Comparative biological study between quinazolinyl–triazinyl semicarbazide and thiosemicarbazide hybrid derivatives

Article abstract of DOI:10.1007/s11030-020-10117-y

Abstract: Practical synthesis and biological activities of quinazolinyl–triazinyl semicarbazides (10a–j) and quinazolinyl–triazinyl thiosemicarbazides (11a–j) have been described. The novel semicarbazides and thiosemicarbazides were prepared by condensati

Full text of DOI:10.1007/s11030-020-10117-y

Molecular Diversity
https://doi.org/10.1007/s11030-020-10117-y
ORIGINAL ARTICLE
Comparative biological study between quinazolinyl–triazinyl
semicarbazide and thiosemicarbazide hybrid derivatives
Janki J. Patel1 · Rahul P. Modh2 · Manjoorahmed Asamdi2 · Kishor H. Chikhalia1
Received: 18 April 2020 / Accepted: 17 June 2020
© Springer Nature Switzerland AG 2020
Abstract
Practical synthesis and biological activities of quinazolinyl–triazinyl semicarbazides (10a–j) and quinazolinyl–triazinyl
thiosemicarbazides (11a–j) have been described. The novel semicarbazides and thiosemicarbazides were prepared by con-
densation of diferent nucleophiles like isocyanate and isothiocyanate by the displacement of chlorine atoms on the basis of
functionality concept on varying conditions. The synthesized quinazolinyl–triazinyl semicarbazide and thiosemicarbazide
derivatives were evaluated for their expected antimicrobial activity. All the fnal synthesized derivatives were characterized
by their melting point, mass spectra, 1H NMR and 13C NMR as well as elemental microanalysis. The fnal analogues were
then analyzed for their in vitro antimicrobial activity against bacteria (Gram positive and negative) and fungus using the agar
streak dilution method as well as in vitro anti-HIV activity against two types of viral strains, viz. HIV type I (IIIB) and type
II (ROD) by using MTT assay method. SAR and HOMO–LUMO studies were also carried out for proving the structural
biological activity. Among them, compounds 10e, 10f, 11h and 11j gave best results as their energy gap is very low which
makes their activity higher.
Graphical abstract
Keywords Semicarbazides · Thiosemicarbazides · s-triazine · Antimicrobial activity · Anti-HIV activity · HOMO–LUMO
study
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11030-020-10117-y) contains
supplementary material, which is available to authorized users.
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Vol.:(0123456789)
1 3

Molecular Diversity
toward both viral strains HIV-I and HIV-II. In addition,
Mahajan et al. [18] further developed 2-(coumarin-4-yloxy)-
4,6-(substituted)-s-triazine derivatives (V) as a potential
leading to a novel class of NNRTIs (Fig. 1).
Introduction
In the present world, the development of the capable and
environmental-friendly methods of organic synthesis is one
of the main priorities of organic chemists to develop novel
heterocyclic compounds in combatting dreadful diseases
[1]. Nowadays, both bacterial and fungal infections are seri-
ous problem for human as well as for animal body. Thus,
researchers have gained advantage from therapeutic sub-
stances of synthetic drugs. In contrast, all causative micro-
organisms have acquired an ability to sustain by developing
a great resistance to every synthetic agent administered [2].
In recent times, a number of diseases are being increased
by dangerous microorganisms. Therefore, serious research
has been made to discover an efcient antimicrobial agent
to withstand against these pathogenic microorganisms [3].
Invasive fungal infection has become a growing issue due to
the great morbidity and mortality rates in patients who expe-
rienced anti-neoplastic chemotherapy, stem cell transplanta-
tion and organ transplant or endured human immunodef-
ciency virus (HIV) infection [4]. Trisubstituted s-triazines
are one of the oldest classes of organic compounds that con-
tinue to be used as important core structure in many chemo-
therapeutic agents due to their interesting pharmacological
properties, including anticancer [5], anti-angiogenesis [6],
anti-HIV [7, 8], antimalarial [9] and antimicrobial activities
[10, 11]. These compounds have also been used as subunits
in the formation of supramolecular structures because they
possess good optical and electronic properties and are able
to form multiple hydrogen bonds [12]. s-Triazine derivatives
have also been found to be P13K and mTOR inhibitors as
well as efcient corrosion inhibitors for mild steel in acidic
solutions [13],
In the consideration of the rising number of application
in most recent years, there has been an enormous rise in the
attraction among biologists and chemists in their synthesis
and bioactivity of quinazoline derivatives. It was recognized
that this class of compounds has activity like antibacterial
[19], analgesic [20], anticancer [21], antifungal [22], anti-
HIV [23], anti-infammatory [24], antimalarial [25], anti-
oxidant [26], antiviral [27], phosphodiesterase inhibitory
agents, sedative–hypnotic agent, and so on. Quinazoline
scafold is a structural backbone for many naturally occur-
ring alkaloids extracted from various plants, animals as well
as microorganisms [28]. Chauhan et al. [29] have designed
and synthesized a series of new class of hybrid 4-aminoquin-
oline triazines (VI), (VII) and screened for their antimalarial
activity against CQ (Chloroquine)-sensitive strain 3D7 of
P. falciparum in an in vitro model and CQ resistance strain
N-67 of P. yoelii in an in vitro assay. Inspired from these
works, we have synthesized quinazoline-based ethylene
diamine linkage between s-triazine and quinazoline instead
of quinoline and checked their antimicrobial and anti-HIV
activities (Fig. 2).
From the last fve years, the acquired immunodefciency
syndrome (AIDS) has already claimed that 21.7 million
people live with HIV and 1.8 million people were newly
infected with human immunodefciency virus (HIV) [30].
Among the NNRTIs (non-nucleoside reverse transcriptase
inhibitors), diaryl triazine (DATA) derivatives (Fig. 3) such
as R129385, R120393 and R106168 displayed high potent
resistant against wild and NNRTIs have attracted consider-
able attention over the past few years [31]. In context to the
above rationale and in continuation of our ongoing program
focused on fnding some new leads with anti-HIV activities,
a novel hybrid series of DATA molecule with a combination
of diferent pharmacophores such as s-triazine, quinazoline,
morpholine and thiosemicarbazides have been designed
which are structurally related to anti-HIV lead compounds
(Fig. 4), i.e., morpholine linked with DATA-NNRTIs deriv-
atives [23], triapine drug having carbazide moiety and DPC
961 with quinazoline moiety.
Derivatives of s-triazines are found to possess valuable
antimicrobial activity against various bacterial and fungal
species, and several reported studies by our group have
shown our enormous involvement in the discovery of poten-
tially biologically active s-triazine derivatives. Chikhalia
et al. [14] have designed, synthesized and examined anti-
microbial activity of some s-triazine derivatives involving
the substitution of 4-hydroxy coumarin (I) as well as mor-
pholine (II) moieties against various Gram-positive and
Gram-negative bacterial and fungal species [15]. Further,
Patel et al. [16] explored some triamino-linked triazines (III)
with remarkable antimicrobial properties. In continuation
of our research for novel therapeutically relevant molecules
via a suitable structural modifcation, Patel et al. [17] syn-
thesized some novel s-triazine-based 3,4-dimethoxy phenyl
ethyl s-triazinyl thioureas analogues (IV) and evaluated their
anti-HIV activity, and some of the fnal analogues exhib-
ited excellent IC50 level as well as minimum cytotoxicity
resulting in derivatives bearing good therapeutic index
Herein, we synthesized a new class of ethylene diamine-
linked quinazoline–triazine–semicarbazide and thiosemicar-
bazide derivatives starting from the s-triazine ring of DATA.
Theoretical calculations of DFT at B3LYP level have been
carried out to determine the structure–activity relationship.
1 3

Molecular Diversity
Fig. 1 Our previous work on s-triazine moiety
formamide acts as a cyclization agent. Compound 3 upon
treatment with POCl3 and N,N′-dimethylaniline aforded
compound 4 6,8-dibromo-4-chloroquinazoline, which on
further treatment with 1,2-diaminoethane gave compound
5 N-(2-aminoethyl)-6,8-dibromoquinazolin-4-amine to cre-
ate the ethylene linkage between fnal moieties.
Chemistry
In view of high pharmacological activity profle of quina-
zoline compounds, we have designed and synthesized this
class of compounds. This part deals with the synthesis of
novel quinazoline–triazine-based analogues involving semi-
carbazide and thiosemicarbazide moieties. Diferent isocy-
anate and isothiocyanate derivatives were condensed to the
hydrazine group to aford semicarbazide and thiosemicar-
bazide, respectively, which was substituted at the s-triazine
ring, and the efects of presence/absence of diferent groups
to semicarbazide and thiosemicarbazide on various biologi-
cal activities of the fnal analogues have been studied. Based
on the synthesized analogues, it was divided into four parts:
(Scheme 1).
In the second part, the generation of triazine analogue
2-(6-chloro-6-hydrazinyl-s-triazin-2-yl) morpholine com-
pound 8 was synthesized. Commercially available s-triazine
compound 6 moiety was condensed with morpholine in the
presence of dry acetone at very low temperature (0–5 °C) to
get compound 7 4-(4,6-dichloro-s-triazin-2-yl) morpholine
which was further treated with hydrazine hydrate in the pres-
ence of dry acetone at 35–40 °C temperature to get the fnal
analogue of s-triazine 2-(6-chloro-6-hydrazinyl-s-triazin-
2-yl) morpholine compound 8.
Hence, in the present study, the frst step comprises the
formation of intermediate 5 in very good yield 80–90%. First
of all, in the frst part analogues N-(2-aminoethyl)-6,8-di-
bromoquinazolin-4-amine compound 5 were synthesized
starting from anthranilic acid 1 via bromination with bro-
mine in glacial acetic acid and refuxed to get compound 2
3,5-dibromo-2-amino benzoic acid which was further treated
with formamide at very high temperature to get compound
3 6,8-dibromo quinazolin-4(3H)-one. Here, in this case
In the third part, the condensation between compound 5
and compound 8 takes place in the presence of acetonitrile at
refux condition to get compound 9 N1-(6,8-dibromoquina-
zolin-4-yl)-N2-(4-hydrazinyl-2-morpholino-s-triazin-6-yl)
ethane-1,2-diamine which was further divided into two
series: In Series-1 compound 9 was treated with diferent
isocyanates in the presence of ethanol to get the title com-
pounds (10a–j) 2-(4-(2-(6,8-dibromoquinazolin-4-yl)amino)
1 3

Molecular Diversity
Fig. 2 Ethylene diamine linkage
between two diferent pharma-
cophores
Fig. 3 The structures of some
trisubstituted DATA (diaryl
triazine) derivatives
1 3

Molecular Diversity
Fig. 4 The design of quinazoline–morpholine–triazine–thiosemicarbazide hybrid derivatives
ethyl) amino)-6-morpholino-s-triazine-2-yl)-N-substituted
hydrazine carboxamides, and in Series-2, compound 9 was
treated with diferent isothiocyanates in the presence of etha-
nol to get the title compounds (11a–j) 2-(4-(2-(6,8-dibro-
moquinazolin-4-yl)amino) ethyl) amino)-6-morpholino-
s-triazin-2-yl)-N-substituted hydrazine carbothioamide
derivatives.
in the experimental part. The fnal analogues were than ana-
lyzed for their in vitro antimicrobial activity against bacteria
(Gram positive and Gram negative) and fungi using the agar
streak dilution method as well as in vitro anti-HIV activity
against two types of viral strains viz, HIV type I (IIIB) and
type II (ROD) using MTT (3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyl-tetrazolium bromide) assay method. The bio-
assay results and relative comparison are discussed in the
results and discussion part.
All the fnal synthesized derivatives were chemically
characterized through melting point, mass spectra, 1H NMR
and 13C NMR as well as elemental microanalysis, elucidated
1 3

Molecular Diversity
1 3

Molecular Diversity
◂Scheme 1 Synthetic pathway of compounds (10a–j) and (11a–j).
Reagents and conditions: (a) Br2, glacial CH3COOH, 3 h, refux (b)
HCONH2, 160 °C, 6 h (c) POCl3, N,N′-dimethylaniline, 2 h, refux
(d) 1,2-diaminoethane, acetonitrile, 8 h, refux (e) morpholine,
0–5 °C, 30 min., acetone (f) hydrazine hydrate, acetone, 35–40 °C,
5–6 h (g) acetonitrile, 12–20 h (h) substituted isocyates, ethanol,
4–6 h (i) substituted isothiocyanates, ethanol, 4–6 h
Culture infectious dose) for culture medium was added to
either the infected or mock-infected wells of the microtiter
tray. Mock-infected cells were used to evaluate the efects
of the test compounds on uninfected cells in order to assess
the cytotoxicity of the test compounds. Exponentially grow-
ing MT-4 cells [34] were centrifuged for 5 min at 1000 rpm
(220 g), and the supernatant was discarded. The MT-4 cells
were resuspended at a fnal concentration of 6×105 cells/
mL, and 50 µL volumes were transferred to the microtiter
tray wells. After 5 days of incubation at 37 °C following
infection, the viability of mock and HIV-infected cells was
examined spectrophotometrically by the MTT assay.
Medicinal chemistry part
In vitro evaluation of antimicrobial activity
In order to study the antimicrobial properties of the novel
hybrid quinazolinyl–triazinyl semicarbazide and thiosemi-
carbazide derivatives, several bacterial (Staphylococcus
aureus MTCC 96, Bacillus Cereus MTCC 430, Pseu-
domonas aeniginosa MTCC 741, Klebsiella pneumaniae
MTCC 109) and fungal (Aspergillus clavatus MTCC 1323
and Candida albicans MTCC 183) species were selected and
minimum inhibitory concentration (MIC) of the compound
was determined by the agar streak dilution method [32].
A stock solution of the tested compound (200 µg/mL) in
DMSO was prepared, and graded quantities of the test com-
pounds were incorporated in a specifed quantity of molten
sterile agar, i.e., nutrient agar for the evaluation of antibac-
terial and sabouraud dextrose agar for antifungal activity,
respectively. The medium containing the test compound was
poured into a petri dish at a depth of 4–5 mm and allowed
to solidify under aseptic conditions. A suspension of the
respective microorganisms of approximately 105 CFU/mL
was prepared and applied to plates with serially diluted com-
pounds with concentrations in the range of 3.125–200 µg/
mL in dimethylsulfoxide and incubated at (37 1) °C for
24 h (bacteria) and 48 h (fungi). The lowest concentration
of the substance that prevents the development of visible
growth is considered to be the MIC values.
The MTT assay is based on the reduction of yellow-
colored MTT (Acros Organics, Geel, Belgium) by mito-
chondrial dehydrogenase of metabolically active cells to a
blue-purple formazan that can be measured spectrophoto-
metrically. The absorbencies were read in an eight-channel
computer-controlled photometer (Safire, Tecan), at two
wavelengths (540 and 690 nm). All data were calculated
using the median optical density values of three wells. The
50% cytotoxic concentration was defned as the concen-
tration of the test compound that reduced the absorbance
(optical density 540) of the mock-infected control sample by
50%. The concentration achieving 50% protection from the
cytopathic efect of the virus in infected cells was defned
as the 50% efective concentrations. Anti-HIV activity and
cytotoxicity of standard drug DDN/DDI were also per-
formed by a similar method in MT-4 cells.
Experimental
Materials and methods
All the chemicals and reagents were of analytical grade of
SD Fine-Chem, Aldrich and Merck unless and otherwise
specifed. All solvents were dried over an appropriate dry-
ing agent and purifed by standard methods. Melting points
were determined in open capillaries on a Veego electronic
apparatus VMP-D (Veego Instrument Corporation, Mum-
bai, India) and are uncorrected. Analytical thin-layer chro-
matography was performed on Merck precoated aluminum
plates 60 F254 with a 02 mm layer of silica gel-G, and
spots were visualized under UV irradiation. NMR spectra
were recorded on a 400 MHz spectrometer (Bruker DRX
400) using DMSO-d6 as a solvent and TMS as an inter-
nal standard, with 1H resonant frequency of 400 MHz and
13C resonant frequency of 100 MHz. All 1H and 13C NMR
chemical shifts are quoted in ppm and were calibrated on
solvent signals and were conducted at Indian Institute of
Science Education and Research, Pune, India. Multiplici-
ties are given as s(singlet), d(doublet), dd(doublet–doublet)
t(triplet), q(quartet) and m(multiplet). Elemental analysis (C,
In vitro evaluation of anti‑HIV assay
The evaluation of the anti-HIV activity of the synthe-
sized compounds against HIV-I strain (IIIB) and HIV-II
strain (ROD) in MT-4 cells was performed using the MTT
(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bro-
mide) assay method as earlier reported [33]. In brief, stock
solutions (10 times fnal concentration) of test compounds
were added in 25 µL volumes to two series of triplicate wells
so as to allow simultaneous evaluation of their efects in
mock- and anti-HIV-infected cells at the beginning of each
experiment. Serial fvefold dilutions of test compounds
were made directly in flat-bottomed 96-well microtiter
trays using a Biomek 3000 robot (Bechman Instruments,
Fullerton, CA). Untreated control HIV- and mock-infected
cell samples were included for each sample. HIV-I (IIIB) or
HIV-II (ROD) stock (50 µL) at 100–300 CCID50 (50% Cell
1 3

Molecular Diversity
H and N) was performed using a GmbH vario Microcube
Elemental Analyzer (Germany).
Step‑IV: Synthesis of N‑(2‑aminoethyl)‑6,8‑dibromoquina‑
zolin‑4‑amine (compound 5)
Synthesis of N‑(2‑aminoethyl)‑6,8‑dibromoquinazo‑
lin‑4‑amine (compound 5)
A mixture of 6,8-dibromo-4-chloro quinazoline compound 4
(25 g, 0.0776 mol) and 1,2-diaminoethane (28 g, 25.27 mL,
0.4654 mol, 6 equiv.) was refuxed for 8 h with stirring.
After the completion of reaction, it was cooled to room tem-
perature and poured into ice water. Progress of the reaction
was monitored by TLC using solvent system ethyl acetate/
hexane (4:6). The precipitate formed was fltered, washed
with water, dried and crystallized from ethanol which
aforded N-(2-aminoethyl)-6,8-dibromoquinazolin-4-amine
compound 5. Yield 93%; m.p. 128–130 °C.
This preparation was prepared in the following four steps:
Step‑I: Synthesis of 3,5‑dibromo‑2‑amino benzoic acid
(compound 2)
A mixture of anthranilic acid compound 1 (50 g, 036 mol)
and bromine (27.5 mL, 0.53 mol) in glacial acetic acid
(100 mL) was refuxed for 3 h (colorless crystals took place).
Progress of the reaction was monitored by TLC using sol-
vent system ethyl acetate/hexane (2:8). After the completion
of reaction, it was cooled to 25 °C. Excess of bromine was
removed by quenching. The crude product was boiled with
distilled water and crystallized from alcohol. Yield 95%;
m.p. 234–235 °C.
Synthesis of 2‑(6‑chloro‑6‑hydrazinyl‑s‑triazin‑2‑yl)
morpholine (compound 8)
It was prepared into the following two steps:
Step‑I: Synthesis of 4‑(4,6‑dichloro‑s‑triazin‑2‑yl) morpho‑
line (compound 7)
Step‑II: Synthesis of 6,8‑dibromo quinazolin‑4(3H)‑one
(compound 3)
A mixture of cyanuric chloride compound 6 (25 g, 0.14 mol)
in dry acetone (125 mL) was cooled to 0–5 °C, and a solu-
tion of morpholine (12.2 g, 0.14 mol) in dry acetone was
added dropwise at 0–5 °C within 30 min. The pH was
adjusted to neutral by the addition of 10% NaHCO3 solu-
tion. After the completion of reaction, it was poured into ice
water. Progress of the reaction was monitored by TLC using
solvent system toluene/acetone (8:2). The solid was fltered,
washed with water, dried and crystallized from chloroform
which aforded the product 4-(4,6-dichloro-s-triazin-2-yl)
morpholine compound 7. Yield 85%; m.p. 150–153 °C.
A mixture of 3,5-dibromo anthranilic acid compound 2
(5.0 g, 0.17 mol) and formamide (15 mL, 0.29 mol) was
heated slowly to 160 °C and maintained for 6 h. After the
completion of the reaction, the mixture was poured into ice
water. Progress of the reaction was monitored by TLC using
solvent system ethyl acetate/hexane (2:8). The solid sepa-
rated was fltered, dried and recrystallized from ethanol to
get 6,8-dibromoquinazolin-4(3H)-one compound 3. Yield
77%; m.p. 265–267 °C.
Step‑III: Synthesis of 6,8‑dibromo‑4‑chloroquinazoline
(compound 4)
Step‑II: Synthesis of 2‑(6‑chloro‑6‑hydrazinyl‑s‑triazin‑2‑yl)
morpholine (compound 8)
A mixture of 6,8-dibromoquinazolin-4(3H)-one compound
3 (5.0 g, 0.0165 mol) phosphorus oxychloride (10 mL,
0.0348 mol) and N,N′-dimethyl aniline (10 mL, 0.0863 mol)
was refuxed for 2 h. After the completion of the reaction,
the excess POCl3 was removed under reduced pressure;
crushed ice (20 g) was added to the reaction mass and neu-
tralized by 1 N NaOH solution. Progress of the reaction was
monitored by TLC using solvent system ethyl acetate/hexane
(2:8). The separated solid was fltered, dried and crystallized
from dichloromethane which aforded 6,8-dibromo-4-chlo-
roquinazoline compound 4. Yield 94%; m.p. 162–163 °C.
A mixture of 4-(4,6-dichloro-s-triazin-2-yl)morpholine com-
pound 7(5.0 g, 0.0213 mol) and hydrazine hydrate (0.7 g,
0.0218 mol) in dry acetone (20 mL) was stirred at 35–40 °C
for 5–6 h. The pH was adjusted to neutral by 10% K2CO3
solution. After the completion of reaction, it was poured
into ice water. Progress of the reaction was monitored by
TLC using solvent system toluene/acetone (8:2). The solid
obtained was fltered, washed with water, dried and recrys-
tallized from chloroform which aforded the 4-(4-chloro-
6-hydrazinyl-s-triazin-2-yl)morpholine compound 8. Yield
64%; m.p. 203–206 °C.
Condensation between compound 5 and compound 8
1 3

Molecular Diversity
Synthesis of N1‑(6,8‑dibromoquina‑
compound 9 (1.5 g, 1.85 mol) and substituted isocyanate
(1.85 mol) in ethanol (15 mL) was refuxed for 4–6 h. The
pH was adjusted to neutral by the addition of 10% K2CO3
solution. After the completion of reaction, it was poured
into ice water. Progress of the reaction was monitored by
TLC using solvent system toluene/acetone (8:2). The prod-
uct thus obtained was fltered, washed with water, dried and
recrystallized from ethanol which aforded the respective
compounds (10a–j).
zolin‑4‑yl)‑N2‑(4‑hydrazinyl‑2‑morpholino‑s‑tria‑
zin‑6‑yl) ethane‑1,2‑diamine (compound 9)
A mixture of 4-(4-chloro-6-hydrazinyl-s-triazin-2-yl) mor-
pholine compound 8 (1.0 g, 4.34 mol) and N-(2-aminoethyl)-
6,8-dibromoquinazolin-4-amine compound 5 (1.5 g,
4.34 mol) in dry acetonitrile (10 mL) was refluxed for
12–20 h. The pH was adjusted to neutral by addition of 10%
K2CO3 solution. After the completion of reaction, it was
poured into ice water. Progress of the reaction was moni-
tored by TLC using toluene/acetone (7:3). The product thus
obtained was fltered, dried and recrystallized from tetrahy-
drofuran (THF) which aforded the title compound 9. Yield
72%; m.p. 231–233 °C.
The physical constant of the synthesized compounds
(10a–j) is tabulated in Table 1.
Series‑2: General method for the preparation
of 2‑(4‑(2‑(6,8‑dibromo quinazolin‑4‑yl) amino)ethylamino
)‑6‑morpholino‑1,3,5‑triazin‑2‑yl)‑N‑substituted hydrazine
carbothiomide (compounds 11a–j)
Series‑1: General method for the preparation
of 2‑(4‑(2‑(6,8‑dibromo quinazolin‑4‑yl) amino)ethylamino
)‑6‑morpholino‑1,3,5‑triazin‑2‑yl)‑N‑substituted hydrazine
carboxamide (compounds 10a–j)
A mixture of N1-(6,8-dibromoquinazolin-4-yl)-N2-(4-
hydrazinyl-2-morpholino-s-triazin-6-yl) ethane-1,2-di-
amine compound 9 (1.5 g, 1.85 mol) and substituted iso-
thiocyanates (1.85 mol) in ethanol (15 mL) was refuxed
for 4–6 h. The pH was adjusted to neutral by the addition
of 10% K2CO3 solution. After the completion of reaction,
A mixture of N1-(6,8-dibromoquinazolin-4-yl)-N2-(4-
hydrazinyl-2-morpholino-s-triazin-6-yl) ethane-1,2-diamine
Table 1 Physical and analytical
data of compounds (10a–j):
series-1
Elemental analysis
%
M.P.
(°C)
Entry
10a
10b
10c
10d
10e
10f
R
Molecular formula
C20H25Br2N11O2
C21H27Br2N11O2
C21H25Br2N11O2
C24H31Br2N11O2
C24H25Br2N11O2
C25H33Br2N11O2
C26H29Br2N11O2
M.W.
611.29
625.32
623.30
665.38
659.34
679.41
687.39
Yield
% C
% H
4.12
4.13
4.35
4.34
4.04
4.05
4.70
4.69
3.82
3.83
4.90
4.91
4.25
4.24
3.49
3.50
3.49
3.48
4.04
4.05
% N
C
F
C
F
C
F
C
F
C
F
C
F
C
F
C
F
C
F
C
F
39.30
39.19
40.34
40.40
40.47
40.38
43.32
43.44
43.72
43.66
44.20
44.07
45.43
45.50
41.55
41.55
41.55
41.66
44.59
44.53
25.20
25.14
24.64
24.58
24.72
24.70
23.16
23.11
23.37
23.43
22.68
22.63
22.41
22.35
22.21
22.19
22.21
22.16
22.88
22.94
S
77
75
72
74
69
65
73
71
68
72
238–239
257
268–270
283
269–270
280–282
269
10g
10h
10i
C24H24Br2ClN11O2 693.78
C24H24Br2ClN11O2 693.78
290–292
252–254
227
C25H27Br2N11O2
673.36
10j
1 3

Molecular Diversity
it was poured into ice water. Progress of the reaction was
monitored by TLC using solvent system toluene/acetone
(8:2). The product thus obtained was fltered, washed with
water, dried and recrystallized from ethanol which aforded
the respective compounds (11a–j).
containing additional chloro group at ortho and meta posi-
tion, respectively, endowed with promising antibacterial
activity (MIC 12.5 µg/mL). However, these sets of com-
pounds were found comparatively inactive showing MIC
varying from 25 to 100, against Bacillus cereus strain. 10f
and 10j compounds with the electron-releasing methyl group
at para and meta position of acyclic and aromatic amine
ring, respectively, prohibit the growth of Pseudomonas aer-
uginosa Gram-negative strain (MIC 12.5 µg/mL). On the
other part, 10a and 10b moieties with only alkyl chain amino
substitution showed similar efcacy against Klebsiella pneu-
moniae with 12.5 µg/mL MIC, than other aromatic com-
pounds. Furthermore, allylic amino derivatives 11c and
aromatic amine containing electron-withdrawing fuoro in
compound 11h contributed similar efcacy with 12.5 µg/
mL MIC value against Staphylococcus aureus strain. The
result of the compounds exhibited good to moderate activ-
ity with 50–100 µg/mL MIC. Among the mentioned set of
compounds, compound 11h and 11i with electron-snatching
fuoro and electron-donating methyl group at para position,
respectively, showed the best inhibition profle of 25 µg/mL
MIC against Bacillus cereus strain whereas remaining were
inactive. Compound 11b with alicyclic, compound 11f and
The physical constant of the synthesized compounds
(11a–j) is tabulated in Table 2.
Results and discussion
Structure–activity relationship study
Antimicrobial activity
In vitro antibacterial and antifungal activity of compounds
(10a–j) and (11a–j) are described in Table 3. Out of all 20
compounds, results suggested that alicyclic ring-bearing
electron-releasing amino group in the compounds 10f,
11d was the most active (MIC 6.25 µg/mL) against Gram-
positive Staphylococcus aureus strain and Gram-negative
Pseudomonas aeruginosa strain at 12.5 µg/mL MIC. Com-
pound 10e bearing aromatic amine and 10h as well as 10i
Table 2 Physical and analytical
data of compounds (11a–j):
series-2
Elemental analysis
%
M.P.
(°C)
Entry
11a
11b
11c
11d
11e
11f
R
Molecular formula
C20H25Br2N11OS
C21H27Br2N11OS
C21H25Br2N11OS
C24H31Br2N11OS
C24H25Br2N11OS
M.W.
627.36
641.39
639.37
681.45
675.40
Yield
% C
% H
4.02
4.01
4.24
4.25
3.94
3.93
4.59
4.64
3.73
3.72
3.41
3.40
3.41
3.41
3.49
3.50
3.95
4.03
3.95
3.89
% N
C
F
C
F
C
F
C
F
C
F
C
F
C
F
C
F
C
F
C
F
38.29
38.20
39.32
39.22
39.45
39.51
42.30
42.43
42.68
42.75
40.61
40.70
40.61
40.50
41.57
41.47
43.55
43.49
43.55
43.47
24.56
24.49
24.02
24.06
24.10
24.04
22.61
22.55
22.81
22.75
21.71
21.67
21.71
21.65
22.22
22.20
22.35
22.41
22.35
22.37
78
80
82
75
79
73
79
77
71
75
240–242
218–219
257–258
179–181
211–212
278–280
251–253
250–252
278–279
256–258
C24H24Br2ClN11OS 709.85
C24H24Br2ClN11OS 709.85
11g
11h
11i
C24H24Br2FN11OS
C25H27Br2N11OS
C25H27Br2N11OS
693.39
689.43
689.43
11j
1 3

Molecular Diversity
Table 3 In vitro antibacterial
and antifungal activity in MIC
(µg/mL) of compounds (10a–j)
and (11a–j)
Gram +Ve
Gram –Ve
Fungal strains
Entr
y
Staphylococc
Bacillus
cereus
Pseudomonas
Klebsiella
Aspergillus
clavatus
Candida
albicans
R
us aureus
MTCC 96
aeruginosa
MTCC 741
pneumoniae
MTCC 109 MTCC 1323 MTCC 183
MTCC 430
100
100
100
100
50
12.5
12.5
100
100
100
100
10a
10b
100
25
50
50
50
100
25
100
25
100
50
100
50
10c
10d
10e
10f
100
12.5
6.25
100
12.5
100
100
100
25
100
100
100
100
12.5
100
100
100
25
12.5
50
100
50
10g
10h
100
100
12.5
100
25
50
50
50
25
10i
10j
100
12.5
100
100
100
100
100
12.5
100
100
50
50
12.5
50
100
100
50
100
100
100
100
100
100
11a
11b
11c
6.25
100
50
50
100
100
100
25
12.5
25
100
50
50
50
100
100
50
11d
11e
11f
100
100
100
100
12.5
12.5
100
12.5
100
12.5
100
12.5
11g
11h
100
50
25
12.5
50
12.5
25
11i
100
100
100
100
100
100
11j
3.125
–
–
3.125
–
–
3.125
–
–
3.125
–
–
–
3.125
–
–
3.125
–
Ciprofloxacin†
Ketoconazole†
DMSO (Control)
*MIC minimum inhibitory concentration
†Standard
11 g with electron-withdrawing chloro group and electron-
donating methyl functionalization on compound 11i showed
the lowest MIC value 12.5 µg/mL than other compounds
against Gram-negative Pseudomonas aeruginosa strain.
Halo substituted compounds 11f and 11h having chloro and
fuoro group, respectively, were endowed with good activ-
ity, i.e., MIC 12.5 µg/mL against Gram-negative Klebsiella
pneumonia bacteria.
toward Candida albicans fungal strain. Compound 11i
with para substituted methyl group existed proper efcacy
to inhibit the growth of Aspergillus clavatus fungal strain
(MIC 12.5 µg/mL). The same compound 11i also showed the
best antifungal activity against Candida albicans strain with
slight increase MIC 25 µg/mL. Rest of the compounds has
efect to a less extent to prevent the mentioned fungal strain
growth with MIC value ranging from 50 to 100 µg/mL.
In terms of antifungal activity, compound 10e having
substituted aromatic amine moiety showed the best activity
against Aspergillus clavatus strain with 12.5 µg/mL MIC
value which is found to be the highest activity from a set
of compounds (10a–j). With MIC values ranging from 25
to 100 µg/mL, these compounds tend to be less afective
Anti‑HIV activity
In this part, ten quinazoline–triazine–semicarbazide deriv-
atives (10a–j) and ten quinazoline–triazine–thiosemicar-
bazide (11a–j) derivatives were prepared and evaluated
1 3

Molecular Diversity
IC50 (µg/mL)a
> 106
CC50 (µg/mL)b
SIC
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
> 12
> 7
> 180
> 189
> 5083
> 4115
Table 4 Anti-HIV-1 (IIIB) and
HIV-2 (ROD) activityd (IC50
in µg/mL) with cytotoxicity of
compounds (10a–j) and (11a–j)
in MT-4 cells
Entry
R
Strains
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
> 106
> or = 106
> 92.7
> or = 92.7
> 51.98
51.98
> 112.25
112.25
> 33.65
33.65
> 89.5
> or = 89.5
> 96.2
> or = 96.2
> 102
> or = 102
> 36.45
36.45
10a
> or = 106
> 92.7
> or = 92.7
> 51.98
51.98
> 112.25
112.25
> 33.65
33.65
> 89.5
> or = 89.5
> 96.2
> or = 96.2
> 102
> or = 102
> 36.45
36.45
10b
10c
10d
10e
10f
10g
10h
10i
> 106
106
> 106
> 106
10j
11a
11b
11c
11d
11e
11f
11g
11h
11i
> 112.95
112.95
> 92.3
> or = 92.3
> 72.40
72.40
> 69.68
69.68
> 106
> or = 106
> 88.2
> or = 88.2
> 125
> 125
> 49.13
49.13
> 70.63
70.63
> 93.8
> or = 93.8
4.35
6.96
0.11
0.11
0.0049
0.0061
> 112.95
112.95
> 92.3
> or = 92.3
> 72.40
72.40
> 69.68
69.68
> 106
> or = 106
> 88.2
> or = 88.2
> 125
> 125
> 49.13
49.13
> 70.63
70.63
> 93.8
> or = 93.8
> 50
> 50
0.03
0.01
0.0074
0.010
11j
DDN/
DDI
DDN/
DDC
DDN/
AZT
2’,3’-Dideoxyinosine
2’,3’-Dideoxycytidine
Azidothymidine
1 3

Molecular Diversity
Table 4 (continued)
aConcentration required to protect the cell against viral cytopathogenicity by 50% in MT-4 cells
bConcentration that reduces the normal uninfected MT-4 cells viability by 50%
cSelectivity index: ratio CC50/IC50, a higher SI means more selective compound
dAll data represent mean values for at least two separate experiments
Each value is the mean of three independent experiments
for their anti-HIV activity against HIV-1 (IIIB) and HIV-2
(ROD) cell cultures. The antiviral screening (HIV-1 and
HIV-2) results of the novel synthesized compounds (10a–j)
and (11a–j) are tabulated in Table 4. The results of the
antiviral screening reveals that compounds 10a with ethyl,
10h with 2-chlorophenyl and 10j with 3-methylphenyl to
semicarbazide were not active as their IC50 and CC50 values
are higher than 100 µg/mL, while compounds 10e with no
substitution and 10i with 3-chloro at phenyl ring to semicar-
bazide appeared with IC50 33.65 and 36.45 µg/mL, respec-
tively, which were lowest IC50 in this set of compounds
against both HIV-1 and HIV-2 viruses. On the other part,
from the results it is worth to note that analogue 11h with
fuoro atom at para position to phenyl was only the most
potent analogues among all the ten quinazoline–triazine–thi-
osemicarbazide derivatives studied with 49.13 µg/mL of
IC50. Compounds 11a with ethyl, 11e with only phenyl and
11g with 4-chlorophenyl to thiosemicarbazide were not
active as their IC50 and CC50 values are higher than 100 µg/
mL (i.e., IC50 112.95, 106 and 125 µg/mL, respectively).
It can be also stated that in all the fnal analogues among
them, compounds (10a–j) have not shown selectivity toward
any type of the HIV viral strains studied and compounds
(11a–j) have shown good selectivity toward any type of the
HIV viral strains studied. On the basis of SAR studies, it can
be concluded that the compounds (10a–j) of this series are
not active or poorly active because they do not ft into the
RT enzyme active site as known in the case of thiosemicar-
bazide derivatives mentioned in the earlier part. The ana-
logues bearing thiosemicarbazide systems were more active
in terms of (IC50 µg/Ml) than those involving semicarbazide
motifs, with selectivity index below one, which is shown in
Fig. 5.
HOMO–LUMO study
To correlate the experimental results, quantum chemi-
cal indices such as HOMO (highest occupied molecular
orbital) energies, LUMO (lowest unoccupied molecular
orbital) energies, HOMO and LUMO energies gap were
calculated for compounds 10e, 10f, 11h and 11i according
to the literature methodology [35]. The good agreement
reported between this demonstrates the validity of DFT
method, which provides a convenient theoretical frame-
work. Results are summarized in Table 5, and the HOMO
and LUMO populations are plotted and shown in Fig. 6.
Positive and negative phases are represented in red and light
green color, respectively. These frontier molecular orbitals
(FMO) can aford important insight into chemical properties.
They determine the way that how molecule interacts with
other species like bacteria and fungi [36]. Thus, the HOMO
and LUMO energies are associated, respectively, with the
electron-donating and electron-accepting abilities of a
Table 5 Energy gap (LUMO–HOMO) of the compounds (10e, 10f,
11h and 11i)
Compound EHOMO (eV) ELUMO (eV) Energy gap
(∆E)=ELUMO − EHOMO
(eV)
10e
10f
11h
11i
− 5.820
− 5.895
− 1.225
− 1.240
− 1.113
− 1.240
− 0.851
− 0.883
4.707
4.655
0.374
0.357
Fig. 5 Comparative SAR study
between the fnal analogues
(10a–j) and (11a–j)
1 3

Molecular Diversity
ELUMO= -1.113 eV
ELUMO=-1.240 eV
∆Egap= 4.707 eV
e-
e-
∆Egap= 4.655 eV
EHOMO= -5.895 eV
EHOMO= -5.820 eV
Compound 10e
Compound 10f
ELUMO= -0.883 eV
ELUMO= -0.851 eV
∆Egap= 0.374 eV
∆Egap= 0.357 eV
e-
e-
EHOMO= -1.225 eV EHOMO= -1.240 eV
Compound 11h
Compound 11i
Fig. 6 HOMO-LUMO plot of compounds 10e, 10f, 11h and 11i
1 3

Molecular Diversity
molecule [37]. The calculated HOMO and LUMO energies
show that charge transfer occurs within the molecule. There-
fore, the high value of HOMO energy indicates a tendency
to donate electrons to appropriate acceptor molecules with
low energy and empty molecular orbital. Also, the lower
value of LUMO energy indicates that this compound would
also accept electrons. Several studies reported correlation
between HOMO–LUMO energies and antimicrobial activity
[38, 39]. This is due to the change in partial charge and to
the change in total dipole moment.
to note that analogue 11h with fuoro atom at para position
to phenyl was only the most potent analogues among all
the ten quinazoline–triazine–thiosemicarbazide derivatives
studied with 49.13 µg/mL of IC50. The analogues bearing
thiosemicarbazide systems were more active in terms of IC50
(µg/mL) than those involving semicarbazide motifs with
selectivity index below one. Based on the computational
study of DFT calculations of HOMO–LUMO energies gap,
it is concluded that lower the value of energy gap the bet-
ter the biological activity against various strains, i.e., 10e,
10f, 11h and 11j. Therefore, the lowest energy gap values
of 11h and 11j (0.374 and 0.357, respectively) compounds
reveal that compounds (11a–j) having thiosemicarbazide
group show best anti-HIV activity compared to compounds
(10a–j) having semicarbazide group. So, it is worth needed
to design more compounds having thiosemicarbazide moi-
ety on another analogues with anticipation of betterment in
biological activity profle in the feld of medicinal chemistry.
In the case of compounds 10e and 10f, HOMO is located
over the N-atom of morpholine and LUMO is located over
quinazoline ring at all C-atoms. So, the HOMO →LUMO
transition implies an electron density transfer to the quina-
zoline ring from the N-atom of morpholine analogue and
in the case of 11h and 11j compounds HOMO is located
over quinazoline and ethylene diamine linkage and LUMO
is located over the substituted amine chain of thiosemicar-
bazide. So, the HOMO→LUMO transition implies an elec-
tron density transfer to the substituted thiosemicarbazide’s
aromatic ring from the quinazoline and ethylene diamine
linkage analogues. The energy of the HOMO directly relates
to the ionization potential, while the energy of the LUMO
directly relates to the electron afnity.
Acknowledgements We are grateful to Prof. N. B. Patel, Head of the
Chemistry Department, Veer Narmad South Gujarat University, Surat,
for giving support and necessary laboratory facilities. The authors are
also expressed their sincere thanks to the Indian Institute of Science
Education and Research, Pune, for spectral analysis. The authors also
wish to ofer their deep sense of gratitude to Department of Microbi-
ology, School of Sciences, Gujarat University, Ahmedabad, to carry
out the biological screenings. They are also grateful to Prof. Eric De
Clercq, Rega Institute for Medical Research, Belgium, to carry out the
HIV screening of the compounds.
Conclusion
Synthesis, characterization and biological activity of quina-
zoline–triazine derivatives bearing ethylene diamine linkage
endowed with semicarbazides and thiosemicarbazides have
been carried out in sequential steps. Out of twenty deriva-
tives screened, compounds 10e having cyclic ring, 10f hav-
ing alicyclic ring, compounds 11d with acyclic ring bearing
electron-releasing amino group, 11h with cyclic ring bearing
electron-withdrawing group fuorine and 11i with cyclic ring
bearing electron-donating methyl group in semicarbazides
and thiosemicarbazides, respectively, exhibited promising
in vitro antibacterial activity inhibitory efects. Compound
11i with a para substituted methyl group exhibited good
in vitro antifungal activity in thiosemicarbazide derivatives.
On the other part, compounds 10a and 10b moieties with
only alkyl chain amino substitution showed similar efcacy.
From the bioassay results presented in these two parts, it can
be stated that semicarbazide and thiosemicarbazide motif
to the s-triazine nucleus showed equipotent activity against
both bacterial and fungal strains when compare to each other.
In the case of anti-HIV activity compounds 10e with no
substitution and 10i with 3-chloro at phenyl ring to semicar-
bazide appeared with the better activity in both, HIV-1 and
HIV-2 viral strains. On the other part, compound 11a with
fuoro atom at para position to phenyl of thiosemicarbazide
was the most potent analogues. From the results it is worth
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Afliations
Janki J. Patel1 · Rahul P. Modh2 · Manjoorahmed Asamdi2 · Kishor H. Chikhalia1
2
* Kishor H. Chikhalia
Department of Chemistry, School of Sciences, Gujarat
University, Ahmedabad 380009, Gujarat, India
Chikhalia_kh@yahoo.com
1
Department of Chemistry, Veer Narmad South Gujarat
University, Surat 395007, Gujarat, India
1 3