4-Arylamino-6-nitroquinazolines: Synthesis and their activities against neglected disease leishmaniasis

Article abstract of DOI:10.1016/j.ejmech.2015.11.016

4-Arylamino-6-nitroquinazolines (2-25) were synthesized and evaluated for their leishmanicidal activities against Leishmania major promastigotes in vitro with IC₅₀ values Combining double low line 1.87-61.48 μM. Among the twenty four synthetic derivatives, 4-[4′-(methylsulfanyl)phenyl]amino-6-nitroquinazoline (21), and 4-(2′-methoxyphenyl)amino-6-nitroquinazoline (8) showed excellent antileishmanial activities with IC₅₀ values 1.87 ± 0.31 and 4.37 ± 0.02 μM, respectively, more active than the standard drug, pentamidine (IC₅₀ Combining double low line 5.09 ± 0.09 μM). Compound 16 (IC₅₀ Combining double low line 6.53 ± 0.21 μM) displayed an activity comparable to the standard. Compounds 15 (IC₅₀ Combining double low line 9.04 ± 0.03 μM), 18 (IC₅₀ Combining double low line 12.28 ± 0.18 μM), 14 (IC₅₀ Combining double low line 19.87 ± 0.22 μM), and 5 (IC₅₀ Combining double low line 24.03 ± 2.71 μM) also showed good activities.

Full text of DOI:10.1016/j.ejmech.2015.11.016

Accepted Manuscript
4-Arylamino-6-nitroquinazolines: Synthesis and their activities against neglected
disease Leishmaniasis
Syed Muhammad Saad, Nida Ghouri, Shahnaz Perveen, Khalid Mohammed Khan,
M.Iqbal Choudhary
PII:
S0223-5234(15)30353-6
10.1016/j.ejmech.2015.11.016
EJMECH 8206
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 15 September 2015
Revised Date: 3 November 2015
Accepted Date: 9 November 2015
Please cite this article as: S.M. Saad, N. Ghouri, S. Perveen, K.M. Khan, M.I. Choudhary, 4-
Arylamino-6-nitroquinazolines: Synthesis and their activities against neglected disease Leishmaniasis,
European Journal of Medicinal Chemistry (2015), doi: 10.1016/j.ejmech.2015.11.016.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
4-Arylamino-6-nitroquinazolines: Synthesis and their activities against
neglected disease Leishmaniasis
Syed Muhammad Saad,1 Nida Ghouri,1 Shahnaz Perveen,2 Khalid Mohammed Khan,1 and
M. Iqbal Choudhary1,3
1H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological
Sciences, University of Karachi, Karachi-75270, Pakistan
2PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi-
75280, Pakistan
3Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah-21412,
Saudi Arabia
Abstract
4-Arylamino-6-nitroquinazolines (2-25) were synthesized and evaluated for their
leishmanicidal activities against Leishmania major promastigotes in vitro with IC50 values =
1.87-61.48
µM.
Among
the
twenty
four
synthetic
derivatives,
4-[4′-
(methylsulfanyl)phenyl]amino-6-nitroquinazoline (21), and 4-(2′-methoxyphenyl)amino-6-
nitroquinazoline (8) showed excellent antileishmanial activities with IC50 values 1.87 ± 0.31
and 4.37 ± 0.02 µM, respectively, more active than the standard drug, pentamidine (IC50 =
5.09 ± 0.09 µM). Compound 16 (IC50 = 6.53 ± 0.21 µM) displayed an activity comparable to
the standard. Compounds 15 (IC50 = 9.04 ± 0.03 µM), 18 (IC50 = 12.28 ± 0.18 µM), 14 (IC50
= 19.87 ± 0.22 µM), and 5 (IC50 = 24.03 ± 2.71 µM) also showed good activities.
Keywords
4-Arylamino-6-nitroquinazolines; Leishmania major; Antileishmanial Agents.
*Corresponding Author: khalid.khan@iccs.edu, hassaan2@super.net.pk, Tel.: 0092-21-34824910; Fax: 0092-
21-34819018
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1. Introduction
Leishmaniasis is a vector-borne disease, caused by the bite of different species of
phlebotomine sandflies, which release protozoa of the genus Leishmania parasites [1].
Among all tropical diseases, leishmaniasis is ranked fourth in morbidity, and second in
mortality rates [2]. Leishmaniasis is widespread among 88 countries of the world, with the
exception of Antarctica [3]. It has affected 12 million people and to make the case worst, this
figure increases to 2 million every year [4,5]. Based on types of species and response of host
immune, leishmaniasis has three basic clinical forms; cutaneous, mucosal, and visceral
leishmaniases. Cutaneous leishmaniasis (CL) is the most common type. It is mainly caused
by L. braziliensis, L. major, L. mexicana, L. tropica, and several other species [6]. Mucosal
leishmaniasis (ML) is usually caused by L. braziliensis. Damage of the palate, nasal septum,
and mucous membranes are associated with this disease [7,8]. Visceral leishmaniasis (VL) is
usually caused by L. infantum and L. donovani. It is the most severe form of leishmaniasis
which can cause death, if left untreated [9,10].
Treatment of leishmaniasis is based on synthetic drugs, such as fluconazole, amphotericin B,
pentamidine, pentavalent antimonials, and miltefosine [11,12]. Treatment of leishmaniasis is
associated with toxic effects, high cost, and emerging resistance [13,14]. Hence, it is a
necessity to develop drugs which are effective, safe, and possessing no or minimum toxicity,
to cure leishmaniasis.
Quinazolines are the nitrogenous binuclear compounds with antitubercular [15], antimicrobial
[16], anti-inflammatory [17], anticonvulsant [18], antiallergic [19], antihyperlipidemic [20],
and antiviral [21] properties. Many drugs possess quinazoline moiety as core part of their
structures. This indicates the importance of quinazoline as a privileged pharmacophore [22-
25]. Literature survey reveals some quinazoline derivatives possess leishmanicidal activities
[26-29]. Our research group is focusing on the discovery of the antileishmanial lead
molecules since last one decade [30-39]. Few years ago, antiparasitic studies were conducted
on the analogs of substituted 4-arylamino-6-nitro-2-sulfonylatedquinazolines [40]. In the light
of these studies, we synthesized structurally similar some easy to prepare analogs of 4-
arylamino-6-nitroquinazolines 2-25 (Figure-1) and evaluated for their leishmanicidal effects
(Table-1). Nine compounds 4, 8, 9, 13, 14, and 21-24 are new, while remaining compounds
are previously reported [41-44].
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Figure-1: Structures of 4-arylamino-6-nitro-2-sulfonylatedquinazolines and 4-arylamino-6-
nitroquinazolines.
2. Results and Discussion
2.1. Chemistry
For the study of antileishmanial activity, twenty-four derivatives of 4-arylamino-6-
nitroquinazolines were synthesized by reacting (E)-N'-(2-cyano-4-nitrophenyl)-N,N-
dimethylformimidamide (1) with various aniline derivatives in acetic acid under reflux
conditions. Precipitates appeared when water was added into the reaction mixture. The
precipitates were filtered, and dried under vacuum (Scheme-1). Prior to this, (E)-N'-(2-cyano-
4-nitrophenyl)-N,N-dimethylformimidamide (1) was synthesized and analyzed by X-ray
crystallography as our research group previously reported [45]. The chemical structures of
1
these derivatives were inferred by H-NMR, 13C-NMR, EI-MS, and IR spectroscopy. All
synthesized compounds yielded acceptable elemental analyses, and HREI-MS data.
Scheme-1: Synthesis of 4-arylamino-6-nitroquinazoline derivatives 2-25.
2.1.1. Characteristic Spectral Feature of Representative Compound 21
1H- and 13C-NMR spectra of most potent anti-leishmanial compound 21 were recorded in
1
deuterated DMSO. In H-NMR spectrum (Figure-2), a downfield broad singlet signal
appeared at δH 10.44 was due to the acidic NH proton. The lone pair of this nitrogen is
involved in extensive conjugation with phenyl and quinazoline rings. H-5 appeared at δH 9.65
(d, J5,7 = 2.1 Hz), showing meta coupling with H-7. Its downfield chemical shift is due to
ortho NO2 and N–C≡N groups. Similarly H-2 lying between the two electronegative nitrogen
atoms of quinazoline nucleus, resonated at δH 8.69 (s). The remaining H-7 and H-8 of this
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basic skeleton appeared as doublets at δH 8.56 (J = 9.3 Hz) and 7.93 (J = 9.3 Hz, 2.1 Hz),
respectively. Four protons of N-phenyl ring (H-2′/H-6′ = δH 7.81) and (H-3′/H-5′ = δH 7.34),
appeared as doublets (J = 8.7 Hz).
Figure-2: 1H-NMR chemical shifts of compound 21.
13C-NMR broad-band decoupled spectrum (Figure-3) showed a total of 13 carbon signals,
including 1 methyl, 6 methine, and 6 quarternary carbons. The quaternary carbon (C-4) lying
between the two nitrogens, had the most downfield signal at δC 158.6. Second most downfield
signal was assigned to C-2 (δC 157.6). This methine carbon is in between the two
electronegative nitrogens of the quinazoline nucleus. C-6, ipso to nitro group, resonated at δC
144.4. Quaternary C-4′, adjacent to sulfur, appeared at δC 133.5. All remaining aromatic
carbons in the structure appeared in the usual aromatic range of δC 114.3-153.0.
Figure-3: 13C-NMR chemical shifts of compound 21.
EI-MS of compound 21 (Figure-4) showed the molecular ion peak [M]+ at m/z 312. The M+ is
also the base peak, indicating its stability. Loss of methyl radical yielded a peak at m/z 297.
Neutral loss of H2C=S gave a radical cation at m/z 266. Cleavage of quinazoline ring
generated a radical cation at m/z 164 which was further fragmented into cations at m/z 163
and 124, with the loss of hydrogen radical and N≡C–N, respectively.
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Figure-4: Key EI-MS fragmentation of compound 21.
2.2. Antileishmanial Activities
The current study describes in vitro leishmanicidal activity, screening the antileishmanial
potential of a broad range of 4-arylamino-6-nitroquinazoline compounds for the first time.
We have screened compounds 2-25 against leismaniasis using pentamidine as a standard drug
(IC50 ± SEM = 5.09 ± 0.09 µM) as per literature protocol [46]. Out of them, compounds 3, 5,
8, 14-16, 18, 20-22, and 24 were identified as good to moderate antileishmanial agents with
IC50 values 61.48 ± 0.37, 24.03 ± 2.71, 4.37 ± 0.02, 19.87 ± 0.215, 9.04 ± 0.03, 6.53 ± 0.21,
12.28 ± 0.175, 38.17 ± 0.73, 1.87 ± 0.31, 44.91 ± 0.47, and 35.88 ± 0.185 µM, respectively
(Table-1). 4-[4′-(Methylsulfanyl)phenyl]amino-6-nitroquinazoline (21) (IC50 = 1.87 ± 0.31
µM) and 4-(2′-methoxyphenyl)amino-6-nitroquinazoline (8) (IC50 = 4.37 ± 0.02 µM) were
found to be more active than the standard, pentamidine (IC50 = 5.09 ± 0.09 µM). Compound
16 (IC50 = 6.53 ± 0.21 µM) displayed an activity comparable to the standard. Compounds 15
(IC50 = 9.04 ± 0.03 µM), 18 (IC50 = 12.28 ± 0.18 µM), 14 (IC50 = 19.87 ± 0.22 µM), and 5
(IC50 = 24.03 ± 2.71 µM) also demonstrated good activities. Compounds 24 (IC50 = 35. 88 ±
0.19 µM), 20 (IC50 = 38.17 ± 0.73 µM), 22 (IC50 = 44.91 ± 0.47 µM), and 3 (IC50 = 61.48 ±
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0.37 µM) exhibited a weak activity. However, remaining compounds were found to be
completely inactive.
Limited structure-activity relationship reveals that the difference in leishmanicidal strength of
4-arylamino-6-nitroquinazoline derivatives is a consequence of variations in substitutions on
the 4-arylamino part of the molecule (Figure-5). A plausible reasoning is discussed below.
Figure-5: 4-Arylamino-6-nitroquinazoline 2-25.
p-Methylsulfanyl substitution as in compound 21 (IC50 = 1.87 ± 0.31 µM) was found to be the
most potent analog among the series when compared with standard pentamidine (IC50 = 5.09
± 0.09 µM). It showed about three-fold more activity than the standard. The presence of
methylsulfanyl substitution at meta position slightly lowered the activity as in compound 14
(IC50 = 19.87 ± 0.215 µM).
o-Methoxy substituted phenyl ring, as in compound 8, showed an IC50 = 4.37 ± 0.02 µM
more active than the standard drug. However, when the methoxy group was shifted to meta or
para positions as in compounds 7 or 6, respectively, the bioactivity entirely diminished. This
clearly illustrates that methoxy group at the ortho position, plays an important role in activity.
When another methoxy residue enters at its para position, as in compound 18 (IC50 = 12.28 ±
0.175 µM), it regains some leishmanicidal activity. Nonetheless, this time the bioactivity
decreases to three-fold, as compared to parent compound 8. The dimethoxy substituted
analog lost its activity completely when a chlorine group is present at C-5′, as in compound
13.
Substitution of methyl group at para position, as in compound 5 (IC50 = 24.03 ± 2.71 µM)
revealed good leishmanicidal activity. A slight decrease in activity was observed when two
methyl groups are present in an ortho fashion, as in compound 24 (IC50 = 35.88 ± 0.185 µM).
While the two methyl groups para to each other, as in compound 9, diminished all activity.
When the methyl group of compound 5 was replaced with an ethyl group, as in compound 20
(IC50 = 38.17 ± 0.73 µM), the activity decreased.
Presence of a bromine at the N-phenyl ring, whether at meta position or at para position, as in
compounds 15 or 3, resulted in having a good antileishmanial effect with IC50 values 9.04 ±
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0.03 and 61.48 ± 0.37 µM, respectively. The presence of fluorine (as in compound 11),
chlorine (as in compounds 2, 10, 12, 17 and 23) or iodine (as in compound 4) decreased the
activity. Surprisingly, only o-chlorinated analog 16 (IC50 = 6.53 ± 0.21 µM) displayed a
comparable activity to standard pentamidine.
Table-1: Antileishmanial activity of 4-arylamino-6-nitroquinazolines (2-25).
Compounds
Ar
IC50 ± SEMa [µM]
N. A.b
2
61.48 ± 0.37
N. A.b
3
4
24.03 ± 2.71
N. A.b
5
6
N. A.b
7
4.37 ± 0.02
N. A.b
8
9
N. A.b
10
11
12
N. A.b
N. A.b
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N. A.b
13
14
15
16
19.87 ± 0.22
9.04 ± 0.03
6.53 ± 0.21
Cl
N. A.b
17
18
19
20
21
22
23
24
12.28 ± 0.18
N. A.b
38.17 ± 0.73
1.87 ± 0.31
44.91 ± 0.47
N. A.b
35.88 ± 0.19
N. A.b
25
Pentamidine
5.09 ± 0.09
Standard
SEMa = Standard Error of the Mean, N. A.b = Not Active
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3. Conclusion
We have prepared twenty-four substituted 4-arylamino-6-nitroquinazolines and evaluated
their antileishmanial activities in comparison to the standard drug, pentamidine. Eleven
compounds (3, 5, 8, 14-16, 18, 20-22, and 24) exhibited a good to moderate leishmanicidal
effect with IC50 values 61.48 ± 0.37, 24.03 ± 2.71, 4.37 ± 0.02, 19.87 ± 0.215, 9.04 ± 0.03,
6.53 ± 0.21, 12.28 ± 0.175, 38.17 ± 0.73, 1.87 ± 0.31, 44.91 ± 0.47, and 35.88 ± 0.185 µM,
respectively. These compounds deserve further research as a novel class of antileishmanial
agents.
4. Experimental
4.1. Material and methods
Fetal Bovine Serum (Cat No. S181H-100 and Lot No. S11302S181H) was purchased from
Biowest (The Serum Specialist). RPMI.1640 Liquid 20 mM HEPES, with L-glutatamine
without NaHCO3 (Cat No. 7388) was purchased from Sigma-Aldrich, USA. Leishmania
major was acquired from DESTO. Neubauer counting chamber (2.5 x 10-3 mm2) was
purchased from Marienfeld, Germany. Standard drug, pentamidine was purchased from
Merck, USA. 5-Nitroanthranilonitrile, dimethylformamide dimethylacetal, substituted
anilines, and acetic acid were purchased from TCI, Japan. All reagents were of analytical
grade and used directly without purification.
1H NMR and 13C NMR experiments were run on Avance Bruker AM 300, 400, and 500 MHz
instruments. Electron Impact Mass Spectrometric (EI-MS) experiments were performed on
Finnigan MAT-311A (Germany) mass spectrometer. Melting points were determined on
Stuart® SMP10 melting point apparatus and are uncorrected. IR spectra (KBr discs) were run
on FTS 3000 MX, Bio-RAD Merlin (Excalibur Model) spectrophotometer. CHN Analyses
were carried out on a Carlo Erba Strumentazione-Mod-1106, Italy. Thin layer
chromatography (TLC) was performed on pre-coated silica gel aluminum plates (Kieselgel
60, 254, E. Merck, Germany). TLC Chromatograms were visualized under UV light at 254
and 365 nm or by applying iodine vapours.
4.2. Assay for Leishmaniasis [46]
Leishmania major were grown in bulk in modified N,N,N-biphasic medium by using normal
physiological saline. Leishmania promastigotes were cultured with RPMI 1640 medium,
supplemented with 10% heat inactivated fetal bovine serum (FBS). Parasites at log phase
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were centrifuged at 2000 rpm for 10 min, and washed three times with saline at same speed
and time. Parasites were diluted with fresh culture medium to a final density of 106 cells/mL.
In a 96-well micro-titer plate, 180
medium was added in other wells. 20
medium, serially diluted. 100 L of parasite culture was also added in all wells. Two rows
µL of medium was added in the first row and 100
µL of
µL of the experimental compounds were added in
µ
were left for negative and positive controls. Negative controls received only medium, while
the positive control contained varying concentrations of standard antileishmanial compound,
̊
pentamidine. The plates were incubated 21-22 C for 72 h. The culture was examined
microscopically on an improved Neubauer counting chamber and IC50 values of compounds
were calculated by Software Ezfit 5.03 Perella Scientific. All assays were performed in
triplicate.
4.3. Procedure for the synthesis of compounds 1-25
(E)-N'-(2-Cyano-4-nitrophenyl)-N,N-dimethylformimidamide (1) was synthesized as per
method reported earlier [45]. 4-Arylamino-6-nitroquinazolines (2-25) were synthesized by
treating substituted anilines (2 mmol) with (E)-N'-(2-cyano-4-nitrophenyl)-N,N-
dimethylformimidamide (1) (2 mmol) in acetic acid (15 mL) under refluxing condition.
Progress of the reaction mixture was monitored by thin layer chromatography. After
completion of the reaction, the reaction mixture was cooled to room temperature and distilled
water was added and shaken until the precipitates appeared. These precipitates were filtered
and washed with water. The yields of title compounds were found to be moderate to high.
4.3.1. (E)-N'-(2-Cyano-4-nitrophenyl)-N,N-dimethylformimidamide (1)
̊
̊
Yield: 94%; m.p. 152-153 C (lit. 153-155 C [41]); Rf: 0.24 (ethyl acetate/hexaness, 3:7); 1H-
NMR: (500 MHz, DMSO-d6): δH 8.47 (d, 1H, J3,5 = 2.5 Hz, H-3), 8.28 (dd, 1H, J5,6 = 9.0 Hz,
J5,3 = 3.0 Hz, H-5), 8.27 (s, 1H, N=CH), 7.38 (d, 1H, J6,5 = 9.5 Hz, H-6), 3.15 (s, 3H, NCH3),
3.07 (s, 3H, NCH3); 13C-NMR: (100 MHz, DMSO-d6): δc 160.4 (C-1), 156.6 (C=N), 140.0
(C-4), 129.4 (C-3), 128.5 (C-5), 118.3 (C-6), 116.7 (C≡N), 105.8 (C-2), 34.3 (H3C-N); IR
(KBr, cm-1): 2222 (C≡N), 1630 (C=N), 1502 (N=O); EI-MS: m/z (rel. abund. %), 218 [M]+
(100), 203 (14), 172 (8); HREI-MS: m/z calcd for C10H10N4O2 [M]+ 218.0804; Found
218.0802; Anal. Calcd for C10H10N4O2: C, 55.04; H, 4.62; N, 25.68; O, 14.66; Found: C,
55.02; H, 4.64; N, 25.69.
4.3.2. 4-(4′-Chlorophenyl)amino-6-nitroquinazoline (2)
10

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̊
Yield: 92%; m.p. 264-265 °C (lit. 264 C [41]); Rf: 0.46 (ethyl acetate/hexanes, 3:7); 1H-NMR:
(300 MHz, DMSO-d6): δH 10.50 (s, 1H, NH), 9.66 (d, 1H, J5,7 = 2.1 Hz, H-5), 8.73 (s, 1H, H-
2), 8.58 (dd, 1H, J7,8 = 9.0 Hz, J7,5 = 2.1 Hz, H-7), 7.96 (d, 1H, J8,7 = 9.0 Hz, H-8), 7.91 (d,
2H, J2′,3′ = J6′,5′ = 8.7 Hz, H-2′, H-6′), 7.49 (d, 2H, J3′,2′ = J5′,6′ = 8.7 Hz, H-3′, H-5′); 13C-NMR:
(100 MHz, DMSO-d6): δc 158.6 (C-4), 157.5 (C-2), 153.0 (C-8a), 144.5 (C-6), 137.4 (C-1′),
129.5 (C-8), 128.4 (C-4′), 128.1 (C-3′, C-5′), 126.6 (C-7), 124.3 (C-2′, C-6′), 120.8 (C-5),
114.3 (C-4a); IR (KBr, cm-1): 3416 (N–H), 1622 (C=N), 1539 (N=O), 1109 (C–Cl); EI-MS:
m/z (rel. abund. %), 302 [M++2] (26), 300 [M]+ (77), 299 (100), 253 (58); HREI-MS: m/z
calcd for C14H9ClN4O2 [M]+ 300.0414; Found 300.0410; Anal. Calcd for C14H9ClN4O2: C,
55.92; H, 3.02; Cl, 11.79; N, 18.63; O, 10.64; Found: C, 55.90; H, 3.04; N, 18.61.
4.3.3. 4-(4′-Bromophenyl)amino-6-nitroquinazoline (3)
̊
̊
1
Yield: 82%; m.p. 278-280 C (lit. 279-280 C [42]); Rf: 0.47 (ethyl acetate/hexanes, 3:7); H-
NMR: (300 MHz, DMSO-d6): δH 10.49 (s, 1H, NH), 9.66 (d, 1H, J5,7 = 2.1 Hz, H-5), 8.73 (s,
1H, H-2), 8.58 (dd, 1H, J7,8 = 9.0 Hz, J7,5 = 2.1 Hz, H-7), 7.96 (d, 1H, J8,7 = 8.1 Hz, H-8),
7.86 (d, 2H, J2′,3′ = J6′,5′ = 8.7 Hz, H-2′, H-6′), 7.62 (d, 2H, J3′,2′ = J5′,6′ = 8.7 Hz, H-3′, H-5′);
13C-NMR: (75 MHz, DMSO-d6): δc 158.6 (C-4), 157.4 (C-2), 152.9 (C-8a), 144.5 (C-6),
137.8 (C-1′), 131.3 (C-8), 129.5 (C-3′, C-5′), 126.6 (C-7), 124.6 (C-2′, C-6′), 120.8 (C-5),
116.2 (C-4′), 114.4 (C-4a); IR (KBr, cm-1): 3416 (N–H), 1616 (C=N), 1537 (N=O), 743 (C–
Br); EI-MS: m/z (rel. abund. %), 346 [M++2] (83), 345 (100), 344 [M]+ (84), 343 (80), 299
(39), 297 (39); HREI-MS: m/z calcd for C14H9BrN4O2 [M]+ 343.9909; Found 343.9892;
Anal. Calcd for C14H9BrN4O2: C, 48.72; H, 2.63; Br, 23.15; N, 16.23; O, 9.27; Found: C,
48.70; H, 2.61; N, 16.25.
4.3.4. 4-(4′-Iodophenyl)amino-6-nitroquinazoline (4)
̊
Yield: 83%; m.p. 270 C; Rf: 0.48 (ethyl acetate/hexanes, 3:7); 1H-NMR: (300 MHz, DMSO-
d6): δH 10.46 (s, 1H, NH), 9.66 (d, 1H, J5,7 = 2.1 Hz, H-5), 8.73 (s, 1H, H-2), 8.58 (dd, 1H,
J7,8 = 9.3 Hz, J7,5 = 2.1 Hz, H-7), 7.96 (d, 1H, J8,7 = 9.0 Hz, H-8), 7.78 (d, 2H, J2′,3′ = J6′,5′
=
8.7 Hz, H-2′, H-6′), 7.72 (d, 2H, J3′,2′ = J5′,6′ = 8.7 Hz, H-3′, H-5′); 13C-NMR: (100 MHz,
DMSO-d6): δc 158.6 (C-4), 157.5 (C-2), 153.0 (C-8a), 144.5 (C-6), 138.3 (C-1′), 137.1 (C-8),
129.5 (C-3′, C-5′), 126.6 (C-7), 124.8 (C-2′, C-6′), 120.8 (C-5), 114.4 (C-4a), 88.4 (C-4′); IR
(KBr, cm-1): 3280 (N–H), 1626 (C=N), 1528 (N=O), 544 (C–I); EI-MS: m/z (rel. abund. %),
392 [M]+ (100), 391 (89), 345 (34), 265 (2), 218 (28); HREI-MS: m/z calcd for C14H9IN4O2
11

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[M]+ 391.9770; Found 391.9785; Anal. Calcd for C14H9IN4O2: C, 42.88; H, 2.31; I, 32.36; N,
14.29; O, 8.16; Found: C, 42.86; H, 2.30; N, 14.31.
4.3.5. 4-(4′-Methylphenyl)amino-6-nitroquinazoline (5)
°
°
1
Yield: 90%; m.p. 208-210 C (lit. 210 C [43]); Rf: 0.38 (ethyl acetate/hexanes, 3:7); H-
NMR: (300 MHz, DMSO-d6): δH 10.40 (s, 1H, NH), 9.65 (d, 1H, J5,7 = 2.1 Hz, H-5), 8.67 (s,
1H, H-2), 8.56 (dd, 1H, J7,8 = 9.0 Hz, J7,5 = 2.1 Hz, H-7), 7.92 (d, 1H, J8,7 = 9.3 Hz, H-8),
7.70 (d, 2H, J2′,3′ = J6′,5′ = 8.1 Hz, H-2′, H-6′), 7.24 (d, 2H, J3′,2′ = J5′,6′ = 8.1 Hz, H-3′, H-5′),
2.31 (s, 3H, 4′-CH3); 13C-NMR: (75 MHz, DMSO-d6): δc 158.8 (C-4), 157.7 (C-2), 153.0 (C-
8a), 144.4 (C-6), 135.7 (C-1′), 133.7 (C-4′), 129.4 (C-8), 128.9 (C-3′, C-5′), 126.5 (C-7),
122.9 (C-2′, C-6′), 120.8 (C-5), 114.3 (C-4a), 20.5 (4′-CH3); IR (KBr, cm-1): 3620 (N–H),
1620 (C=N), 1529 (N=O); EI-MS: m/z (rel. abund. %), 280 [M]+ (96), 279 (100), 233 (72),
106 (7), 91 (6); HREI-MS: m/z calcd for C15H12N4O2 [M]+ 280.0960; Found 280.0950; Anal.
Calcd for C15H12N4O2: C, 64.28; H, 4.32; N, 19.99; O, 11.42; Found: C, 64.26; H, 4.35; N,
19.97.
4.3.6. 4-(4′-Methoxyphenyl)amino-6-nitroquinazoline (6)
̊
̊
Yield: Quantitative; m.p. 197-199 C (lit. 198-200 C [43]); Rf: 0.29 (ethyl acetate/hexanes,
3:7); 1H-NMR: (300 MHz, DMSO-d6): δH 10.38 (s, 1H, NH), 9.62 (d, 1H, J5,7 = 2.1 Hz, H-5),
8.63 (s, 1H, H-2), 8.54 (dd, 1H, J7,8 = 9.0 Hz, J7,5 = 2.1 Hz, H-7), 7.91 (d, 1H, J8,7 = 9.3 Hz,
H-8), 7.69 (d, 2H, J2′,3′ = J6′,5′ = 9.0 Hz, H-2′, H-6′), 7.00 (d, 2H, J3′,2′ = J5′,6′ = 9.0 Hz, H-3′, H-
5′), 3.77 (s, 3H, 4′-OCH3); 13C-NMR: (100 MHz, DMSO-d6): δc 158.8 (C-4), 157.8 (C-2),
156.3 (C-4′), 153.0 (C-8a), 144.3 (C-6), 131.0 (C-1′), 129.3 (C-8), 126.4 (C-7), 124.6 (C-2′,
C-6′), 120.7 (C-5), 114.2 (C-4a), 113.7 (C-3′, C-5′), 55.2 (4′-OCH3); IR (KBr, cm-1): 3622
(N–H), 1622 (C=N), 1526 (N=O), 1236 (C–O); EI-MS: m/z (rel. abund. %), 296 [M]+ (100),
295 (49), 281 (50), 249 (19); HREI-MS: m/z calcd for C15H12N4O3 [M]+ 296.0909; Found
296.0923; Anal. Calcd for C15H12N4O3: C, 60.81; H, 4.08; N, 18.91; O, 16.20; Found: C,
60.83; H, 4.06; N, 18.93.
4.3.7. 4-(3′-Methoxyphenyl)amino-6-nitroquinazoline (7)
̊
̊
Yield: 88%; m.p. 242 C (lit. 241-242 C [42]); Rf: 0.46 (ethyl acetate/hexanes, 3:7); 1H-NMR:
(300 MHz, DMSO-d6): δH 10.39 (s, 1H, NH), 9.67 (d, 1H, J5,7 = 2.1 Hz, H-5), 8.73 (s, 1H, H-
2), 8.57 (dd, 1H, J7,8 = 9.3 Hz, J7,5 = 2.1 Hz, H-7), 7.95 (d, 1H, J8,7 = 9.3 Hz, H-8), 7.50 (m,
2H, H-2′, H-6′), 7.35 (t, 1H, J5′(4′,6′) = 8.1 Hz, H-5′), 6.79 (dd, 1H, J4′,5′ = 8.1 Hz, J4′,6′ = 1.8 Hz,
12

ACCEPTED MANUSCRIPT
13
H-4′), 3.78 (s, 3H, 3′-OCH3); C-NMR: (75 MHz, DMSO-d6): δc 159.3 (C-4), 158.7 (C-3′),
157.6 (C-2), 153.0 (C-8a), 144.5 (C-6), 139.5 (C-1′), 129.4 (C-8), 129.2 (C-7), 126.5 (C-5′),
120.8 (C-5), 115.0 (C-4′), 114.4 (C-4a), 109.8 (C-6′), 108.6 (C-2′), 55.1 (3′-OCH3); IR (KBr,
cm-1): 3298 (N–H), 1624 (C=N), 1528 (N=O), 1227 (C–O); EI-MS: m/z (rel. abund. %), 296
[M]+ (95), 295 (100), 281 (4), 249 (63); HREI-MS: m/z calcd for C15H12N4O3 [M]+ 296.0909;
Found 296.0928; Anal. Calcd for C15H12N4O3: C, 60.75; H, 4.08; N, 18.91; O, 16.20; Found:
C, 60.78; H, 4.10; N, 18.92.
4.3.8. 4-(2′-Methoxyphenyl)amino-6-nitroquinazoline (8)
̊
Yield: 74%; m.p. 215 C; Rf: 0.36 (ethyl acetate/hexanes, 3:7); 1H-NMR: (300 MHz, DMSO-
d6): δH 10.24 (s, 1H, NH), 9.60 (d, 1H, J5,7 = 2.1 Hz, H-5), 8.55 (m, 2H, H-7, H-2), 7.91 (d,
1H, J8,7 = 9.3 Hz, H-8), 7.44 (d, 1H, J6′,5′ = 6.9 Hz, H-6′), 7.33 (t, 1H, J5′(4′,6′) = 7.2 Hz, H-5′),
7.16 (d, 1H, J3′,4′ = 7.8 Hz, H-3′), 7.03 (t, 1H, J4′(3′,5′) = 7.5 Hz, H-4′), 3.76 (s, 3H, 2′-OCH3);
13C-NMR: (100 MHz, DMSO-d6): δc 160.0 (C-4), 158.0 (C-2), 154.1 (C-2′), 153.0 (C-8a),
144.3 (C-6), 129.3 (C-8), 128.0 (C-7), 127.6 (C-4′), 126.5 (C-5), 126.2 (C-1′),120.9 (C-5′),
120.2 (C-3′), 114.0 (C-4a), 112.1 (C-6′), 55.5 (2′-OCH3); IR (KBr, cm-1): 3289 (N–H), 1616
(C=N), 1533 (N=O), 1242 (C–O); EI-MS: m/z (rel. abund. %), 296 [M]+ (7), 281 (2), 265
(100), 249 (5), 235 (34), 219 (46); HREI-MS: m/z calcd for C15H12N4O3 [M]+ 296.0909;
Found 296.0928; Anal. Calcd for C15H12N4O3: C, 60.81; H, 4.08; N, 18.91; O, 16.20; Found:
C, 60.83; H, 4.11; N, 18.94.
4.3.9. 4-(2′,5′-Dimethylphenyl)amino-6-nitroquinazoline (9)
̊
Yield: 43%; m.p. 145 C; Rf: 0.40 (ethyl acetate/hexanes, 3:7); 1H-NMR: (300 MHz, DMSO-
d6): δH 10.35 (s, 1H, NH), 9.58 (d, 1H, J5,7 = 2.4 Hz, H-5), 8.56 (m, 2H, H-7, H-2), 7.92 (d,
1H, J8,7 = 9.0 Hz, H-8), 7.22 (d, 1H, J3′,4′ = 7.8 Hz, H-3′), 7.11 (m, 2H, H-4′, H-6′), 2.29 (s,
13
3H, 5′-CH3), 2.12 (s, 3H, 2′-CH3); C-NMR: (100 MHz, DMSO-d6): δc 159.9 (C-4), 158.1
(C-2), 153.0 (C-8a), 144.3 (C-6), 136.2 (C-5′), 135.4 (C-2′), 131.7 (C-1′), 130.3 (C-3′), 129.3
(C-8), 127.9 (C-7), 127.5 (C-5),126.5 (C-4′), 120.9 (C-6′), 113.9 (C-4a), 20.4 (5′-CH3), 17.5
(2′-CH3); IR (KBr, cm-1): 3616 (N–H), 1622 (C=N), 1531 (N=O); EI-MS: m/z (rel. abund.
%), 294 [M]+ (100), 279 (98), 247 (40), 233 (60), 120 (20); HREI-MS: m/z calcd for
C16H14N4O2 [M]+ 294.1117; Found 294.1125; Anal. Calcd for C16H14N4O2: C, 65.30; H,
4.79; N, 19.04; O, 10.87; Found: C, 65.32; H, 4.81; N, 19.06.
4.3.10. 4-(2′,4′-Dichlorophenyl)amino-6-nitroquinazoline (10)
13

ACCEPTED MANUSCRIPT
̊
̊
1
Yield: 49%; m.p. 255-257 C (lit. 256-258 C [41]); Rf: 0.47 (ethyl acetate/hexanes, 3:7); H-
NMR: (300 MHz, DMSO-d6): δH 10.64 (s, 1H, NH), 9.56 (s, 1H, H-5), 8.57 (m, 2H, H-7, H-
13
8), 8.00 (m, 1H, H-5′), 7.82 (m, 1H, H-6′), 7.52 (m, 2H, H-2, H-3′); C-NMR: (100 MHz,
DMSO-d6): δc 158.6 (C-4), 157.7 (C-2), 152.9 (C-8a), 144.6 (C-6), 139.9 (C-1′), 134.4 (C-5′),
132.7 (C-3′), 130.1 (C-2′), 129.3 (C-8), 127.9 (C-4′), 126.8 (C-7), 125.7 (C-6′), 120.9 (C-5),
114.3 (C-4a); IR (KBr, cm-1): 3402 (N–H), 1618 (C=N), 1524 (N=O), 1105 (C–Cl); EI-MS:
m/z (rel. abund. %), 338 [M++4] (2), 336 [M++2] (7), 334 [M]+ (9), 299 (100), 265 (52), 253
(72); HREI-MS: m/z calcd for C14H8Cl2N4O2 [M]+ 334.0024; Found 334.0026; Anal. Calcd
for C14H8Cl2N4O2: C, 50.17; H, 2.41; Cl, 21.16; N, 16.72; O, 9.55; Found: C, 50.15; H, 2.42;
N, 16.74.
4.3.11. 4-(4′-Fluorophenyl)amino-6-nitroquinazoline (11)
̊
̊
1
Yield: 96%; m.p. 257-258 C (lit. 257-258 C [42]); Rf: 0.46 (ethyl acetate/hexanes, 3:7); H-
NMR: (300 MHz, DMSO-d6): δH 10.48 (s, 1H, NH), 9.64 (d, 1H, J5,7 = 2.4 Hz, H-5), 8.69 (s,
1H, H-2), 8.57 (dd, 1H, J7,8 = 9.3 Hz, J7,5 = 2.4 Hz, H-7), 7.95 (d, 1H, J8,7 = 9.3 Hz, H-8),
7.85 (d, 2H, J2′,3′ = J6′,5′ = 8.7 Hz, H-2′, H-6′), 7.29 (t, 2H, J3′(2′,F) = J5′(6′,F) = 8.7 Hz, H-3′, H-5′);
13C-NMR: (125 MHz, DMSO-d6): δc 159.8 (C-4), 158.8 (C-4′), 157.6 (C-2), 153.0 (C-8a),
144.4 (C-6), 134.6 (C-1′), 129.4 (C-8), 126.6 (C-7), 125.0 (C-2′, C-6′), 120.7 (C-5), 115.2 (C-
3′, C-5′), 114.2 (4a); IR (KBr, cm-1): 3624 (N–H), 1624 (C=N), 1537 (N=O), 1223 (C–F); EI-
MS: m/z (rel. abund. %), 284 [M]+ (98), 283 (100), 265 (2), 253 (11), 237 (87); HREI-MS:
m/z calcd for C14H9FN4O2 [M]+ 284.0710; Found 284.0697; Anal. Calcd for C14H9FN4O2: C,
59.16; H, 3.19; F, 6.68; N, 19.71; O, 11.26; Found: C, 59.17; H, 3.16; N, 19.70.
4.3.12. 4-(3′-Chlorophenyl)amino-6-nitroquinazoline (12)
̊
̊
1
Yield: 93%; m.p. 284-286 C (lit. 285-286 C [42]); Rf: 0.32 (ethyl acetate/hexanes, 3:7); H-
NMR: (300 MHz, DMSO-d6): δH 10.49 (s, 1H, NH), 9.66 (d, 1H, J5,7 = 1.8 Hz, H-5), 8.78 (s,
1H, H-2), 8.58 (dd, 1H, J7,8 = 9.3 Hz, J7,5 = 1.8 Hz, H-7), 8.07 (s, 1H, H-2′), 7.97 (d, 1H, J8,7
= 9.3 Hz, H-8), 7.85 (d, 1H, J6′,5′ = 7.8 Hz, H-6′), 7.47 (t, 1H, J5′(4′,6′) = 8.1 Hz, H-5′), 7.24 (d,
1H, J4′,5′ = 7.8 Hz, H-4′); 13C-NMR: (100 MHz, DMSO-d6): δc 158.6 (C-4), 157.4 (C-2),
152.9 (C-8a), 144.6 (C-6), 139.9 (C-1′), 132.7 (C-3′), 130.1 (C-5′), 129.5 (C-8), 126.6 (C-7),
123.9 (C-4′), 121.9 (C-2′), 120.8 (C-5), 120.7 (C-6′), 114.3 (C-4a); IR (KBr, cm-1): 3287 (N–
H), 1620 (C=N), 1528 (N=O), 1109 (C–Cl); EI-MS: m/z (rel. abund. %), 302 [M++2] (18),
300 [M]+ (57), 299 (100), 253 (85); HREI-MS: m/z calcd for C14H9ClN4O2 [M]+ 300.0414;
14

ACCEPTED MANUSCRIPT
Found 300.0424; Anal. Calcd for C14H9ClN4O2: C, 55.92; H, 3.02; Cl, 11.79; N, 18.63; O,
10.64; Found: C, 55.90; H, 3.04; N, 18.65.
4.3.13. 4-(5′-Chloro-2′,4′-dimethoxyphenyl)amino-6-nitroquinazoline (13)
̊
1
Yield: Quantitative; m.p. 232-235 C; Rf: 0.10 (ethyl acetate/hexanes, 3:7); H-NMR: (300
MHz, DMSO-d6): δH 10.18 (s, 1H, NH), 9.57 (d, 1H, J5,7 = 2.1 Hz, H-5), 8.54 (m, 2H, H-7,
H-2), 7.91 (d, 1H, J8,7 = 9.3 Hz, H-8), 7.46 (s, 1H, H-6′), 6.91 (s, 1H, H-3′), 3.94 (s, 3H, 4′-
OCH3), 3.82 (s, 3H, 2′-OCH3); 13C-NMR: (100 MHz, DMSO-d6): δc 160.2 (C-4), 158.0 (C-2),
154.2 (C-4′), 153.9 (C-2′), 152.9 (C-8a), 144.3 (C-6), 129.3 (C-8), 128.7 (C-6′), 126.5 (C-7),
120.8 (C-5), 119.1 (C-1′), 113.9 (C-4a), 111.1 (C-5′), 98.2 (C-3′), 56.4 (2′-OCH3), 56.1 (4′-
OCH3); IR (KBr, cm-1): 3414 (N–H), 1593 (C=N), 1533 (N=O), 1256 (C–O), 1109 (C–Cl);
EI-MS: m/z (rel. abund. %), 362 [M++2] (11), 360 [M]+ (29), 345 (8), 329 (100); HREI-MS:
m/z calcd for C16H13ClN4O4 [M]+ 360.0625; Found 360.0644; Anal. Calcd for C16H13ClN4O4:
C, 53.27; H, 3.63; Cl, 9.83; N, 15.53; O, 17.74; Found: C, 53.28; H, 3.61; N, 15.55.
4.3.14. 4-[3′-(Methylsulfanyl)phenyl]amino-6-nitroquinazoline (14)
̊
1
Yield: 60%; m.p. 196-197 C; Rf: 0.32 (ethyl acetate/hexanes, 3:7); H-NMR: (300 MHz,
DMSO-d6): δH 10.41 (s, 1H, NH), 9.66 (d, 1H, J5,7 = 1.8 Hz, H-5), 8.74 (s, 1H, H-2), 8.58
(dd, 1H, J7,8 = 9.0 Hz, J7,5 = 1.8 Hz, H-7), 7.96 (d, 1H, J8,7 = 9.0 Hz, H-8), 7.77 (s, 1H, H-2′),
7.69 (d, 1H, J6′,5′ = 7.8 Hz, H-6′), 7.39 (t, 1H, J5′(4′,6′) = 8.1 Hz, H-5′), 7.09 (d, 1H, J4′,5′ = 7.8
Hz, H-4′), 3.29 (s, 3H, 3′-SCH3); 13C-NMR: (100 MHz, DMSO-d6): δc 158.7 (C-4), 157.6 (C-
2), 153.0 (C-8a), 144.5 (C-6), 139.0 (C-1′), 138.4 (C-3′), 129.5 (C-8), 129.0 (C-5′), 126.6 (C-
7), 121.8 (C-4′), 120.8 (C-5), 119.9 (C-6′), 119.3 (C-2′), 114.4 (C-4a), 14.8 (3′-SCH3); IR
(KBr, cm-1): 3609 (N–H), 1576 (C=N), 1533 (N=O), 1117 (C–S); EI-MS: m/z (rel. abund.
%), 312 [M]+ (100), 311 (98), 297 (3), 265 (43); HREI-MS: m/z calcd for C15H12N4O2S [M]+
312.0681; Found 312.0675; Anal. Calcd for C15H12N4O2S: C, 57.68; H, 3.87; N, 17.94; O,
10.24; S, 10.27; Found: C, 57.69; H, 3.89; N, 17.93.
4.3.15. 4-(3′-Bromophenyl)amino-6-nitroquinazoline (15)
̊
̊
1
Yield: 82%; m.p. 269-271 C (lit. 267-270 C [41]); Rf: 0.64 (ethyl acetate/hexanes, 3:7); H-
NMR: (300 MHz, DMSO-d6): δH 10.49 (s, 1H, NH), 9.67 (d, 1H, J5,7 = 1.8 Hz, H-5), 8.78 (s,
1H, H-2), 8.59 (dd, 1H, J7,8 = 9.0 Hz, J7,5 = 1.8 Hz, H-7), 8.19 (s, 1H, H-2′), 7.98 (d, 1H, J8,7
13
= 9.3 Hz, H-8), 7.92 (d, 1H, J6′,5′ = 6.9 Hz, H-6′), 7.39 (m, 2H, H-4′, H-5′); C-NMR: (100
MHz, DMSO-d6): δc 158.5 (C-4), 157.4 (C-2), 152.9 (C-8a), 144.5 (C-6), 140.1 (C-1′), 130.4
15

ACCEPTED MANUSCRIPT
(C-5′), 129.5 (C-8), 126.8 (C-4′), 126.6 (C-7), 124.7 (C-6′), 121.2 (C-2′), 121.1 (C-3′), 120.7
(C-5), 114.3 (C-4a); IR (KBr, cm-1): 3300 (N–H), 1618 (C=N), 1524 (N=O), 745 (C–Br); EI-
MS: m/z (rel. abund. %), 346 [M++2] (57), 345 (100), 344 [M]+ (63), 343 (97), 299 (46), 297
(46); HREI-MS: m/z calcd for C14H9BrN4O2 [M]+ 343.9909; Found 343.9799; Anal. Calcd
for C14H9BrN4O2: C, 48.72; H, 2.63; Br, 23.15; N, 16.23; O, 9.27; Found: C, 48.74; H, 2.62;
N, 16.25.
4.3.16. 4-(2′-Chlorophenyl)amino-6-nitroquinazoline (16)
̊
̊
1
Yield: 44%; m.p. 181-182 C (lit. 180-182 C [41]); Rf: 0.34 (ethyl acetate/hexanes, 3:7); H-
NMR: (300 MHz, DMSO-d6): δH 10.63 (s, 1H, NH), 9.60 (s, 1H, H-5), 8.58 (m, 2H, H-7, H-
13
2), 7.96 (d, 1H, J8,7 = 8.7 Hz, H-8), 7.62 (m, 2H, H-6′, H-3′), 7.46 (m, 2H, H-4′, H-5′); C-
NMR: (100 MHz, DMSO-d6): δc 158.6 (C-4), 157.5 (C-2), 153.0 (C-8a), 144.5 (C-6), 137.4
(C-1′), 134.4 (C-3′), 131.2 (C-5′), 129.8 (C-8), 128.4 (C-7), 127.8 (C-4′), 126.7 (C-2′), 124.3
(C-5), 120.9 (C-6′), 114.3 (C-4a); IR (KBr, cm-1): 3362 (N–H), 1620 (C=N), 1512 (N=O),
1115 (C–Cl); EI-MS: m/z (rel. abund. %), 302 [M++2] (4), 300 [M]+ (9), 265 (100), 219 (73);
HREI-MS: m/z calcd for C14H9ClN4O2 [M]+ 300.0414; Found 300.0397; Anal. Calcd for
C14H9ClN4O2: C, 55.92; H, 3.02; Cl, 11.79; N, 18.63; O, 10.64; Found: C, 55.94; H, 3.04; N,
18.66.
4.3.17. 4-(3′,4′-Dichlorophenyl)amino-6-nitroquinazoline (17)
̊
̊
1
Yield: 66%; m.p. 297-298 C (lit. 297-298 C [42]); Rf: 0.16 (ethyl acetate/hexanes, 3:7); H-
NMR: (300 MHz, DMSO-d6): δH 10.53 (s, 1H, NH), 9.65 (d, 1H, J5,7 = 2.4 Hz, H-5), 8.08 (s,
1H, H-2), 8.59 (dd, 1H, J7,8 = 9.3 Hz, J7,5 = 2.4 Hz, H-7), 8.29 (d, 1H, J2′,6′ = 1.8 Hz, H-2′),
7.98 (d, 1H, J8′,7′ = 9.3 Hz, H-8′), 7.93 (dd, 1H, J6′,5′ = 8.7 Hz, J6′,2′ = 1.8 Hz, H-6′), 7.69 (d,
1H, J5′,6′ = 8.7 Hz, H-5′); 13C-NMR: (100 MHz, DMSO-d6): δc 158.5 (C-4), 157.3 (C-2),
152.9 (C-8a), 144.6 (C-6), 138.7 (C-1′), 130.7 (C-3′), 130.3 (C-5′), 129.6 (C-8), 126.7 (C-7),
125.7 (C-4′), 123.5 (C-2′), 122.2 (C-6′), 120.7 (C-5), 114.4 (C-4a); IR (KBr, cm-1): 3400 (N–
H), 1610 (C=N), 1526 (N=O), 1113 (C–Cl); EI-MS: m/z (rel. abund. %), 338 [M++4] (10),
336 [M++2] (55), 334 [M]+ (90), 333 (100), 289 (34), 287 (52), 253 (16); HREI-MS: m/z
calcd for C14H8Cl2N4O2 [M]+ 334.0024; Found 334.0013; Anal. Calcd for C14H8Cl2N4O2: C,
50.17; H, 2.41; Cl, 21.16; N, 16.72; O, 9.55; Found: C, 50.19; H, 2.39; N, 16.74.
4.3.18. 4-(2′,5′-Dimethoxyphenyl)amino-6-nitroquinazoline (18)
16

ACCEPTED MANUSCRIPT
̊
1
Yield: 54%; m.p. 170-172 C; Rf: 0.11 (ethyl acetate/hexanes, 3:7); H-NMR: (300 MHz,
DMSO-d6): δH 10.22 (s, 1H, NH), 9.58 (d, 1H, J5,7 = 1.8 Hz, H-5), 8.56 (m, 2H, H-7, H-2),
7.91 (d, 1H, J8,7 = 9.3 Hz, H-8), 7.09 (d, 1H, J6′,4′ = 1.8 Hz, H-6′), 7.05 (s, 1H, H-3′), 6.89
(dd, 1H, J4′,3′ = 8.7 Hz, J4′,6′ = 2.7 Hz, H-4′), 3.72 (s, 3H, 5′-OCH3), 3.71 (s, 3H, 2′-OCH3);
13C-NMR: (100 MHz, DMSO-d6): δc 159.9 (C-4), 157.9 (C-2), 152.9 (C-8a), 152.1 (C-5′),
148.1 (C-2′), 144.3 (C-6), 138.7 (C-1′), 129.2 (C-8), 126.9 (C-4a), 126.4 (C-7), 120.9 (C-5),
114.0 (C-3′), 112.8 (C-4′), 111.8 (C-6′), 56.0 (5′-OCH3), 55.4 (2′-OCH3); IR (KBr, cm-1): 3420
(N–H), 1618 (C=N), 1539 (N=O), 1263 (C–O); EI-MS: m/z (rel. abund. %), 326 [M]+ (16),
311 (3), 295 (100), 249 (36); HREI-MS: m/z calcd for C16H14N4O4 [M]+ 326.1015; Found
326.1044; Anal. Calcd for C16H14N4O4: C, 58.89; H, 4.32; N, 17.17; O, 19.61; Found: C,
58.87; H, 4.30; N, 17.18.
4.3.19. 4-Phenylamino-6-nitroquinazoline (19)
̊
̊
1
Yield: 82%; m.p. 241-242 C (lit. 242-243 C [44]); Rf: 0.34 (ethyl acetate/hexanes, 3:7); H-
NMR: (300 MHz, DMSO-d6): δH 10.45 (s, 1H, NH), 9.67 (d, 1H, J5,7 = 2.1 Hz, H-5), 8.70 (s,
1H, H-2), 8.57 (dd, 1H, J7,8 = 9.0 Hz, J7,5 = 2.1 Hz, H-7), 7.94 (d, 1H, J8,7 = 9.0 Hz, H-8),
7.84 (d, 2H, J2′,3′ = J6′,5′ = 7.8 Hz, H-2′, H-6′), 7.45 (d, 2H, J3′,2′ = J5′,6′ = 7.8 Hz, H-3′, H-5′),
7.21 (t, 1H, J4′(3′,2′) = J4′(5′,6′) = 7.5 Hz, H-4′); 13C-NMR: (100 MHz, DMSO-d6): δc 158.7 (C-4),
157.6 (C-2), 153.0 (C-8a), 144.4 (C-6), 138.3 (C-1′), 129.4 (C-8), 128.4 (C-3′, C-5′), 126.5
(C-7), 124.5 (C-4′), 122.9 (C-2′, C-6′), 120.8 (C-5), 114.3 (C-4a); IR (KBr, cm-1): 3279 (N–
H), 1624 (C=N), 1531 (N=O); EI-MS: m/z (rel. abund. %), 266 [M]+ (90), 265 (100), 219
(100), 77 (12); HREI-MS: m/z calcd for C14H10N4O2 [M]+ 266.0804; Found 266.0792; Anal.
Calcd for C14H10N4O2: C, 63.15; H, 3.79; N, 21.04; O, 12.02; Found: C, 63.13; H, 3.81; N,
21.05.
4.3.20. 4-(4′-Ethylphenyl)amino-6-nitroquinazoline (20)
̊
Yield: 75%; m.p. 195 C; Rf: 0.42 (ethyl acetate/hexanes, 3:7); 1H-NMR: (300 MHz, DMSO-
d6): δH 10.41 (s, 1H, NH), 9.65 (d, 1H, J5,7 = 2.1 Hz, H-5), 8.66 (s, 1H, H-2), 8.56 (dd, 1H,
J7,8 = 9.0 Hz, J7,5 = 2.1 Hz, H-7), 7.93 (d, 1H, J8,7 = 9.3 Hz, H-8), 7.72 (d, 2H, J2′,3′ = J6′,5′
=
8.4 Hz, H-2′, H-6′), 7.27 (d, 2H, J3′,2′ = J5′,6′ = 8.4 Hz, H-3′, H-5′), 2.63 (q, 2H, J = 15.3 Hz, 7.5
13
Hz, CH2), 1.22 (t, 3H, J = 7.5 Hz, CH3); C-NMR: (150 MHz, DMSO-d6): δc 158.8 (C-4),
157.8 (C-2), 153.1 (C-8a), 144.4 (C-6), 140.1 (C-4′), 135.9 (C-1′), 129.4 (C-8), 127.8 (C-3′,
C-5′), 126.5 (C-7), 123.1 (C-2′, C-6′), 120.8 (C-5), 114.3 (C-4a), 27.7 (4′-CH2CH3), 15.7 (4′-
CH2CH3); IR (KBr, cm-1): 3400 (N–H), 1620 (C=N), 1537 (N=O); EI-MS: m/z (rel. abund.
17

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%), 294 [M]+ (100), 293 (96), 279 (56), 263 (11), 247 (27), 233 (29); HREI-MS: m/z calcd
for C16H14N4O2 [M]+ 294.1117; Found 294.1095; Anal. Calcd for C16H14N4O2: C, 65.30; H,
4.79; N, 19.04; O, 10.87; Found: C, 65.28; H, 4.78; N, 19.06.
4.3.21. 4-[4′-(Methylsulfanyl)phenyl]amino-6-nitroquinazoline (21)
̊
1
Yield: 86%; m.p. 203-205 C; Rf: 0.31 (ethyl acetate/hexanes, 3:7); H-NMR: (300 MHz,
DMSO-d6): δH 10.44 (s, 1H, NH), 9.65 (d, 1H, J5,7 = 2.1 Hz, H-5), 8.69 (s, 1H, H-2), 8.56
(dd, 1H, J7,8 = 9.3 Hz, J7,5 = 2.1 Hz, H-7), 7.93 (d, 1H, J8,7 = 9.3 Hz, H-8), 7.81 (d, 2H, J2′,3′
=
J6′,5′ = 8.7 Hz, H-2′, H-6′), 7.34 (d, 2H, J3′,2′ = J5′,6′ = 8.7 Hz, H-3′, H-5′), 3.30 (s, 3H, 4′-SCH3);
13C-NMR: (100 MHz, DMSO-d6): δc 158.6 (C-4), 157.6 (C-2), 153.0 (C-8a), 144.4 (C-6),
135.6 (C-1′), 133.5 (C-4′), 129.3 (C-8), 126.5 (C-7), 126.4 (C-3′, C-5′), 123.4 (C-2′, C-6′),
120.7 (C-5), 114.3 (C-4a), 15.2 (4′-SCH3); IR (KBr, cm-1): 3628 (N–H), 1589 (C=N), 1526
(N=O), 1121 (C–S); EI-MS: m/z (rel. abund. %), 312 [M]+ (100), 311 (40), 297 (10), 265
(16); HREI-MS: m/z calcd for C15H12N4O2S [M]+ 312.0681; Found 312.0687; Anal. Calcd
for C15H12N4O2S: C, 57.68; H, 3.87; N, 17.94; O, 10.24; S, 10.27; Found: C, 57.70; H, 3.89;
N, 17.92.
4.3.22. 4-(5′-Chloro-2′-methylphenyl)amino-6-nitroquinazoline (22)
̊
1
Yield: 42%; m.p. 184-185 C; Rf: 0.38 (ethyl acetate/hexanes, 3:7); H-NMR: (300 MHz,
DMSO-d6): δH 10.42 (s, 1H, NH), 9.55 (s, 1H, H-5), 8.56 (m, 2H, H-7, H-2), 7.93 (d, 1H, J8,7
= 9.0 Hz, H-8), 7.43 (s, 1H, H-6′), 7.37 (d, 1H, J3′,4′ = 8.1 Hz, H-3′), 7.31 (d, 1H, J4′,3′ = 7.8
Hz, H-4′), 2.17 (s, 3H, 2′-CH3); 13C-NMR: (75 MHz, DMSO-d6): δc 158.9 (C-4), 157.8 (C-2),
153.0 (C-8a), 144.4 (C-6), 136.2 (C-1′), 132.0 (C-5′), 130.0 (C-3′), 129.3 (C-8), 127.1 (C-2′),
126.6 (C-7), 126.5 (C-4′), 122.8 (C-6′), 120.9 (C-5), 114.3 (C-4a), 17.4 (2′-CH3); IR (KBr,
cm-1): 3481 (N–H), 1620 (C=N), 1528 (N=O), 1111 (C–Cl); EI-MS: m/z (rel. abund. %), 316
[M++2] (36), 314 [M]+ (100), 299 (94), 267 (42), 253 (52); HREI-MS: m/z calcd for
C15H11ClN4O2 [M]+ 314.0571; Found 314.0549; Anal. Calcd for C15H11ClN4O2: C, 57.24; H,
3.52; Cl, 11.26; N, 17.80; O, 10.17; Found: C, 57.22; H, 3.54; N, 17.82.
4.3.23. 4-(2′,5′-Dichlorophenyl)amino-6-nitroquinazoline (23)
̊
1
Yield: 45%; m.p. 222-224 C; Rf: 0.50 (ethyl acetate/hexanes, 3:7); H-NMR: (300 MHz,
DMSO-d6): δH 10.67 (s, 1H, NH), 9.57 (s, 1H, H-5), 8.63 (m, 2H, H-7,8), 7.98 (s, 1H, H-2),
7.74 (m, 2H, H-3′, H-4′), 7.44 (s, 1H, H-6′); 13C-NMR: (150 MHz, DMSO-d6): δc 158.6 (C-4),
157.7 (C-2), 152.8 (C-8a), 144.6 (C-6), 136.7 (C-1′), 135.4 (C-5′), 132.3 (C-3′), 130.4 (C-2′),
18

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129.2 (C-8), 128.2 (C-4′), 126.9 (C-7), 122.8 (C-6′), 120.9 (C-5), 114.1 (C-4a); IR (KBr, cm-
1): 3410 (N–H), 1616 (C=N), 1533 (N=O), 1120 (C–Cl); EI-MS: m/z (rel. abund. %), 336
[M++2] (5), 334 [M]+ (7), 299 (100), 287 (5), 253 (62); HREI-MS: m/z calcd for
C14H8Cl2N4O2 [M]+ 334.0024; Found 334.0034; Anal. Calcd for C14H8Cl2N4O2: C, 50.17; H,
2.41; Cl, 21.16; N, 16.72; O, 9.55; Found: C, 50.19; H, 2.40; N, 16.71.
4.3.24. 4-(3′,4′-Dimethylphenyl)amino-6-nitroquinazoline (24)
̊
1
Yield: 88%; m.p. 232-233 C; Rf: 0.46 (ethyl acetate/hexanes, 3:7); H-NMR: (300 MHz,
DMSO-d6): δH 10.34 (s, 1H, NH), 9.65 (d, 1H, J5,7 = 2.1 Hz, H-5), 8.66 (s, 1H, H-2), 8.54
(dd, 1H, J7,8 = 9.3 Hz, J7,5 = 2.1 Hz, H-7), 7.91 (d, 1H, J8,7 = 9.3 Hz, H-8), 7.56 (m, 2H, H-6′,
H-2′), 7.18 (d, 1H, J5′,6′ = 8.7 Hz, H-5′), 2.25 (s, 3H, 3′-CH3), 2.22 (s, 3H, 4′-CH3); 13C-NMR:
(100 MHz, DMSO-d6): δc 158.8 (C-4), 157.8 (C-2), 153.1 (C-8a), 144.4 (C-6), 136.2 (C-1′),
135.9 (C-3′), 132.6 (C-4′), 129.4 (C-8), 129.0 (C-5′), 126.4 (C-7), 124.1 (C-6′), 120.8 (C-5),
120.5 (C-2′), 114.3 (C-4a), 19.5 (C-3′), 18.8 (C-4′); IR (KBr, cm-1): 3277 (N–H), 1626 (C=N),
1528 (N=O); EI-MS: m/z (rel. abund. %), 294 [M]+ (85), 293 (100), 279 (2), 263 (18), 247
(50), 120 (5); HREI-MS: m/z calcd for C16H14N4O2 [M]+ 294.1117; Found 294.1137; Anal.
Calcd for C16H14N4O2: C, 65.30; H, 4.79; N, 19.04; O, 10.87; Found: C, 65.33; H, 4.81; N,
19.02.
4.3.25. 4-(3′-Hydroxyphenyl)amino-6-nitroquinazoline (25)
̊
̊
1
Yield: 91%; m.p. 307-308 C (lit. 306-308 C [41]); Rf: 0.16 (ethyl acetate/hexanes, 3:7); H-
NMR: (300 MHz, DMSO-d6): δH 10.32 (s, 1H, NH), 9.67 (d, 1H, J5,7 = 2.1 Hz, H-5), 9.51 (s,
1H, 3′-OH), 8.70 (s, 1H, H-2), 8.56 (dd, 1H, J7,8 = 9.0 Hz, J7,5 = 2.1 Hz, H-7), 7.93 (d, 1H, J8,7
= 9.0 Hz, H-8), 7.36 (s, 1H, H-2′), 7.26 (d, 1H, J6′,5′ = 8.1 Hz, H-6′), 7.21 (t, 1H, J5′(4′,6′) = 7.8
Hz, H-5′), 6.60 (d, 1H, J4′,5′ = 7.5 Hz, H-4′); 13C-NMR: (100 MHz, DMSO-d6): δc 158.8 (C-4),
157.7 (C-2), 157.4 (C-3′), 153.1 (C-8a), 144.5 (C-6), 139.3 (C-1′), 129.4 (C-8), 129.1 (C-5′),
126.5 (C-7), 120.9 (C-5), 114.4 (C-4a), 113.5 (C-6′), 111.7 (C-4′), 110.0 (C-2′); IR (KBr, cm-
1): 3483 (O–H), 3383 (N–H), 1618 (C=N), 1539 (N=O), 1254 (C–O); EI-MS: m/z (rel. abund.
%), 282 [M]+ (57), 281 (100), 265 (2), 250 (16), 235 (64); HREI-MS: m/z calcd for
C14H10N4O3 [M]+ 282.0753; Found 282.0757; Anal. Calcd for C14H10N4O3: C, 59.57; H,
3.57; N, 19.85; O, 17.01; Found: C, 59.59; H, 3.59; N, 19.84.
Acknowledgements: The authors are thankful to the Higher Education Commission (HEC)
Pakistan, for their financial support for research project No. 20-2073.
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[46] Atta-ur-Rahman, M. I. Choudhary, and W. J. Thomsen, Bioassay Techniques for
Drug Development, Amsterdam: Harwood Academic Publishers, 2001, 54–58.
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Highlights:
Synthesis of twenty-four different derivatives of 4-Arylamino-6-nitroquinazolines
In vitro antileishmanial potential assesment
Discovery of a novel class of antileshmanial compounds