Compared to the situation in com- arrangement about the –C(O)NH–N=C- fragment is

pound 1a, the presence of the carbonyl group in the (E)_C_O_N_H/(E)_N₌_C[69, 78]. The molecule is non-planar as

acylhydrazone derivative results in the suppression of any shown by the interplanar angles as in 2d, the acylhy-

intermolecular activity of this nitrogen atom.

drazone molecule in 2e⋅(H O), also has a slight S-shape.

2

A view of the packing of the molecules is illustrated in Further details are summarized in Table 3 [71].

Figure 4e, looking down the b axis.

.3.4 Compound 2e·(H O)

The intermolecular interactions in compound 2e

are OW–HW⋯N, N–H⋯OW and C–H⋯O hydrogen bonds

3

and C8=O8⋯π

A

and C17–H17A⋯π interactions (Table 4).

B

2

The water molecules indirectly link the acylhydrazone

The atom arrangement and numbering scheme and a side- molecules into chains, via N3–H3⋯Ow, Ow–H2⋯N2 and

on view of the conformation of 2e⋅(H O), are shown in Ow–H2⋯N2 hydrogen bonds (Figure 5a). A view of a chain

2

A.C. Pinheiro et al.: A study of antituberculosis activities and crystal structures

1019

Figure 4: Compound 2d.

(

a) Part of a sheet of molecules formed from

O15–H15⋯O8(carbonyl), C16–

H16⋯O8(carbonyl), C7–H7⋯O12(hydroxy),

C13–H13⋯N2 and C5–H5⋯O15 hydrogen

bonds (b) another view, looking down the b

axis, of the portion of the twisted,

undulating sheet shown in Figure 4a,

(

c) carbonyl·π (C8=O8⋯π) interactions,

which combine with the sheets, to form a

three-dimensional array, (d) a view of the

overlap of acylhydrazone molecules in

successive rows of the stack shown in

Figure 4c, showing the positioning of the

N–H moiety over a phenyl ring, (e) a view of

the packing of the molecules, looking down

the b axis.

indicating its undulating nature is shown in Figure 5b. the acylhydrazone molecules either in green or blue,

3

2

Within the chain, R (7) rings are formed from the combi- depending on their symmetry relation. Each acylhy-

nation of the Ow–H2⋯N2 and N3–H3⋯Ow hydrogen drazone molecule is linked to molecules in the same row

bonds. Successive acylhydrazone molecules in the chain and to molecules in both the rows above and below in a

are anti-parallel.

PLATON revealed C8=O8⋯π_Aand C17–H17A⋯π_Bin- two acylhydrazone molecules (Figure 6).

teractions linking stacks of molecules, in which successive

spiral arrangement. Each water molecule is connected to

molecules are off-set by 3.25 Å, but orientated in the same 3.3.5 Comparisons of structures of 2d and 2e·(H O)

2

sense (Figure 5c). The offset is required to accommodate

the C17–H17A⋯π_Binteractions – and places the C=N The conformations of the acylhydrazone molecules in 2d

moiety in an ideal position to form a C=N⋯π interaction and 2e·(H O) are very similar (Figure 3). However, the

2

with

a

phenyl

ring

in

the

2

Cg₍_C₌_N₎⋯Cg₍_P_h_B₎= 3.41 Å (Figure 5c). Figure 5d illustrates marked differences in the structures. These water mole-

the extensive overlap of three molecules in consecutive cules are only involved in the formation of hydrogen

layers of a π stack. These π stacks are linked into two- bonded chains indirectly linking acylhydrazone mole-

dimensional arrays by C4–H4⋯O8₍_c_a_r_b_o_n_y_l₎hydrogen cules, while connections between these chains and the

bonds (Figure 5e): the molecules drawn in different colours direct links between acylhydrazone molecules are pro-

are related by different symmetry operations. Figures 5e vided by C–H⋯O₍_c_a_r_b_o_n_y_l₎and by both C–H⋯π and C=O⋯π

and f provide two views of the interactions, both the indi- interactions: the latter is also present in anhydrous 2d, but

rect acylhydrazone-acylhydrazone links, involving the the C–H⋯π interaction is absent. The C=O⋯π interactions

water molecules, and the direct acylhydrazone-acyl provide the direct links between the hydrogen bonded

hydrazone links. Water molecules are drawn in red and sheets of the acylhydrazone molecules in 2d, which result

1

020

A.C. Pinheiro et al.: A study of antituberculosis activities and crystal structures

Figure 5: Compound 2e⋅(H

a) Part of a column of acylhydrazone molecules linked indirectly by water molecules, utilizing N1–H1⋯Ow, Ow–H2⋯N2 and N3–H3⋯OW

hydrogen bonds, (b) a side-on view of the column shown in Figure 5a, (c) part of a stack of acylhydrazone molecules formed from C8=O8⋯πA,

C17–H17A⋯π and π(C=N) ··π(PhB) interactions, (d) overlap of three consecutive layers of molecules in the π stack, (e) arrangement of the

2

O).

(

B

acylhydrazone molecules formed from linking the π stack by C4–H4⋯O8 hydrogen bonds, (f) and (g) two views of the arrangement of linked

acylhydrazone and water molecules: water molecules are drawn in red and acylhydrazone molecules in green or blue, depending on the

symmetry operation.

A.C. Pinheiro et al.: A study of antituberculosis activities and crystal structures

1021

Figure 6: Compound 2e⋅(H

2

O).

The arrangement around the water

molecule: angles and distances calculated

using the MERCURY program.

in a three-dimensional structure. The different arrange- just a neutral compound: interplanar angles between the

ments of the layers in the stacks in 2d and 2e·(H O), result terminal aryl groups are less than 12°, the one exception

2

in different sets of π interactions.

.3.6 Comparisons with reported structures

The search of the CCDC data base on 29th April 2020 [49]

being one of the two independent molecules of compound

[19.98(10)°], a sterically hindered compound with addi-

tional aryl groups, including fused groups (entry 5 in

Table 5).

3

Just two of the compounds in Table 5 are anhydrous

indicated very few structures of pyrimidin-2-ylhydrazones: derivatives with a 2-hydroxyphenyl group, and are thus

the only known structures of pyrimidin-2-ylacylhydrazones most similar to compound 1a. These compounds are

are the two reported in this article. For the substructure, 2-methoxy-6-({2-[4-(triﬂuoromethyl)pyrimidin-2-yl]hydra-

2

-(C–C=N–NH)-1,3-N C H , only 13 different hits are found, zinylidene}methyl)phenol, 4 [CCDC codes: SIFNON:

2 4 3

in addition to our compound 1a (Table 5). In Table 5, the 1544930] [73] and 2-(N-(4,6-dimethyl-2-pyrimidinyl)etha-

numbering scheme used follows that employed for 1a and nehydrazonoyl)phenol, 5 [CCDC codes: BOSCIW, 678939]

could thus be different from that used in the original re- [74]. In these compounds, as in compound 1a, intra-

ports. In the discussion which follows, the emphasis is on molecular O–H⋯N1 hydrogen bonding involving the

the main intermolecular interactions involving the hydra- 2-hydroxy group ﬁxes the conformation about the C2–N3

zone moiety, the hydroxyl groups, if any, and the π bond.

interactions.

In crystals of compounds 1a and 5, there are strong

intermolecular N3–H3⋯N1 interactions, pairs of which

2

3

.3.7 Hydrazones

create R2(8) dimers (central part of Figure 2a). These di-

mers are further linked into three-dimensional structures

All the pyrimidin-2-ylhydrazone structures reported herein by π⋯π interactions and by weaker interactions, such as

have an (E) conﬁguration about the N4–C7 bond, as gener- C–H⋯O and C–H⋯π. For compound 1a, the symmetric

ally most hydrazones do in the solid state, a consequence of dimers are very nearly planar as there are no substituents

the much greater stability of the (E) form over the (Z) form. present to cause any steric hindrance. However, in 5 with

Due to the fact that rotations around the C2–N3 and C7–C11 its two independent molecules, the asymmetric dimers

bonds require less energy, compounds with unsymmetri- have an interplanar angle of 60.5° between the two

cally substituted pyrimidin-2-yl and phenyl groups can monomeric units. With the conformation at the C2–N3

adopt different conformations, as revealed below.

bond ﬁxed in both monomeric units to allow the intra-

For each of the compounds, bar one, in Table 5, the molecular O–H⋯N1 hydrogen bond, methyl groups at both

core of the hydrazone molecule, consisting of the non- the pyridinyl and phenyl rings are placed on the sides in

hydrogen atoms making up the aryl rings and the linker each molecule to minimise the steric consequences.

chain, has a slightly distorted planar conformation, no

A very significant difference is found in 4: here tetramers

matter whether the hydrazone is protonated or solvated or are generated from the two independent molecules through

1

022

A.C. Pinheiro et al.: A study of antituberculosis activities and crystal structures

1023

1

024

A.C. Pinheiro et al.: A study of antituberculosis activities and crystal structures

1025

1026

A.C. Pinheiro et al.: A study of antituberculosis activities and crystal structures

strong N3–H3⋯N1 and N3–H3⋯O1 hydrogen bonds and

strong π⋯π interactions [Cg ⋯Cg = 3.6326(16) Å and slip-

4

Conclusions

A

B

pages of 1.124 and 1.260 Å]. The formation of the tetramers

can be considered to arise from linking the different mole-

cules via a N3A–H3A⋯N1B hydrogen bond to yield an

asymmetric dimer, with an inter-planar angle of near 87°,

which is further linked to another dimer, involving N3B–

H3B⋯O1A hydrogen bonds and π ⋯π interactions. Further

π⋯π interactions and C–H⋯F and C–H⋯N interactions link

the tetramers into a three-dimensional array. As can be seen

in Table 4, entry number 2, the conformation adopted does

not explain why there is no N3–H3⋯N1 linked dimer, as the

sides of the molecules which would be linked in such a dimer

are free of any bulky group.

While the anti-mycobacterial activities of the compounds

studied cover a large range, there is sufficient indication

that further study would be useful. The most active com-

pounds were (E)-5-nitro-2-((2-(pyrimidin-2-yl)hydrazono)

methyl)phenol, 1f, and (E)-N′-((5-nitrothiophen-2-yl)meth-

ylene)pyrimidine-2-carbohydrazide, 2i, with different sub-

stituents in the aryl moiety. A comparison of the effect of

the substituents at the aryl group on the anti-TB activities

in other heteroarylhydrazone compounds, Ar-CH=N–

NH-heteroaryl indicated a range of activities, i.e., there was

no consistent inﬂuence of the Ar groups on the activities.

With the pyrimidinyl compounds, 1, the results indicated that

the donor abilities of the Ar group, [e.g. 2-hydroxyphenyl

or pyridine-2-yl], was not of prime importance. In contrast

with Ar-CH=N–NH–CO-heteroaryl compounds, cases with

Ar = 5-nitrofuran-2-yl generally produce the more active

compounds.

A

B

The principal hydrogen bond in ((methylbenzylidene)

hydrazinyl)-5-methyl-4-(trifluoromethyl)pyrimidine, 6 [Ta-

ble5, entry no. 4], a compound withouta 2-hydroxygroup, is

also the N3–H3⋯N1 hydrogen bond. However in this case,

2

chains are formed rather than R (8) dimers. The confor-

mation of 6, about the C7–C12 bond, and the positioning of

the triﬂuoromethyl group indicate that dimer formation,

involving pairs of N3–H3 units, would create signiﬁcant

sterichindrance. Although compound 3 [Table 5, entryno. 5]

has no fused aromatic rings, it does have a conformation

which allows the formation of N3–H3⋯N1 linked non-

planar dimers with a relatively large angle of 54.5° between

the best planes through the different monomer units.

Compound 7 [Table 5, entry no. 6], with a different

type of hydrazone unit, has a different set of intermolecular

interactions. No N–H⋯N hydrogen bonds or π⋯π

interactions are detected, but various C–H⋯N, C–H⋯π

and C–H⋯F hydrogen bondsforming essentially separated

planar sheets.

The remaining compounds in Table 5 are either sol-

vates or protonated pyrimidinyl compounds. In the case of

the solvates, the solvate molecule is very strongly involved

in the intermolecular interactions with consequential in-

direct hydrazone–hydrazone contacts. The involvement of

the water molecule varies strongly with the substituents in

the hydrazine. In most cases, π⋯π interactions remain

important. As expected, water has a more signiﬁcant

impact then does ethanol, and the effect of two molecules

of water is more dramatic than that of just one (compare

entry 10 with entries 7–9). The perchlorate salts, entries 12

and 13, exhibit various intermolecular interactions,

While there have been few reports of the structures of

pyrimidin-2-yl hydrazones, some general conclusions can

still be made. There is a very strong indication of the

importance of the N3–H3 hydrogen bonding, either to form

dimers, especially in the absence of steric effects, or chains.

There is also a strong indication that π interactions, espe-

cially π⋯π interactions, are an important feature, especially

in linking sheets and chains of molecules, formed primarily

from hydrogen bonding interactions. Even N-protonated

and solvated compounds show a propensity to maintain

intramolecular O12–H12⋯N1 hydrogen bonds in hydra-

zones formed from 2-hydroxybenzaldehyde precursors and

to possess π⋯π interactions. The inﬂuence of solvate mol-

ecules on the structures is very signiﬁcant through the for-

mation of many indirect links between the hydrazones.

There are even fewer reports of the structures of

pyrimidin-2-ylacyl hydrazones. Here too, O12–H12⋯N1

hydrogen bonds in acylhydrazones formed from

2

-hydroxybenzaldehyde precursors prevail, but not

π₍_a_r_y_l₎⋯π₍_a_r_y_l₎interactions. However, due to the fact that the

molecules, contain potential donor sites, e.g., nitrogen and

oxygen groups, and a C=N moiety, can form stacks with

parallel or antiparallel arrangements, with different off-

sets, other π interactions can arise, such as N–H⋯π,

C=O⋯π, C–O⋯π and or C=N⋯π, as found in 2d and

2

e⋅(H O). The hydrazine compound 1a exhibited π

2

(ary-

including N–H⋯O(ClO ) hydrogen bonds. The salt 8

3

_l₎⋯π₍_a_r_y_l₎, but apart from C–H⋯π interactions, did not

exhibit any X–Y⋯π interactions. However, the hydra-

zonyl compounds, 8 and 9, entries 7 and 8, in Table 5, do:

compound 8 exhibits a N–H⋯Cg₍_P_h₎interaction and

compound 9 a π₍_C₌_N₎⋯π₍_P_h₎interaction. Thus it is also a

maintains π⋯π interactions, whereas the salt 9 maintains

the intramolecular O12–H12⋯N1 hydrogen bond, indi-

cating the importance of such interactions, where appro-

priate, also in the pyrimidin-2-yl hydrazones.

A.C. Pinheiro et al.: A study of antituberculosis activities and crystal structures

1027

feature found in pyrimidin-2-ylacyl hydrazones, with a 12. Sankarganesh M., Raja J. D., Sakthikumar K., Solomon R. V.,

Vijayakumar V. Bioorg. Chem. 2018, 81, 144.

3. Atta K. F. M., Ibrahim T. M., Farahat O. O. M., Al-Shargabi T. Q.,

suitable positioning of the molecules in the stacks.

1

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4. Chaturvedi R. N., Arish M., Kashif M., Kumar V., Reenu P. K., Rub

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Supporting information

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CCDC 2008878, 2008885 and 2008879 for 1a, 2d and

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1

6. Guimaraes D. G., Rolim L. A., Gonsalves A. D., Araujo C. R. M. Rev.

Virtual Quim 2017, 9, 2551.

2

tallographic data for this paper. These data can be obtained

free of charge from The Cambridge Crystallographic Data

Centre via http://www.ccdc.cam.ac.uk/data_request/cif.

The details of the crystal structure determinations in cif

format are also available in the online version (https://doi.

org/10.1515/znb-2020-0108).

17. Verma G., Marella A., Shaquiquzzaman M., Akhtar M., Ali M. R.,

Alam M. M. J. Pharm. BioAllied Sci. 2014, 6, 69.

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8. Singh N., Ranjana R., Kumari M., Kumar B. Int. J. Pharm. Clin. Res.

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1

9. Rodrigues F. A. R., Oliveira A. C. A., Cavalcanti B. C., Pessoa C. O.,

Pinheiro A. C., de Souza M V. N. Sci. Pharm. J. 2014, 82, 21.

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Acknowledgements: The authors thank the National

Crystallographic Service, University of Southampton for

the data collection, and for their help and advice.

Author contribution: All the authors have accepted

responsibility for the entire content of this submitted

manuscript and approved submission.

2

1. Rodrigues F. A. R., Bomﬁm I. S., Cavalcanti B. C., Pessoa C. O.,

Wardell J. L., Wardell S. M. S. V., Pinheiro A. C., Kaiser C. R.,

Nogueira T. C. M., Low J. N., Gomes L. R., de Souza M. V. N. Bioorg.

Med. Chem. Lett 2014, 24, 934.

2

2. Guerreiro D. D., Lima L. F., Sá N. A. R., Mbemya G. T., Ferreira

A. C. A., Alves B. G., Maranhao S. S., Pessoa C. Ó., Pinheiro A. C.,

Nogueira T. C. M., de Souza M. V. N., de Figueiredo J. R., Rodrigues

A. P. R. Res. Vet. Sci. 2020, 128, 261.

Research funding: None declared.

Conﬂict of interest statement: The authors declare no 23. Maranhão S. S., Moura A. F., Oliveira A. C. A., Lima D. J. B., Barros-

Nepomuceno F. W. A., Paier C. R. K., Pinheiro A. C., Nogueira

T. C. M., de Souza M. V. N., Pessoa C. Bioorg. Med. Chem. Lett

conﬂicts of interest regarding this article.

2

020, 30, 126851.

2

4. Alves M. S. D., das Neves R. N., Sena-Lopes A., Domingues M.,

Casaril A. M., Segatto N. V., Nogueira T. C. M., de Souza M. V. N.,

Savegnago L., Seixas F. K., Collares T., Borsuk S. Parasites

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A study of antituberculosis activities and crystal structures of (E)-2-[2-(arylidene)hydrazinyl] pyrimidine and (E)-N1-(arylidene)pyrimidine-2-carbohydrazide derivatives

DOI: 10.1515/znb-2020-0108

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