Synthesis, characterization, and antimicrobial activity of novel hydrazone-bearing tricyclic quinazolines

Article abstract of DOI:10.1007/s11164-018-03731-x

Abstract: A series of novel substituted hydrazone-bearing (unsymmetrical azines, RR₁C=N–N=CR₂R₃) tricyclic quinazoline derivatives are reported. All novel compounds were characterized by ¹H, ¹³C nuclear magnetic resonance (NMR), and Fourier-transform infrared (FT-IR) analyses. An important intermediate (E/Z)-hydrazono-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline (8) was synthesized from tricyclic quinazoline-4-thione 7 using 80?% of hydrazine hydrate. In addition, the antimicrobial activity of all synthesized novel compounds against three types of pathogenic microorganism was tested, revealing that some compounds showed satisfactory good activity and could serve as lead compounds for further drug discovery and development. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-018-03731-x

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-018-03731-x
Synthesis, characterization, and antimicrobial activity
of novel hydrazone‑bearing tricyclic quinazolines
Azizbek Nasrullaev, et al. [full author details at the end of the article]
Received: 1 September 2018 / Accepted: 29 December 2018
© Springer Nature B.V. 2019
Abstract
A series of novel substituted hydrazone-bearing (unsymmetrical azines, RR1C=N–
N=CR2R3) tricyclic quinazoline derivatives are reported. All novel compounds were
characterized by 1H, 13C nuclear magnetic resonance (NMR), and Fourier-transform
infrared (FT-IR) analyses. An important intermediate (E/Z)-hydrazono-1,2,3,9-
tetrahydropyrrolo[2,1-b]quinazoline (8) was synthesized from tricyclic quinazoline-
4-thione 7 using 80 % of hydrazine hydrate. In addition, the antimicrobial activity of
all synthesized novel compounds against three types of pathogenic microorganism
was tested, revealing that some compounds showed satisfactory good activity and
could serve as lead compounds for further drug discovery and development.
Graphical abstract
Keywords Quinazoline · Quinazoline-thione · Hydrazone · Thioamide ·
Antimicrobial activity
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4-018-03731-x) contains supplementary material, which is available to authorized users.
Vol.:(0123456789)
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A. Nasrullaev et al.
Introduction
Quinazoline scafolds have attracted special attention because of their diverse chem-
ical and biological features [1]. In a tricyclic quinazoline molecule, there are three
important moieties: benzene, pyrimidine, and an additional cyclic side-chain portion
[2, 3]. Besides, tricyclic quinazolines contain several reaction centers, such as the
nitrogen atoms at positions N-1 and N-3, and the carbonyl and imine groups at the
C-4 carbon atom in the pyrimidine ring. The presence of these fragments contrib-
utes to multireactivity in various types of reaction. Besides, thieno[2,3-d]pyrimidine
[4, 5], pyrrolo[2,3-d]pyrimidine [6], and furo[2,3-d]pyrimidine [7] derivatives are
interesting fve-membered heterocyclic analogues of quinazoline alkaloids from a
chemical point of view.
Quinazolines are an interesting class of small molecule from a biological point
of view [8]. A broad range of bioactivities and applications of quinazolines, such as
anticancer [9–11], antimicrobial [12–16], antiviral [17], antidiabetic [18], antileish-
manial [19], and inhibitory activities toward diverse kinases [20, 21] as well as cho-
linesterases [22–24] have been reported in various areas of medicinal chemistry and
pharmaceutical sciences. In particular, this class of compounds contains interesting
synthons for pharmacologists to develop novel antibiotics based on the quinazoline
skeleton. Unfortunately, development of multidrug resistance by common pathogens
seriously limits the efcacy of antibiotic therapy [25], resulting in an urgent medi-
cal need for the development of new classes of antibiotics that are refractory to or
may restrain or inhibit most common mechanisms of bacterial resistance [26]. In
this regard, several studies have been dedicated to the synthesis and antimicrobial
activities of quinazoline derivatives; For example, a series of N2,N4-disubstituted
quinazoline-2,4-diamines were synthesized and tested against multidrug-resistant
Staphylococcus aureus in 2014 [27]. A detailed structure–activity relationship study
focused on the 2-position, the 4-position, and the quinazoline’s benzenoid ring. It
was observed that quinazoline-2,4-diamines 1 (Fig. 1) represent an excellent plat-
form for future development of antibacterial agents. Detailed study of the synthesis
and in vitro and in vivo activity of aminoquinazolinediones as novel antibacterial
agents has also been carried out [28]. This class of compounds (2, Fig. 1) was shown
to be inhibitory against bacterial gyrase and topoisomerase IV in a fuoroquinolone-
like manner and demonstrates signifcant antibacterial activity against wild-type
and multidrug-resistant organisms. It was observed that the quinazolines 3 (Fig. 1)
Fig. 1 Quinazoline-based antimicrobial leads
1 3

Synthesis, characterization, and antimicrobial activity…
exhibited interesting but varying antibacterial activity against nine Gram-positive
and Gram-negative bacterial strains [29]. In addition, several quinazoline scafolds
(with compound 4 being more active, Fig. 1) have been identifed as antibacterial
agents that inhibit FtsZ-Zing formation [13].
Thus, we report herein the synthesis, characterization, and antimicrobial evalua-
tion of novel hydrazones of tricyclic quinazolines for the frst time. The targets were
obtained from two important (thio- and hydrazono-related) quinazoline intermedi-
ates. In vitro antimicrobial screening was also carried out to identify novel antibiotic
agents.
Results and discussion
Synthesis and characterization
The synthetic route for the target hydrazones of tricyclic quinazolines (9a–n) is
described in Scheme 1. Desoxyvasicinone (6) was synthesized by condensation
from ethyl 2-aminobenzoate (5) and 2-pyrrolidone [30] using phosphoryl chlo-
ride as condensing agent [31, 32]. Quinazoline thioamide (7) was obtained by the
interaction of compound 6 with phosphorus pentasulfde in m-xylene [33]. Herein,
note that thioamide 7 was synthesized to investigate a hydrazonation reaction with
80 % of hydrazine hydrate, inasmuch as hydrazonation of desoxyvasicinone under
hydrazine hydrate failed under diferent conditions. Because the oxygen atom has
a relatively high electronegativity, and due to the mesomeric efect, a high electron
density is concentrated on the oxygen atom. In contrast, the thiocarbonyl group is
much less “strong” than the carbonyl group, due to the absence of strong bonding
between carbon and sulfur, because of the almost equal electronegativity values of
these elements. Therefore, the thiocarbonyl group is more easily attacked by nucleo-
philic reagents. We assumed that C=O group is more stable than C=S fragment,
with regard to conversion to C=N group.
Scheme 1 Synthesis of target compounds 9a–n
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A. Nasrullaev et al.
To explore the hydrazonation of thioamide 7 with 80 % of hydrazine hydrate, we
optimized the ipso-hydrazonation reaction by studying various conditions (Table 1).
In solvent-free condition at room temperature (up to 48 h) and maintaining a reac-
tion temperature of 70 °C during 5 h, hydrazone-containing quinazoline (8) was
aforded in 15 % and 20 %, respectively (Table 1, entries 1 and 2). When ethanol
was used as solvent, we obtained up to 30 % fnal product; however, pyridine was
found to be a suitable solvent for hydrazonation of compound 7, and was further
used to identify the optimal condition for formation of the target hydrazone 8. In
turn, hydrazones are important building blocks for synthesis of azomethines and
construction of new heterocycles. Therefore, we also synthesized hydrazones of tri-
cyclic quinazolines (9a–n) from appropriate aldehydes using toluene as solvent in
high yield (up to 92 %).
The chemical structure of newly synthesized compounds of the series (8, 9a–n)
1
1
was established on the basis of H and 13C NMR spectroscopic analysis. The H
NMR spectrum of compound 8 showed three proton signals for the tricyclic side-
chain portion of quinazoline at 2.93 (2H, t, J=8.0, H-9), 2.15 (2H, m, H-10), and
3.82 (2H, t, J=7.2, H-11). At the center of the spectrum for 8, a broadened sin-
glet signal for NH2 group was observed at 4.85 ppm. Additionally, in the aromatic
region of the spectrum, there were four multiplet signals at 7.41 (H-5), 7.20 (H-6),
7.47 (H-7), and 7.68 (H-8) ppm, which can be assigned to the four benzene ring
protons of the quinazoline molecule. The 13C NMR spectrum of 8 confrmed the
presence of 11 carbons, including 3 methylene carbons at 32.33 (C-9), 18.99 (C-10),
and 48.08 (C-11), 4 aromatic methine carbons at 124.00 (C-5), 126.58 (C-6), 131.77
(C-7), and 127.61 (C-8), and 4 quaternary carbons at 160.21 (C-2), 141.59 (C-4),
1
118.31 (C-4a), and 148.11 (C-8a). The H and 13C NMR spectroscopic data of the
Table 1 Optimization of conditions for hydrazonation of tricyclic quinazoline-4-thione (7) with 80 % of
hydrazine hydrate
Entry
Solvent
Temperature (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
–
–
r.t.
70
r.t.
78
r.t.
70
115
48
5
18
18
48
5
15
20
15
30
30
65
85
EtOH
EtOH
Pyridine
Pyridine
Pyridine
5
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Synthesis, characterization, and antimicrobial activity…
quinazoline moiety in 9a–n were similar to those of compound 8. Additionally, in
1
the H and 13C NMR spectra of 9a, two signals for methyl groups appeared. For
compounds 9b–n, a diastereoisomeric mixture was obtained, and further purif-
cation by recrystallization and chromatography using diferent solvent mixtures
did not permit separation of the two diastereoisomers. These compounds are thus
reported as a mixture (E/Z). The ylidene proton (=CHR1) signal appeared in the 1H
NMR spectra as a singlet in the range of 7.73–8.62 ppm. In the 13C NMR spectra,
ylidene carbon signals resonated in the range of 152.31–155.85 ppm for the six-
membered arylidene derivatives (9b–f, m, n), with the exception of compound 9g
(146.90 ppm), but at 138.59–145.27 ppm for the fve-membered heterocyclic deriva-
tives (9h–l).
In addition, the structure of compound 8 was further confrmed by X-ray
difraction analysis (Fig. 2, CCDC no. 1819031) [33]. The title compound (8)
crystallizes in centrosymmetric triclinic P-1 space group as monohydrate. The
molecule adopts an E-conformation with respect to the C=N double bond. The
N12–N13 bond distance of 1.412(4) Å in the molecule and the experimentally
determined hydrogen positions indicate sp3 hybridization of nitrogen atom of
amino group. The C4=N12 bond distance of 1.297(4) Å corresponds to delocal-
ized C=N bond. The molecule is planar (excluding methylene and hydrazone
hydrogen atoms) with root-mean-square (rms) deviation of all nonhydrogen
atoms of 0.020 Å. Although the observed geometry of the fve-membered ring
containing three methylene groups of the molecule is planar, the ring is inclined
to have convert conformation, as refected in the displacement parameter of the
C10 carbon atom: the equivalent isotropic displacement parameter of the latter
Fig. 2 Crystal structure of compound 8
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A. Nasrullaev et al.
atom [0.103(2) Å2] is noticeably greater than the displacement parameters of
other atoms of the molecule. Displacement ellipsoid plots and the numbering
scheme for the molecule are provided in Fig. 2. The hydrogen bond geometry is
given in Table S1 (Supplementary Material).
Crystal structure analysis showed that water molecule forms hydrogen bonds
with the N1 and N13 nitrogen atoms of centrosymmetric related quinazoline mol-
ecules, generating hydrogen-bonded ring with graph-set motif R4(18). A second
4
hydrogen-bonded ring with graph-set motif R4(8) is formed by hydrogen bonds
4
formed between water molecule and amino group of the title compound (Fig. 3).
Antimicrobial activity
The antimicrobial activity of the target hydrazones 9a–n was tested against two
bacterial (Staphylococcus aureus and Escherichia coli) and one fungal (Can-
dida albicans) strain. The results revealed that most of the screened quinazolines
showed moderate inhibition zones (IZ) in comparison with positive control drugs
ampicillin and amphotericin B. However, derivative 9k containing 5-(4′-NO2-
phenyl)-furan-2-yl fragment was found to be more active (IZ = 15 mm) among
all 14 compounds against Candida albicans strain. Moreover, quinazolines with
thienyl (compound 9h, IZ = 9 mm), pyridyl-4-yl (compound 9n, IZ = 9 mm), and
5-iodo-furfuryl (compound 9j, IZ = 10) moieties also demonstrated good antifun-
gal activity. Besides, derivative 9n displayed an IZ of 15 mm against Staphylo-
coccus aureus bacterial strain (Table 2). Against the Escherichia coli strain, only
9h showed moderate antibacterial activity, while samples 9b, d, n demonstrated
weak IZ. Note that the quinazolines containing fve-membered heterocyclic frag-
ments afected the selected microorganisms.
Fig. 3 Hydrogen bonds in crystal structure (hydrogen atoms shown only for atoms involved in hydrogen
bonding)
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Synthesis, characterization, and antimicrobial activity…
Table 2 Inhibition zones
Compounds
Microbial pathogens
of tested compounds 9a–n
Inhibition zone/diameter (mm)
against Staphylococcus aureus,
Escherichia coli, and Candida
albicans microbial pathogens
Staphylococ- Escherichia colib
Candida
albicansc
cus aureusa
9a
≤5.5
≤5.5
≤5.5
≤5.5
≤5.5
9
≤5.5
7
≤5.5
8
≤5.5
≤5.5
7
9b
9c
9d
7
9e
≤5.5
≤5.5
≤5.5
10.5
≤5.5
≤5.5
≤5.5
≤5.5
≤5.5
8
≤5.5
≤5.5
≤5.5
9
≤5.5
10
9f
9g
8
9h
≤5.5
≤5.5
10
9i
9j
9k
9l
9m
9n
8
15
≤5.5
≤5.5
15
–
16
≤5.5
≤5.5
9
15
–
Ampicillin
Amphotericin B
20
–
aStaphylococcus aureus (ATCC 6538) bacterial strain
bEscherichia coli (ATCC 11229) bacterial strain
cCandida albicans (ATCC 10231) fungal strain
Conclusions
A new series of quinazoline derivatives containing hydrazone fragment were
synthesized and their antimicrobial potential evaluated. An efective method
for ipso-hydrazonation of 7 (a thio-analogue of the natural alkaloid deoxyvasi-
cinone) is described herein for the frst time. Moreover, the ipso-hydrazonation
reaction for thioamide 7 under 80 % of hydrazine hydrate was optimized using
various conditions. The synthesized hydrazone 8 and its electrophilic addi-
tion–elimination products with various aldehydes (unsymmetrical azines, 9a–n,
RR1C=N–N=CR2R3) are very convenient synthons for design of new heterocy-
clic systems. In addition, the antimicrobial activity of all the novel samples was
tested against three microorganisms, revealing that quinazoline 9k containing
5-(4′-NO2-phenyl)-furan-2-yl fragment displayed better antimicrobial property,
showing antifungal activity against Candida albicans strain similar to the stand-
ard drug ampicillin. Although several of the synthesized quinazolines showed
weak to good antimicrobial potentials, half of them (9f, g, h, j, k, n) may serve
as lead compounds for further development regarding antimicrobial screening of
quinazoline scafolds.
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A. Nasrullaev et al.
Experimental
Materials and methods
Reagents and solvents were purchased from Sigma, and used without further puri-
fcation. Thin-layer chromatography (TLC) was carried out on glass plates coated
with silica gel (Qingdao Haiyang Chemical Co., G60F-254) and visualized by ultra-
violet (UV) light (254 nm). Melting points were determined on a Büchi B-540 appa-
1
ratus and are uncorrected. H (400 MHz) and 13C NMR (100 MHz) spectra were
recorded on a Varian NMR spectrometer in CDCl3 and CD3OD, using tetramethyl-
silane (TMS) as internal standard. IR spectra were recorded on an IR Fury System
2000 (PerkinElmer) FT-IR infrared spectrometer (KBr). High-resolution mass spec-
tra (HRMS) were recorded on a AB SCIEX QSTAR Elite quadrupole time-of-fight
mass spectrometer. Ampicillin and amphotericin B were purchased from Sigma
Chemicals Co., and AMRESCO LLC, respectively.
Procedure for synthesis of (E/Z)‑9‑hydrazono‑1,2,3,9‑tetrahydropyrrolo[2,1‑b]quinazo-
line (8) Compound 7 (10 mmol) was dissolved in pyridine (30 mL), and the solu-
tion was added to 10 mL of a solution of NH2NH2·H2O (80 %). The reaction mix-
ture was refuxed for 4 h, then cooled to room temperature. The resulting precipitate
was fltered of, washed with water, dried, and recrystallized from methanol. Yellow
powder; yield: 88 %; m.p. 160–161 °C; 1H NMR (400 MHz, CDCl3, δ, ppm, J/Hz):
7.41 (1H, dd, J=8.1, 1.5, H-5), 7.20 (1H, ddd, J=8.1, 6.9, 1.5, H-6), 7.47 (1H, ddd,
J=8.1, 6.9, 1.5, H-7), 7.68 (1H, dd, J=8.1, 1.5, H-8), 2.93 (2H, t, J=8.0, H-9), 2.15
(2H, m, H-10), 3.82 (2H, т, J=7.2, H-11), 4.85 (2H, br.s., NH2). 13C NMR (CDCl3,
100 MHz, δ ppm): 160.21 (C-2), 141.59 (C-4), 118.31 (C-4a), 124.00 (C-5), 126.58
(C-6), 131.77 (C-7), 127.61 (C-8), 148.11 (C-8a), 32.33 (C-9), 18.99 (C-10), 48.08
(C-11).
General procedure for synthesis of hydrazone derivatives 9a–n All target hydrazone
derivatives were synthesized by previously reported procedure [34]. Briefy, acetone
and aromatic aldehydes (0.6 mmol) were added to 0.4 mmol solution of compound 8
in toluene (20 mL). The mixture was refuxed for 4 h. Then, the solution was evapo-
rated at low pressure, and the residue was purifed and recrystallized from methanol
or ethanol.
(E/Z)‑9‑(Propan‑2‑ylidenehydrazono)‑1,2,3,9‑tetrahydropyrrolo[2,1‑b]quinazoline
(9a) Yellow powder; yield: 92 %; m.p. 110–112 °C; IR (ν, cm−1): 3466, 3062,
1
2904 (CH, CH2, CH3), 1629, 1598, 1565 (>C=N–N=C<), 1135 (N–N). H NMR
(400 MHz, CDCl3, δ, ppm, J/Hz): 7.44 (1H, dd, J=8.1, 1.4, H-5), 7.23 (1H, ddd,
J=7.9, 7.1, 1.4, H-6), 7.50 (1H, ddd, J=8.2, 7.0, 1.4, H-7), 9.09 (1H, d, J=8.1,
H-8), 3.04 (2H, t, J=8.0, H-9), 2.21 (2H, m, H-10), 4.05 (2H, т, J=7.3, H-11), 2.03
(3H, s, CH3), 2.15 (3H, s, CH3). 13C NMR (CDCl3, 100 MHz, δ ppm): 161.44 (C-2),
159.48 (N=C), 145.13 (C-4), 118.54 (C-4a), 124.88 (C-5), 126.28 (C-6), 132.12
(C-7), 131.25 (C-8), 148.04 (C-8a), 32.43 (C-9), 19.08 (C-10), 48.57 (C-11), 25.30
1 3

Synthesis, characterization, and antimicrobial activity…
(CH3), 17.70 (CH3). HRMS (ESI). Calcd. for C14H16N4 [M–H]−: m/z 240.3157.
Found: m/z 240.3168.
(9E/Z)‑9‑((4‑Methylbenzylidene)hydrazono)‑1,2,3,9‑tetrahydropyrrolo[2,1‑b]quinazo-
line (9b) Yellow powder; yield: 72 %; m.p. 138–140 °C; IR (ν, cm−1): 3415, 3056,
1
2959 (CH, CH2, CH3), 1633, 1602, 1567 (>C=N–N=C<), 1127 (N–N). H NMR
(400 MHz, CDCl3, δ, ppm, J/Hz): 9.36 (1H, d, J=8.3, H-8), 7.55 (1H, dd, J=8.0,
7.1, H-7), 7.49 (1H, d, J=7.8, H-5), 7.21 (1H, dd, J=8.1, 7.3, H-6), 7.71 (2H, d,
J=8.0, H-2′,6′), 8.36 (1H, s, H-7′), 7.26 (2H, d, J=8.0, H-3′,5′), 3.07 (2H, t, J=8.0,
H-9), 2.23 (2H, m, H-10), 4.14 (2H, т, J=7.7, H-11). 13C NMR (CDCl3, 100 MHz,
δ ppm): 159.20 (C-2), 155.42 (C-4), 118.38 (C-4a), 125.29 (C-5), 126.63 (C-6),
132.48 (C-7), 131.82 (C-8), 148.29 (C-8a), 32.40 (C-9), 19.21 (C-10), 48.93 (C-11),
132.24 (C-1′), 127.87 (C-2′,6′), 129.63 (C-3′,5′), 140.24 (C-4′), 155.85 (C-7′), 21.69
(Ar-CH3). HRMS (ESI). Calcd. for C14H16N4 [M–H]−: m/z 302.3713. Found: m/z
302.3721.
(9E/Z)‑9‑((4‑Fluorobenzylidene)hydrazono)‑1,2,3,9‑tetrahydropyrrolo[2,1‑b]quinazo-
line (9c) Yellow powder; yield: 73 %; m.p. 134–135 °C; IR (ν, cm−1): 3421, 3030,
1
2950 (CH, CH2), 1637, 1601, 1581 (>C=N–N=C<), 1226 (C-F), 1128 (N–N). H
NMR (400 MHz, CDCl3, δ, ppm, J/Hz): 9.32 (1H, d, J=8.3, H-8), 7.57 (1H, dd,
J=7.8, 7.3, H-7), 7.51 (1H, d, J=7.8, H-5), 7.33 (1H, dd, J=7.8, 7.3, H-6), 7.80
(2H, dd, J=8.6, 5.7, H-2′,6′), 8.37 (1H, s, H-7′), 7.14 (2H, m, H-3′,5′), 3.09 (2H,
t, J=8.0, H-9), 2.25 (2H, m, H-10), 4.15 (2H, т, J=7.3, H-11). 13C NMR (CDCl3,
100 MHz, δ ppm): 159.22 (C-2), 154.14 (C-4), 118.27 (C-4a), 125.39 (C-5), 126.73
(C-6), 132.63 (C-7), 131.67 (C-8), 149.75 (C-8a), 32.40 (C-9), 19.24 (C-10), 49.00
(C-11), 131.94 (d, J=3.2, C-1′), 129.63 (d, J=8.4, C-2′,6′), 116.05 (d, J=22.0,
C-3′,5′), 163.94 (d, J=250.2, C-4′), 154.61 (C-7′).
(9E/Z)‑9‑((3,5‑Bis(trifuoromethyl)benzylidene)hydrazono)‑1,2,3,9‑tetrahydropyrrolo[2,
1‑b]quinazoline (9d) Yellow powder; yield: 68 %; m.p. 169–170 °C; IR (ν, cm−1):
3432, 3053, 2923 (CH, CH2), 1642, 1593, 1557 (>C=N–N=C<), 1287 (C-F), 1125
(N–N). 1H NMR (400 MHz, CDCl3, δ, ppm, J/Hz): 9.22 (1H, d, J=8.3, H-8), 7.62
(1H, dd, J=8.0, 7.2, H-7), 7.56 (1H, d, J=7.9, H-5), 7.25 (1H, dd, J=8.0, 7.2, H-6),
8.21 (2H, br.s, H-2′,6′), 8.46 (1H, s, H-7′), 7.88 (1H, br.s, H-4′), 3.13 (2H, t, J=8.0,
H-9), 2.28 (2H, m, H-10), 4.19 (2H, т, J=7.4, H-11). 13C NMR (CDCl3, 100 MHz,
δ ppm): 159.07 (C-2), 151.90 (C-4), 117.81 (C-4a), 125.79 (C-5), 126.99 (C-6),
133.07 (C-7), 131.45 (C-8), 148.40 (C-8a), 32.35 (C-9), 19.26 (C-10), 49.18 (C-11),
127.25 (C-2′,6′), 132.53 (C-3′,5′), 137.96 (C-1′), 122.83 (C-4′), 152.31 (C-7′).
(9E/Z)‑9‑(((2,3‑Dihydrobenzo[b][1,4]dioxin‑6‑yl)methylene)hydrazono)‑1,2,3,9‑tetrahy
dropyrrolo[2,1‑b]quinazoline (9e) Yellow powder; yield: 81 %; m.p. 144–146 °C; IR
(ν, cm−1): 3429, 3053, 2924 (CH, CH2), 1630, 1600, 1576 (>C=N–N=C<), 1124
1
(N–N), 1064 (C–O–C). H NMR (400 MHz, CDCl3, δ, ppm, J/Hz): 9.35 (1H, d,
J=8.2, H-8), 7.54 (1H, dd, J=8.0, 7.1, H-7), 7.48 (1H, d, J=7.8, H-5), 7.29 (2H,
m, H-6, 6′), 7.36 (1H, d, J=1.7, H-2′), 8.26 (1H, s, H-7′), 6.92 (1H, d, J=8.3, H-5′),
1 3

A. Nasrullaev et al.
3.05 (2H, t, J=8.0, H-9), 2.21 (2H, m, H-10), 4.11 (2H, т, J=7.3, H-11), 4.30 (4H,
s, H-8′,9′). 13C NMR (CDCl3, 100 MHz, δ ppm): 159.16 (C-2), 154.82 (C-4), 118.36
(C-4a), 125.28 (C-5), 126.54 (C-6), 132.41 (C-7), 131.75 (C-8), 148.17 (C-8a),
32.35 (C-9), 19.14 (C-10), 48.89 (C-11), 129.38 (C-1′), 116.32 (C-2′), 143.84 (C-3′),
149.22 (C-4′), 117.69 (C-5′), 121.77 (C-6′), 155.33 (C-7′), 64.40 (C-8), 64.66 (C-9).
(9E/Z)‑9‑((3,4,5‑Trimethoxybenzylidene)hydrazono)‑1,2,3,9‑tetrahydropyrrolo[2,1‑b]
quinazoline (9f) Yellow powder; yield: 67 %; m.p. 131–133 °C; IR (ν, cm−1): 3419,
2997, 2936 (CH, CH2, CH3), 1629, 1599, 1574 (>C=N–N=C<), 1230 (C–O–C),
1130 (N–N). 1H NMR (400 MHz, CDCl3, δ, ppm, J/Hz): 9.29 (1H, d, J=8.2, H-8),
8.31 (1H, c, H-7′), 7.55 (2H, m, H-5,7), 7.29 (1H, m, H-6), 7.08 (2H, c, H-2′,6′),
3.95 (6H, c, 3′,5′-OCH3), 3.92 (3H, c, 4′-OCH3), 3.10 (2H, t, J=8.0, H-9), 2.26
(2H, m, H-10), 4.16 (2H, т, J=7.3, H-11). 13C NMR (CDCl3, 100 MHz, δ ppm):
159.28 (C-2), 154.99 (C-4), 118.26 (C-4a), 125.15 (C-5), 126.67 (C-6), 132.61
(C-7), 131.74 (C-8), 149.51 (C-8a), 32.39 (C-9), 19.25 (C-10), 49.00 (C-11), 131.24
(C-1′), 104.85 (C-2′,6′), 155.17 (C-3′,5′), 139.98 (C-4′), 153.67 (C-7′), 56.31 (3′,5′-
OCH3), 61.14 (4′-OCH3).
(9E/Z)‑9‑((3‑Chloro‑2‑fuoro‑6‑(trifuoromethyl)benzylidene)hydrazono)‑1,2,3,9‑tetrah
ydropyrrolo[2,1‑b]quinazoline (9g) Yellow powder; yield: 85 %; m.p. 188–189 °C;
IR (ν, cm−1): 3436, 3070, 2933 (CH, CH2), 1644, 1605, 1577 (>C=N–N=C<),
1
1170 (N–N), 1273, 1232 (C-F), 541 (C-I). H NMR (400 MHz, CDCl3, δ, ppm, J/
Hz): 9.21 (1H, d, J=8.3, H-8), 7.61 (2H, m, H-7, 5′), 7.69 (1H, d, J=7.4, H-5), 7.34
(1H, br.t., J=7.4, H-6), 8.25 (1H, d, J=5.4, H-4′), 8.62 (1H, s, H-6′), 3.17 (1H, t,
J=8.0, H-9), 2.29 (2H, m, H-10), 4.21 (2H, т, J=7.3, H-11). 13C NMR (CDCl3,
100 MHz, δ ppm): 159.32 (C-2), 146.54 (C-4), 117.75 (C-4a), 125.95 (C-5), 126.63
(C-6), 133.18 (C-7), 131.49 (C-8), 142.70 (C-8a), 32.21 (C-9), 19.26 (C-10), 49.31
(C-11), 128.22 (C-1′), 159.30 (C-2′), 125.70 (C-3′), 132.99 (C-4′), 126.04 (C-5′),
126.72 (C-6′).
(9E/Z)‑9‑((Thiophen‑2‑ylmethylene)hydrazono)‑1,2,3,9‑tetrahydropyrrolo[2,1‑b]quina-
zoline (9h) Yellow powder; yield: 84 %; m.p. 136–138 °C; IR (ν, cm−1): 3433,
3064, 2918 (CH, CH2), 1632, 1601, 1579 (>C=N–N=C<), 1125 (N–N), 767 (C-S-
C). 1H NMR (400 MHz, CDCl3, δ, ppm, J/Hz): 9.41 (1H, d, J=8.2, H-8), 7.53 (3H,
m, H-5,7,2′), 7.31 (1H, dd, J=8.0, 7.3, H-6), 7.41 (1H, d, J=3.8, H-4′), 7.10 (1H,
dd, J=4.7, 4.0, H-3′), 3.11 (2H, t, J=8.0, H-9), 2.31 (2H, m, H-10), 4.41 (2H, т,
J=7.4, H-11). 13C NMR (CDCl3, 100 MHz, δ ppm): 159.16 (C-2), 149.73 (C-4),
118.27 (C-4a), 125.43 (C-5), 126.57 (C-6), 132.04 (C-7), 131.73 (C-8), 148.38
(C-8a), 32.35 (C-9), 19.35 (C-10), 50.21 (C-11), 126.23 (C-2′), 131.83 (C-3′),
132.75 (C-4′), 144.67 (C-5′), 145.27 (C-6′).
(9E/Z)‑9‑(((5‑Methylfuran‑2‑yl)methylene)hydrazono)‑1,2,3,9‑tetrahydropyrrolo[2,1‑b]
quinazoline (9i) Yellow powder; yield: 76 %; m.p. 98–100 °C; IR (ν, cm−1): 3434,
3058, 2924 (CH, CH2, CH3), 1630, 1599, 1585 (>C=N–N=C<), 1129 (N–N), 1019
1
(C–O–C). H NMR (400 MHz, CDCl3, δ, ppm, J/Hz): 9.41 (1H, d, J=8.3, H-8),
1 3

Synthesis, characterization, and antimicrobial activity…
7.55 (1H, dd, J=7.9, 7.1 H-7), 7.50 (1H, d, J=7.6, H-5), 7.34 (1H, dd, J=7.6, 7.1,
H-6), 6.13 (1H, d, J=3.2, H-3′), 6.68 (1H, d, J=3.2, H-4′), 8.16 (1H, s, H-6′), 3.09
(1H, t, J=8.1, H-9), 2.24 (2H, m, H-10), 4.13 (2H, т, J=7.4, H-11), 2.43 (3H, s,
2-CH3). 13C NMR (CDCl3, 100 MHz, δ ppm): 159.17 (C-2), 149.69 (C-4), 118.35
(C-4a), 125.63 (C-5), 126.28 (C-6), 132.54 (C-7), 131.83 (C-8), 140.63 (C-8a),
32.34 (C-9), 19.18 (C-10), 49.03 (C-11), 155.33 (C-2′), 108.54 (C-3′), 114.94 (C-4′),
144.21 (C-5′), 144.95 (C-6′).
(9E/Z)‑9‑(((5‑Iodofuran‑2‑yl)methylene)hydrazono)‑1,2,3,9‑tetrahydropyrrolo[2,1
‑b]quinazoline (9j) Yellow powder; yield: 79 %; m.p. 176–178 °C; IR (ν, cm−1):
3436, 3103, 2918 (CH, CH2), 1632, 1591, 1557 (>C=N–N=C<), 1157 (N–N),
1
1030 (C–O–C), 525 (C-I). H NMR (400 MHz, CDCl3 +CD3OD, δ, ppm, J/Hz):
9.03 (1H, d, J=8.3, H-8), 7.50 (1H, m, H-7), 7.38 (1H, d, J=8.1, H-5), 7.24 (1H,
t, J=7.7, H-6), 6.63 (1H, d, J=3.4, H-3′), 7.14 (1H, d, J=3.4, H-4′), 7.73 (1H, s,
H-6′), 3.03 (1H, t, J=7.9, H-9), 2.26 (2H, m, H-10), 4.15 (2H, т, J=7.1, H-11).
13C NMR (CDCl3, 100 MHz, δ ppm): 158.90 (C-2), 152.77 (C-4), 116.86 (C-4a),
118.66 (C-5), 124.76 (C-6), 132.03 (C-7), 130.46 (C-8), 142.90 (C-8a), 30.93 (C-9),
18.06 (C-10), 48.48 (C-11), 91.08 (C-2′), 122.01 (C-3′), 124.73 (C-4′), 146.49
(C-5′), 138.59 (C-6′).
(9E/Z)‑9‑(((5‑(4‑Nitrophenyl)furan‑2‑yl)methylene)hydrazono)‑1,2,3,9‑tetrahydropyrro
lo[2,1‑b]quinazoline (9k) Red powder; yield: 85 %; m.p. 220–222 °C; IR (ν, cm−1):
3434, 3058, 2918 (CH, CH2), 1629, 1613, 1597 (>C=N–N=C<), 1515 (NO2), 1108
1
(N–N), 1032 (C–O–C). H NMR (400 MHz, CDCl3, δ, ppm, J/Hz): 9.51 (1H, d,
J=8.4, H-8), 7.61 (1H, m, H-7), 7.54 (1H, d, J=8.0, H-5), 7.38 (1H, dd, J=7.9,
7.4, H-6), 6.93 (1H, d, J=3.6, H-3′), 7.01 (1H, d, J=3.6, H-4′), 8.28 (1H, s, H-6′),
8.29 (2H, d, J=8.8, H-3″,5″), 7.90 (2H, d, J=8.8, H-2″,6″), 3.11 (1H, t, J=8.0,
H-9), 2.27 (2H, m, H-10), 4.17 (2H, т, J=7.4, H-11). 13C NMR (CDCl3, 100 MHz,
δ ppm): 159.06 (C-2), 152.96 (C-4, 2′), 118.26 (C-4a), 125.63 (C-5), 126.83 (C-6),
132.86 (C-7), 131.85 (C-8), 146.84 (C-8a), 32.36 (C-9), 19.24 (C-10), 49.13 (C-11),
111.37 (C-3′), 114.75 (C-4′), 150.48 (C-5′), 143.82 (C-6′), 135.94 (C-1″), 124.57
(C-2″, 6″), 124.43 (C-3″,5′), 143.19 (C-4″).
(9E/Z)‑9‑(((4,5‑Dimethylfuran‑2‑yl)methylene)hydrazono)‑1,2,3,9‑tetrahydropyrrolo[2
,1‑b]quinazoline (9l) Yellow powder; yield: 75 %; m.p. 175–177 °C; IR (ν, cm−1):
3432, 2963, 2920 (CH, CH2, CH3), 1629, 1595, 1557 (>C=N–N=C<), 1143 (N–N),
1
1046 (C–O–C). H NMR (400 MHz, CDCl3, δ, ppm, J/Hz): 9.40 (1H, d, J=8.3,
H-8), 7.54 (1H, ddd, J=8.0, 7.1, 1.3, H-7), 7.47 (1H, dd, J=8.0, 1.3, H-5), 7.33
(1H, ddd, J=8.0, 7.1, 1.3, H-6), 6.58 (1H, s, H-4′), 8.11 (1H, s, H-6′), 2.33 (3H, s,
2′-CH3), 2.00 (3H, s, 3′-CH3), 3.07 (1H, t, J=8.0, H-9), 2.29 (2H, m, H-10), 4.12
(2H, т, J=7.3, H-11). 13C NMR (CDCl3, 100 MHz, δ ppm): 159.13 (C-2), 149.17
(C-4), 118.52 (C-4a), 125.51 (C-5), 126.43 (C-6), 132.44 (C-7), 131.84 (C-8),
148.37 (C-8a), 32.38 (C-9), 19.20 (C-10), 48.93 (C-11), 150.98 (C-2′), 132.16
(C-3′), 117.07 (C-4′), 144.22 (C-5′), 144.87 (C-6′), 11.99 (2′-CH3), 10.00 (3′-CH3).
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A. Nasrullaev et al.
(9E/Z)‑9‑((Ferrocene‑2‑yl)methylene)hydrazono)‑1,2,3,9‑tetrahydropyrrolo[2,1‑b]
quinazoline (9m) Red powder; yield: 75 %; m.p. 168–170 °C; IR (ν, cm−1): 3432,
3078, 3019, 2958 (CH, CH2, Cp-H), 1626, 1599, 1560 (>C=N–N=C<), 1154
(N–N). 1H NMR (400 MHz, CDCl3, δ, ppm, J/Hz): 9.34 (1H, d, J=8.2, H-8), 7.55
(1H, m, H-7), 7.49 (1H, d, J=7.8, H-5), 7.33 (1H, br.t., J=7.2, H-6), 8.22 (1H, s,
N=CH), 4.74 (2H, s, ferrocene-H), 4.43 (2H, s, ferrocene-H), 4.22 (5H, s, ferro-
cene-H), 3.07 (1H, t, J=8.0, H-9), 2.23 (2H, m, H-10), 4.11 (2H, т, J=7.2, H-11).
13C NMR (CDCl3, 100 MHz, δ ppm): 159.37 (C-2), 155.73 (N=CH), 155.34 (C-4),
118.67 (C-4a), 125.03 (C-5), 126.45 (C-6), 132.39 (C-7), 131.72 (C-8), 147.89
(C-8a), 32.41 (C-9), 19.23 (C-10), 48.93 (C-11), 70.46 (C-ferrocene), 69.35 (C-fer-
rocene), 68.32 (C-ferrocene).
(9E/Z)‑9‑((Pyridin‑4‑ylmethylene)hydrazono)‑1,2,3,9‑tetrahydropyrrolo[2,1‑b]quina-
zoline (9n) Yellow powder; yield: 82 %; m.p. 124–126 °C; IR (ν, cm−1): 3435,
1
3067, 2956 (CH, CH2), 1634, 1594, 1559 (>C=N–N=C<), 1129 (N–N). H NMR
(400 MHz, CDCl3, δ, ppm, J/Hz): 9.26 (1H, d, J=8.3, H-8), 7.61 (1H, dd, J=8.1,
7.2, H-7), 7.55 (1H, d, J=6.9, H-5), 7.37 (1H, dd, J=8.0, 6.9, H-6), 8.70 (2H,
d, J=5.3, H-3′, 5′), 7.66 (2H, d, J=5.3, H-2′, 6′), 8.35 (1H, s, H-7′), 3.11 (2H, t,
J=8.0, H-9), 2.27 (2H, m, H-10), 4.18 (2H, т, J=7.4, H-11). 13C NMR (CDCl3,
100 MHz, δ ppm): 159.00 (C-2), 152.71 (C-4), 117.91 (C-4a), 125.77 (C-5), 126.98
(C-6), 132.97 (C-7), 131.59 (C-8), 148.52 (C-8a), 32.35 (C-9), 19.24 (C-10), 49.13
(C-11), 121.58 (C-2′,6′), 150.45 (C-3′,5′), 142.90 (C-1′), 153.25 (C-7′).
Antimicrobial screening
The antimicrobial activity of compounds 9a–n was measured using a previously
reported method [35]. Microbial pathogens [Staphylococcus aureus (ATCC 6538),
Escherichia coli (ATCC 11229), and Candida albicans (ATCC 10231)] were used
as indicator strains for this analysis. These microorganisms were aseptically inocu-
lated into appropriate liquid media and incubated for 18 h at 37 °C. Five paper disks
(5.0 mm diameter) were fxed onto agar media plate. Then, the cells were centri-
fuged at 6000 rpm for 10 min, and then suspended in sterile water. The diferent
cells (1 mL) were added to appropriate agar media (100 mL) prior to plating; the
wells were made using an agar well borer. To these wells, diferent concentrations of
9a–n were added and subsequently incubated at 37 °C for 24 h. Zones of inhibition
were estimated by measuring the diameter of the microbial growth inhibition zone.
Acknowledgements This work was funded by grants from the Chinese Academy of Sciences President’s
International Fellowship Initiative (K. Bozorov, grant no. 2019PT054), the Central Asia Drug Research
and Development Center of Chinese Academy of Sciences, and the Academy of Sciences of the Republic
of Uzbekistan (grant no. VA-FA-F-7-006).
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A. Nasrullaev et al.
Afliations
Azizbek Nasrullaev1,2 · Khurshed Bozorov1,2 · Khayrulla Bobakulov1,2
·
Jiangyu Zhao1 · Li Fei Nie1 · Kambarali K. Turgunov2 · Burkhon Elmuradov2 ·
Haji A. Aisa1
*
Haji A. Aisa
haji@ms.xjb.ac.cn
1
Key Laboratory of Plant Resources and Chemistry in Arid Regions, Xinjiang Technical
Institute of Physics and Chemistry, Chinese Academy of Sciences, 40-1 South Beijing Rd,
Ürümqi 830011, People’s Republic of China
2
Institute of the Chemistry of Plant Substances, Academy of Sciences of Uzbekistan, Mirzo
Ulugbek Str. 77, Tashkent, Uzbekistan 100170
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