Straightforward synthesis of 2-chloro-N-(5-(cyanomethyl)-1,3,4-thiadiazol-2-yl)benzamide as a precursor for synthesis of novel heterocyclic compounds with insecticidal activity

Article abstract of DOI:10.1080/00397911.2020.1802652

The current work is devoted to the synthesis of 2-chloro-N-(5-(cyanomethyl)-1,3,4-thiadiazol-2-yl)benzamide 5 by an efficient synthetic methodology. The authors decided to exploit the reactivity of cyanomethylene functionality to construct new heterocycle

Full text of DOI:10.1080/00397911.2020.1802652

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Straightforward synthesis of 2-chloro-N-(5-
(cyanomethyl)-1,3,4-thiadiazol-2-yl)benzamide
as a precursor for synthesis of novel heterocyclic
compounds with insecticidal activity
Ali M. M. Mohamed , Mahmoud F. Ismail , Hassan M. F. Madkour , Aly Fahmy
Aly & Marwa S. Salem
To cite this article: Ali M. M. Mohamed , Mahmoud F. Ismail , Hassan M. F. Madkour , Aly Fahmy
Aly & Marwa S. Salem (2020): Straightforward synthesis of 2-chloro-N-(5-(cyanomethyl)-1,3,4-
thiadiazol-2-yl)benzamide as a precursor for synthesis of novel heterocyclic compounds with
insecticidal activity, Synthetic Communications, DOI: 10.1080/00397911.2020.1802652
To link to this article: https://doi.org/10.1080/00397911.2020.1802652
View supplementary material
Published online: 06 Aug 2020.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

R
SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1802652
Straightforward synthesis of 2-chloro-N-(5-(cyanomethyl)-
1,3,4-thiadiazol-2-yl)benzamide as a precursor for synthesis
of novel heterocyclic compounds with insecticidal activity
Ali M. M. Mohameda, Mahmoud F. Ismaila , Hassan M. F. Madkoura,
Aly Fahmy Alyb, and Marwa S. Salema
b
aDepartment of Chemistry, Faculty of Science, Ain Shams University, Cairo, Abbassia, Egypt; Pesticide
Formulations Department, Central Agricultural Pesticide Lab., Agricultural research Center, Giza,
Dokky, Egypt
ABSTRACT
ARTICLE HISTORY
Received 26 April 2020
The current work is devoted to the synthesis of 2-chloro-N-(5-(cyano-
methyl)-1,3,4-thiadiazol-2-yl)benzamide 5 by an efficient synthetic
methodology. The authors decided to exploit the reactivity of cyano-
methylene functionality to construct new heterocycles hybrid with
1,3,4-thiadiazole moiety. These compounds have been structurally
characterized with the aid of elemental analysis and spectroscopic
techniques such as IR, 1H and 13C NMR and mass spectra. The syn-
thesized compounds were evaluated for the insecticidal activity
against cotton leaf worm (spodoptera littoralis). Among of them,
compounds 7, 10, 12 and 17 showed much higher insecticidal activ-
ity. In particular, compound 12 exhibited the highest insecticidal
activity.
KEYWORDS
Aryl isothiocyanate;
cyanoacetohydrazide;
cyanomethylene moiety;
insecticidal activity;
1,3,4-thiadiazole
GRAPHICAL ABSTRACT
Introduction
Nowadays, 1,3,4-thiadiazole is one of the essential motifs in agricultural, pharmaceutical,
and environmental aspects because of their diverse biological activities, probably by vir-
tue of the –N¼C–S– group.[1,2] For examples, the 2,5-disubstituted-1,3,4-thiadiazoles[3,4]
possess a broad spectrum of biological activities including antimicrobial,[5–10]
antifungal,[11–14] antibacterial,[15,16] insecticidal,[17–21] acaricidal,[21] herbicidal,[22]
CONTACT Mahmoud F. Ismail
fawzy2010@sci.asu.edu.eg
Department of Chemistry, Faculty of Science, Ain
Shams University, Cairo, Abbassia, Egypt.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
A. M. M. MOHAMED ET AL.
Figure 1. Commercially available 1,3,4-thiadiazol moiety in variant aspects.
anticancer,[23–27] antioxidant,[28,29] antiviral,[30] analgesic,[31] anti-inflammatory,[32] anti-
tuberculosis,[33,34] anticonvulsant,[35,36] antidiabetic,[37] antidepressant,[38,39] anxio-
lytic,[39] antipsychotic,[40] antihypertensive,[41] antihistamine,[42] anti-hepatitis B viral,[43]
antiproliferative[44] and antiparkinson.[45]
Commercially, 1,3,4-thiadiazole moiety participates in numerous fields such as
Furidiazine (antimicrobial), Sulfamethizole (antibacterial), Thiazafluron (pesticide),
Tebuthiuron (pesticide), Desaglybuzole (antidiabetic), Acetazolamide (for glaucoma),
and Butazolamide (diuretic) as exemplified in Figure 1. According to their importance,
this endowed us enormous impetus to study the insecticidal activity of the newly syn-
thesized 1,3,4-thiadiazole derivatives.
The rational use of agrochemicals plays a pivotal role in agricultural production
by effectively controlling plant diseases.[46–48] Unfortunately, due to the rapidly
developing resistance of insects to pesticides[46] and their negative impacts on the
environment,[18] the application of traditional pesticides is greatly limited.[18,47]
Therefore, the discovery of new leading structures with ideal properties and environ-
mentally friendly agrochemicals remains an arduous challenge in pesticide
chemistry.[49,50]
To the best of our knowledge,[51–54] the 1,3,4-thiadiazole moiety has been synthesized
using variant methods as described in the literatures.[3,4,55,56] Herein, the formation of
1,3,4-thiadiazole moiety was performed by combination of aryl isothiocyanate with cya-
noacetohydrazide, followed by cyclization in glacial acetic acid.[3]
On the other hand, the requisite cyanomethylene unit possesses two neighboring
reactive sites, one of them, the methylene group which act as a nucleophilic site in the
presence of a base, and the other is the cyano group which act as an electrophilic site.
Noteworthy, it plays a vital role as a key material in building another heterocyclic moi-
ety beside 1,3,4-thiadiazole ring to study the insecticidal activity against cotton leaf

R
SYNTHETIC COMMUNICATIONSV
3
Scheme 1. The strategy pathway to synthesize 2-chloro-N-(5-(cyanomethyl)-1,3,4-thiadiazol-2-yl)benza-
mide (5).
worm (spodoptera littoralis) for the newly compounds. By considering the facts afore-
mentioned, 2-chloro-N-(5-(cyanomethyl)-1,3,4-thiadiazol-2-yl)benzamide 5 was utilized
as available precursor for performance novel 1,3,4-thiadiazole derivatives have
bright prospects.
Results and discussion
Chemistry
The synthetic strategy was implemented for the synthesis of hitherto undocumented title
compound as exemplified in Scheme 1. Stirring of 2-chlorobenzoyl chloride 1 with
ammonium thiocyanate in dry acetonitrile afforded the 2-chlorobenzoyl isothiocyanate
2, in situ cyanoacetohydrazide 3 was added on the later under stirring at ambient tem-
perature, followed by refluxing of the engendered 2-chloro-N-(2-(2-cyanoacetyl)hydra-
zine-1-carbonothioyl)benzamide (4) in glacial acetic acid to afford 1,3,4-thiadiazole
derivative 5 (Scheme 1).
The IR spectrum of compound 4 exhibited absorption bands for tNH at 3375 and
3217 cmꢀ1, tCꢁN at 2257 cmꢀ1, tC¼O at 1700 cmꢀ1 and tC¼S at 1244 cmꢀ1. Moreover,
1
the H NMR spectrum manifested the presence of three singlet peaks at 12.24, 12.11
and 11.21 ppm exchangeable with D2O compatible with three NH protons, a multiplet
peak at 7.60-7.41 ppm compatible with four aromatic protons and a singlet peak at
3.85 ppm compatible with CH2 protons. Furthermore, the 13C NMR spectrum showed
three peaks at 178.0, 167.6 and 167.1 ppm corresponding to the carbons of C¼S and
two C¼O groups, respectively.
On the other hand, the chemical structure of 5 was unequivocally elaborated by spec-
troscopic data and elemental analysis. For example, the 1H NMR of compound 5
revealed only one singlet characteristic peak exchangeable with D2O at 13.26 ppm corre-
sponding to one NH proton and a singlet peak at d ¼ 4.61 ppm corresponding to the
methylene protons. Also, the 13C NMR spectrum of compound 5 fits with the foresee-
able structure.

4
A. M. M. MOHAMED ET AL.
Scheme 2. Synthetic pathway of compounds 6 and 7.
The reactivity of cyanomethylene moiety of compound 5 encouraged us to a robust
approach for the synthesis of diverse novel heterocyclic compounds. Therefore, hetero-
cyclization of 5 with thioglycolic acid in dry pyridine afforded the thiazolidinone deriva-
tive 6 (Scheme 2), which proved the reactivity of cyano group. The IR spectrum of 6
displayed a band at 1723 cmꢀ1 corresponding to C¼O(thiazolidinone) and lacked the
1
stretching band for CꢁN group. Furthermore, in DMSO-d6 solution, the H NMR spec-
trum of 6 unambiguously ascertained the chemical structure of it by the showing of two
singlet peaks at 13.02 and 11.43 ppm corresponding to two NH protons exchangeable
with D2O and two singlet peaks at 6.36 and 3.94 ppm corresponding to olefinic and
methylene protons, respectively. Moreover, the 13C NMR spectrum of 6 manifested
peaks at 173.7, 146.7 and 34.2 ppm compatible with the three carbons of thiazolidinone
ring (C¼O, CN(S), CH2) and a peak at 90.0 compatible with the olefinic carbon.
The reactivity of the methylene group of the thiazolidinone ring of compound 6 was
examined, through the reaction with p-nitrobenzaldehyde in the presence of anhydrous
sodium acetate as a basic catalyst in glacial acetic acid, which afforded the condensed
product 7 (Scheme 2). The mass spectrum of compound 7 showed Mþ¼485 (64.27%)
corresponding to molecular formula C20H12ClN5O4S2.
On the other hand, the reactivity of active methylene of the parent compound 5 was
estimated with various electrophilic reagents, namely aromatic aldehyde, heterocyclic
aldehyde, heterocyclic ketone, diazonium salt, arylidene malononitrile, phenyl isothio-
cyanate and carbon disulfide.
Practically, refluxing ethanolic mixture of compound 5 with heterocyclic aldehyde,
namely 1,3-diphenyl-1H-pyrazole-4-carbaldehyde including drops of piperidine as a
basic catalyst yielded the foreseeable condensed pyrazole derivative 8 as the sole product
(Scheme 3). The IR spectrum of compound 8 exhibited a band at 2222 cmꢀ1 character-
1
istic for the conjugated nitrile group. Additionally, the H NMR spectrum exhibited two
singlet characteristic peaks at 9.22 and 7.95 ppm for C5-H(pyrazole) and olefinic proton.
Hydrazinolysis of compound 8 with hydrazine monohydrate in boiling dioxane
afforded 3,40-bipyrazole derivative 9 (Scheme 3). The chemical structure of 9 was

R
SYNTHETIC COMMUNICATIONSV
5
Scheme 3. Synthetic pathway of compounds 8–13.
1
elaborated by variant spectroscopic data and elemental analysis. The H-NMR spectrum
of compound 9 indicated the presence of extra signals and protons, as two singlet peaks
at 9.12 and 8.68 ppm compatible with C5-Hpyrazole and a multiplet peak at
8.01–7.38 ppm compatible with twenty four aromatic protons beside two broad singlet
peaks at 4.60 and 3.33 ppm (exchangeable with D2O) corresponding to NH2 protons,
which indicated the presence of compound 9 in two atropisomers 9 A and 9B, because
of the rotation of 1,3-diphenyl pyrazole ring around another pyrazole moiety about
pivot bond was hindered[57] (Fig. 2).
Smoothly, reaction of 5 with either 4-(dimethylamino)benzaldehyde or 2-(4-(dimethyla-
mino)benzylidene)malononitrile in ethanolic solution containing a catalytic amount of
piperidine achieved the same condensed product 10 in an excellent yield as orange crystals

6
A. M. M. MOHAMED ET AL.
Figure 2. The atropisomers of compound 9.
Figure 3. The lactam-lactim tautomers of compound 11.
(Scheme 3). The chemical structure of 10 was ascertained on the fundaments of spectral and
elemental data.
On the other hand, refluxing a mixture of compound 5, p-anisaldehyde and drops of
piperidine in ethanol afforded the condensed product 11 after partially hydrolyzed
1
of the cyano group into the corresponding amide (Scheme 3). The H NMR spectrum
of compound 11 in DMSO-d6 solution emerged the existence of it in lactam-lactim tau-
tomers[57,58] in the ratio 45:55. The higher proportion of the lactim tautomer is due to
the formation of intramolecular chelation H-bond in six membered ring as depicted in
Figure 3.
The indolinone moiety 12 was emanated from the condensation of isatin with
compound 5 at the active methylene group in ethanolic solution containing few
drops of piperidine (Scheme 3). As a confirming of the proposed structure of 12,
the IR spectrum showed bands at 2223 and 1711 cmꢀ1 corresponding to CꢁN and
1
C¼O(indolinone) groups, respectively. Moreover, the H NMR of compound 12 exhib-
ited two singlet peaks at 13.50 and 11.27 ppm compatible with deshielded two NH
protons, beside extra four protons in aromatic region characteristic to indoli-
none moiety.
The 2-carbohydrazonoyl cyanide 13 was commenced by stirring a mixture of com-
pound 5, p-anisidine diazonium chloride and anhydrous sodium acetate under cooling
system in ethanol (Scheme 3). The IR of compound 13 manifested stretching absorption
bands for tNH at 3245 and 3135 cmꢀ1, tCꢁN at 2202 cmꢀ1 and tC¼O at 1692 cmꢀ1
.
Additionally, the 13C NMR spectrum of 13 revealed peak at 55.7 ppm corresponding to
the carbon of OMe group.
At ambient temperature, reaction of compound 5 with phenyl isothiocyanate in
dimethyl formamide (DMF) containing KOH gave the intermediate A, in situ firstly
acidification of the intermediate A with dil HCl awarded 14 as brown precipitate
(Scheme 4). Secondly treatment of the intermediate A with ethyl chloroacetate afforded
the uncyclized product 15 instead of the expected 1,3-thiazolidin-4-one moiety[59] 16

R
SYNTHETIC COMMUNICATIONSV
7
Scheme 4. Synthetic pathway of compounds 14–17.
(Scheme 4), it was explained by the appearance of a broad peak which disappeared with
1
D2O corresponding to two NH protons at 13.20 ppm in the H NMR spectrum beside
the appearance of a quartet and a triplet signals at 4.19 and 1.21 ppm compatible with
the ethyl protons of the ester group.
Similarly, the uncyclized product 17 was obtained instead of the 1,3-dithiolan-4-one
moiety[60] 18 when the intermediate B was treated with ethyl chloroacetate, whereas,
the intermediate B was obtained by stirring the target compound 5 with carbon disul-
fide in dimethyl formamide (DMF) containing KOH at ambient temperature
(Scheme 4).
The proclivity of both cyano and methylene groups was investigated toward
reagents having electrophilic and nucleophilic centers, for example, refluxing com-
pound 5 with salicylaldehyde in the presence of few drops of piperidine as a base in
ethanolic solution to give iminocoumarin derivative 19 (Scheme 5).[61] The structure
19 was supported by spectral data, whereas its IR spectrum lacked the absorption
band of cyano group and its 1H NMR spectrum exhibited the appearance of
deshielded two NH protons at d ¼ 13.10 and 9.05 ppm and a singlet peak at
d ¼ 8.60 ppm corresponding to C4-H(iminocoumarin) beside the absence of a singlet
peak of the methylene group.
Reaction of compound 5 with benzoin in ethanolic KOH was fluently done to afford
the furan moiety 20 (Scheme 5). As well, affording of N-(5-(4-amino-3-phenyl-2-thi-
oxo-2,3-dihydrothiazol-5-yl)-1,3,4-thiadiazol-2-yl)-2-chlorobenzamide 21 was emanated
from refluxing a mixture of compound 5, phenyl isothiocyanate and elemental sulfur in
absolute ethanol under basic condition (triethyl amine) (Scheme 5). The foreseeable
structure of 21 was ambiguously proven via inspection of the IR spectrum, which

8
A. M. M. MOHAMED ET AL.
Scheme 5. Synthetic pathway of compounds 19–24.
exhibited the absorption band for tC¼S at 1238 cmꢀ1 and the absence of CꢁN group.
Additionally, the 1H NMR spectrum conspicuously manifested a singlet peak at
6.60 ppm exchangeable with D2O corresponding to NH2 protons. Moreover, the 13C
NMR of 21 revealed a peak at 185.9 ppm compatible with the carbon of the thi-
one group.
Treatment of a mixture of compound 5, acetone and elemental sulfur in dioxane as a
solvent containing triethyl amine as a base gave thiophen-2(5H)-imine moiety 22
(Scheme 5). The expected structure 22 was explicated by the disappearance of cyano
group from the IR spectrum and the existence of two singlet peaks at 2.92 and
2.06 ppm corresponding to CH2 and CH3 groups, respectively. At the same time, the

R
SYNTHETIC COMMUNICATIONSV
9
Table 1. Insecticidal activity of arylidiene containing thiadiazole derivatives against cotton leaf worm
(spodoptera littoralis).
Concentration in ppm
Compounds
250
500
750
1000
1250
1500
LC50
Toxicity index
Slope
7
8
10
11
12
39.16
32.51
36.81
25.51
41.16
56.69
54.92
58.24
46.95
63.48
66.57
67.77
70.08
60.40
75.07
72.98
75.83
77.42
69.33
81.92
77.48
81.23
82.33
75.57
86.32
80.83
85.05
85.80
80.11
89.33
384.26
431.02
383.78
547.79
328.34
85.45
76.18
85.56
59.94
100
1.474
1.917
1.810
1.933
1.886
Figure 4. The Ldp line of the synthesized thiadiazole arylidiene derivatives.
mass spectrum recorded the molecular ion peak at m/z ¼ 350 (22.71%) which is in keep-
ing with its molecular formula C14H11ClN4OS2.
Unfortunately, refluxing of compound 5 with ethyl cyanoacetate and elemental sulfur
in ethanol containing morpholine as a base furnished the corresponding amide deriva-
tive 24 instead of the prospective thiophene derivative[62] 23 (Scheme 5). On the basis
of spectroscopic analyses, the formation of compound 23 was excluded, because of the
absorption band of C ¼ O of ester group does not exist in the IR spectrum, as well, the
1
quartet and triplet peaks of ethyl group of ester were lacked in the H NMR spectrum.
Whereas the IR spectrum showed absorption bands at 3330 and 3140 cmꢀ1 correspond-
ing to tNH2 and at 1687 cmꢀ1 corresponding to tC¼O(amide) with the absence of cyano
1
group. Moreover, the H NMR spectrum manifested a singlet peak at 3.96 ppm attribut-
able to CH2 protons and two singlet peaks exchangeable with D2O at 7.76 and 7.25 ppm
corresponding to NH2 protons of amide, one of them more deshielded than the other
because one proton became more deshielded due to it makes intramolecular H-bonding
chelated in six-membered ring with the nitrogen atom of 1,3,4-thiadiazole ring. As well,
the 13C NMR spectrum of 24 is keeping with its chemical structure.
Insecticidal activity
The insecticidal activity of arylidene thiadiazole analogues against cotton leaf worm
(spodoptera littoralis) was listed in Table 1 and the Ldp curves were shown by Figure 4.
As it is clear from these data, we first showed that, as the treatment concentration

10
A. M. M. MOHAMED ET AL.
Table 2. Insecticidal activity of Sulfur containing thiadiazole derivatives against cotton leaf worm
(spodoptera littoralis).
Concentration in ppm
Compounds
250
500
750
1000
1250
1500
LC50
Toxicity index
Slope
14
15
17
32.33
32.71
37.90
53.00
56.94
61.03
63.74
70.50
73.37
71.35
78.74
80.73
76.67
84.08
85.48
80.58
87.72
88.72
465.60
411.64
359.41
77.19
87.31
100.00
1.698
2.068
1.954
Figure 5. The Ldp line of the synthesized sulfur containing thiadiazole derivatives.
increase the insecticidal potency of the tested thiadizole derivatives also increase. It is
also evident that, arylidene thiadiazole 12 was the most effective compound against tar-
get pest where this derivative recorded LC50 of 328.34 ppm. While compound 11 was
the least effective compound and its LC50 was 547.79 ppm. We can now proceed analo-
gously to the other compounds where they arranged as 10, 7 and 8 with LC50 values
383.78, 384.26 and 431.02 ppm respectively. Concerning on the toxicity index values
(Table 1), it is quite clear that the toxicity of 12 against (spodoptera littoralis) was 1.17-
fold more toxic than both 10 and 7 and 1.3- and 1.6-fold more toxic than 8 and 11,
respectively.
Table 2 and Figure 5 plots the mortality percent versus the concentration of the treat-
ment sulfur containing thiadiazole derivatives against cotton leaf worm (spodoptera lit-
toralis). The data revealed that the mortality percent is directly proportional to the
treatment concentration of sulfur thiadiazole derivatives. From these data, it can be also
concluded that, compound 17 was the most potent derivative among these categories of
prepared thiadiazole derivatives where its LC50 was 359.41 ppm followed by compound
15 and finally 14 where their LC50 were 411.64 and 465.60 ppm on consequence.
On the other hand, toxicity index of 17 was 1.15- and 1.3-fold more toxic than both 15
and 14 consecutively.
Data tabulated in Table 3 and depicted by Figure 6 illustrated the relation between
mortality percent of the tested benzamide derivatives of the thiadiazole and its treat-
ment concentration against cotton leaf worm (spodoptera littoralis). These data indicated
that, there is a direct relationship between the treatment concentration of the benzamide
thiadiazole derivatives and the mortality percent caused by these compounds. As shown
in Table 3 and Figure 6, the mortality percent of this group of compounds are so close

R
SYNTHETIC COMMUNICATIONSV
11
Table 3. Insecticidal activity of some benzamide thiadiazole derivatives against cotton leaf worm
(spodoptera littoralis).
Concentration in ppm
Compounds
250
500
750
1000
1250
1500
LC50
Toxicity index
Slope
4
5
13
21
24
30.00
26.67
22.53
26.54
26.00
36.67
40.00
42.97
48.26
44.00
53.33
56.67
56.38
61.69
58.00
60.00
63.33
65.55
70.51
65.00
66.67
70.00
72.11
76.64
78.00
76.67
82.00
76.98
81.07
91.00
647.08
605.85
618.50
526.69
553.99
81.40
86.93
85.16
100.00
95.07
1.584
1.863
1.918
1.937
2.225
Figure 6. The Ldp line of the some synthesized benzamide thiadiazole derivatives.
Table 4. Insecticidal activity of some benzamide thiadiazole derivatives against cotton leaf worm
(spodoptera littoralis).
Concentration in ppm
Compounds
250
500
750
1000
1250
1500
LC50
Toxicity index
Slope
6
9
19
20
22
11.55
14.46
14.00
11.44
17.56
27.73
32.90
31.51
28.25
37.51
40.68
46.75
44.77
41.76
51.61
50.65
56.93
56.64
52.10
61.60
58.38
64.55
62.14
60.06
68.88
64.48
70.39
67.97
66.28
74.34
981.70
821.94
873.56
943.60
716.60
73.00
87.18
82.03
75.94
100.00
2.017
2.050
1.989
2.087
2.039
to each other where the difference in LC50 values of the most effective compound 21
which recorded LC50 of 526.69 ppm and the least potent one 4 which recorded LC50 of
647.08 ppm is only 120.39 ppm. The other derivatives are arranged as follow 24, 5 and
13 their LC50 were 553.99, 605.85 and 618.50 consecutively. From the toxicity index
data, it was clear that 21 was more toxic by 1.07- to 1.3-fold than the other derivatives
24, 5, 13 and 4 respectively.
Table 4 and Figure 7 exhibited the insecticidal activity of the other benzamide thia-
diazole derivatives against cotton leaf worm (spodoptera littoralis). It is clear that, these
compounds are the least potent than other benzamide derivatives and among the overall
tested thiadiazole componds. Among these compounds the most functional derivative

12
A. M. M. MOHAMED ET AL.
Figure 7. The Ldp line of the some synthesized benzamide thiadiazole derivatives.
was 22 where its LC50 was 716.60 ppm while the less influential one all over the overall
experiment were 6 and 20 where their LC50 were 981.7 and 943.6 ppm, respectively.
The rest of the tested compounds were 9 and 19 their LC50 were 821.94 and 873.56,
respectively. Taking in consideration the toxicity index data, it was evident that com-
pound 22 was 1.14- and 1.22-fold more toxic than 9 and 19, while it was 1.34- and
1.37-fold more toxic than 20 and 6, respectively.
In this study, the mortality percentage of eighteen tested thiadiazole derivatives 4 and
5-24 against cotton leaf worm (spodoptera littoralis) imply that the insecticidal activity
of tested thiadiazole depends mainly on the substituent present on C-2 of thiadiazole
moiety where the activity increases when substituents are group carrying electron with-
drawing functional group as CN, C ¼ O, p-NO2 phenyl group, it is clear that as these
groups become in direct attachment to the thiadiazole the insecticidal activity of the
compound increase as in 12, 17, 15, 24 and 10 as examples. Also, it was found that, the
insecticidal activity decreased as the substituent on C-2 of thiadiazole is an electron rich
group as p-metoxyphenyl, aminofuran, dihydrothiophene, iminochromone, thiazolidene
and subimidazole moieties as in 11, 20, 22, 19, 6 and 9.
Generally, the insecticidal potency of the thiadiazole results from its interference with
the RNA in the processes of protein synthesis affected by the substituent position on
thiadiazole ring, as the electron withdrawing of the substituents group, the bioactivity of
the synthesized product also increases.[63] Finally, the bioactivity increases as the num-
ber of electron deficient groups increase and vice versa.
Conclusion
In summary, a novel of variant heterocyclic compounds incorporating 1,3,4-thiadiazole
moiety were synthesized and characterized efficiently. Eighteen compounds were eval-
uated for their insecticidal activity against cotton leaf worm (spodoptera littoralis). The
results of this evaluation imply that compounds 7, 10, 12 and 17 showed promising
insecticidal activity. In particular, compound 12 emerged the most potent insecti-
cidal activity.

R
SYNTHETIC COMMUNICATIONSV
13
Full experimental details and spectroscopic data for all synthesized compounds could
be found via the “Supplementary Content” section of this article’s webpage.
Experimental
The melting points were measured by utilizing Mel-Temp II melting point apparatus
and are uncorrected. IR spectra were recorded on Nicolet iS10 FT-IR spectrometer
(Thermo Scientific, Waltham, USA) by using the KBr wafer technique in the region
1
(400 ꢀ 4000 cmꢀ1). The H-NMR (at 400 MHz) and 13C-NMR (at 100 MHz) spectra
were implemented at chemical warfare labs, Cairo, Egypt, with a Varian Gemini spec-
trometer (International Equipment Trading Ltd., Mundelein, Illinois, USA) by using tet-
ramethylsilane (TMS) as a reference in DMSO-d6 as a solvent. CHN elemental analysis
was performed on Perkin-Elmer 2400 CHN elemental analyzer (PerkinElmer, Inc.,
Waltham, USA at Faculty of Science, Cairo University, Egypt). The mass spectrum was
performed on Shimadzu GC-MS QP1000EX apparatus (Shimadzu, Kyoto, Japan) at
Faculty of Science, El-Azhar University, Cairo, Egypt. All reactions were monitored by
thin layer chromatography (TLC) (Kieselgel 60 F254, Merck, Darmstadt, Germany) and
spots were visualized under UV lamp (Thomas Scientific, Swedesboro, New Jersey,
USA) (254 nm). The insecticidal activity assays were carried out at Central Agricultural
Pesticide Lab., Pesticide Formulations Department, Agricultural research Center,
Giza, Egypt.
2-Chloro-N-(2-(2-cyanoacetyl)hydrazine-1-carbonothioyl)benzamide 4
A mixture of 2-chlorobenzoyl chloride 1 (1.75 ml, 0.1 mol) and ammonium thiocyanate
(1.14 g, 0.15 mol) in 10 ml of acetonitrile was stirred at room temperature for 30 min,
follow filtration, then cyanoacetohydrazid 3 (0.99 g, 0.1 mol) was added to the filtrate
and 5 ml of acetonitrile was added, and the mixture was stirred at room temperature
for 4 h. The solid formed was filtrated, dried and then recrystallized from ethanol to
give 4 as white crystals; m.p.:193–195 ꢂC, yield: 55%. Anal. Calcd. for C11H9ClN4O2S
(296.73): C, 44.53; H, 3.06; Cl, 11.95; N, 18.88; S, 10.80. Found: C, 44.39; H, 2.97; Cl,
11.91; N, 18.91; S, 10.79. FTIR (KBr, ꢀ/cmꢀ1): 3375, 3217 (NH), 2953, 2915 (C–Haliph.),
2257 (CꢁN), 1700 (C¼O), 1244 (C¼S). MS m/z (%): 296 (M.þ; 26.65). 1H-NMR
(DMSO-d6) d (ppm): 12.24 (s, 1H, NH, exchangeable with D2O), 12.11 (s, 1H, NH,
exchangeable with D2O), 11.21 (s, 1H, NH, exchangeable with D2O), 7.60–7.41 (m, 4H,
Ar-H), 3.85 (s, 2H, CH2). 13C-NMR (DMSO-d6) d (ppm): 178.0, 167.6, 167.1, 134.4,
132.6, 131.9, 130.3, 129.7, 128.0, 127.5, 25.0.
2-Chloro-N-(5-(cyanomethyl)-1,3,4-thiadiazol-2-yl)benzamide 5
Compound 4 (2.96 g, 0.01 mol) was refluxed in glacial acetic acid (30 ml) for 4 h, the
reaction mixture was poured onto ice cold water. The precipitated solid was filtered off,
dried and then recrystallized from toluene to give 5 as white crystals; m.p.: 253–255 ꢂC,
yield: 73%. Anal. Calc. for C11H7ClN4OS (278.71): C, 47.40; H, 2.53; Cl, 12.72; N, 20.10;
S, 11.50. Found: C, 47.34; H, 2.49; Cl, 12.76; N, 20.01; S, 11.43. FTIR (KBr, ꢀ/cmꢀ1):

14
A. M. M. MOHAMED ET AL.
3160 (NH), 2942, 2915 (C–Haliph.), 2255 (CꢁN) 1667 (C ¼ O). MS m/z (%): 279
(M.þþ1;1.43). 1H-NMR (DMSO-d6) d (ppm): 13.26 (s, 1H, NH, exchangeable with
D2O), 7.69–7.67 (d, 1H, Ar-H, J ¼ 7.3 Hz), 7.59–7.48 (m, 3H, Ar-H), 4.61 (s, 2H, CH2).
13C-NMR (DMSO-d6) d (ppm): 160.0, 154.9, 149.0, 134.0, 132.7, 130.7, 130.3, 130.0,
127.7, 116.9, 18.8.
Insecticidal activity
Materials and methods
Cotton leaf worm strain
Susceptible strain of S. littoralis was mass reared in the laboratory under the higrother-
mic conditions of 25 2 ꢂC and 75 5% R.H. as described by El-Defrawi (1964) away
from any chemical pressure. The larvae were fed on castor oil-bean leaves (Ricinus com-
munis L.) and kept in 1-litre glass jars covered with muslin which fixed tightly by a rub-
ber band. The number of larvae per jar was differed according to the developing instar.
After pupation, the resulting pupae were sexed and grouped in groups of 12 pupae at a
sex ratio of 2$: 1# and then placed in the glass jar. After the emergence of the moths,
they were supplied with a piece of cotton moistened with 10% sugar solution and paper
strips to act as sites for egg deposition. The deposited egg masses were daily collected
and left till hatching. The newly hatched larvae were transferred to clean jar and sup-
plied with fresh leaves.[64,65]
Chemical used
The newly synthesized thiadiazole heterocyclic compounds.
Bioassay technique
The leaf-dipping bioassay method was used to determine the median lethal concentra-
tion (LC50) values. A stock solution of each chemical was freshly prepared. Subsequent
water dilutions were made to get series of concentrations of 250,500, 750, 1000, 1250
and 1500 ppm of the tested compounds. Castor-bean leaves were dipped for 30 seconds
in each concentration then left for one hour to dry. The treated leaves were offered to
newly molted 4th instar larvae of susceptible strain. Mortality percentages were recorded
after 24 hrs and corrected according to Abbott (1925).[66] To estimate the LC50 values,
the data were analyzed using an adopted computer program based on a standard imple-
[67]
mentation of the probit analysis recommended by Finney (1971).
calculated according to Yun-Pei Sun equation.[68]
The toxicity index
Toxicity index ¼ LC50of most potent compound=LC50of tested compound ꢃ 100
ORCID
Mahmoud F. Ismail
http://orcid.org/0000-0002-9243-6236

R
SYNTHETIC COMMUNICATIONSV
15
References
[1] Luo, Y. P.; Yang, G. F. Discovery of a New Insecticide Lead by Optimizing a Target-
Diverse Scaffold: Tetrazolinone Derivatives. Bioorg. Med. Chem. 2007, 15, 1716–1724.
DOI: 10.1016/j.bmc.2006.12.002.
[2] Hiroshi, K.; Rokuro, S.; Isao, H.; Takuo, O. Herbicidal Activity of 1,3,4-Thiadiazole
Derivatives. J. Agric. Food Chem. 1970, 18, 60–65.
[3] Mahmoud, M. R.; Shiba, S. A.; El-Ziaty, A. K.; Abu El-Azm, F. S. M.; Ismail, M. F.
Synthesis and Reactions of Novel 2,5-Disubstituted 1,3,4-Thiadiazoles. Synth. Commun.
2014, 44, 1094–1102. DOI: 10.1080/00397911.2013.846381.
[4] Mahmoud, M. R.; Ismail, M. F. Recent Developments in Chemistry of 1,3,4-Thiadiazoles.
Jac. 2014, 10, 2812–2842. DOI: 10.24297/jac.v10i6.5507.
[5] Farghaly, T. A.; Abdallah, M. A.; Aziz, M. R. A. Synthesis and Antimicrobial Activity of
Some New 1,3,4-thiadiazole Derivatives. Molecules. 2012, 17, 14625–14636. DOI: 10.3390/
molecules171214625.
[6] El-Gohary, N. S.; Shaaban, M. I. Synthesis, Antimicrobial, Antiquorum-Sensing,
Antitumor and Cytotoxic Activities of New Series of Fused [1,3,4]Thiadiazoles. Eur. J.
Med. Chem. 2013, 63, 185–195. DOI: 10.1016/j.ejmech.2013.02.010.
[7] Sah, P.; Bidawat, P.; Seth, M.; Gharu, C. P. Synthesis and Biological Significances of 1,3,4-
Thiadiazolines and Related Heterocyclic Compounds. Arabian. J. Chem. 2014, 7, 181–187.
DOI: 10.1016/j.arabjc.2010.10.023.
€
_
ꢀ
[8] Gu€r, M.; S¸ener, N.; Muglu, H.; C¸avu¸s, M. S.; Ozkan, O. E.; Kandemirli, F.; S¸ener, I. S¸ener,
I. New 1,3,4-Thiadiazole Compounds Including Pyrazine Moiety: Synthesis, Structural
Properties and Antimicrobial Features. J. Mol. Struct. 2017, 1139, 111–118. DOI: 10.1016/
j.molstruc.2017.03.019.
€
ꢀ
[9] Gu€r, M.; S¸ener, N.; Ka¸sta¸s, C¸. A.; Ozkan, O. E.; Muglu, H.; Elmaswari, M. A. M. Synthesis
and Characterization of Some New Heteroaromatic Compounds Having Chirality
Adjacent to a 1,3,4-Thiadiazole Moiety and Their Antimicrobial Activities. J. Heterocyclic.
Chem. 2017, 54, 3578–3590. DOI: 10.1002/jhet.2984.
[10] Sekhar, M. M.; Nagarjuna, U.; Padmavathi, V.; Padmaja, A.; Reddy, N. V.; Vijaya, T.
Synthesis and Antimicrobial Activity of Pyrimidinyl 1,3,4-Oxadiazoles, 1,3,4-Thiadiazoles
and 1,2,4-Triazoles. Eur. J. Med. Chem. 2018, 145, 1–10. DOI: 10.1016/j.ejmech.2017.12.
067.
[11] Chen, C. J.; Song, B. A.; Yang, S.; Xu, G. F.; Bhadury, P. S.; Jin, L. H.; Hu, D. Y.; Li,
Q. Z.; Liu, F.; Xue, W.; et al. Synthesis and Antifungal Activities of 5-(3,4,5-
Trimethoxyphenyl)-2-Sulfonyl-1,3,4-Thiadiazole
and
5-(3,4,5-Trimethoxyphenyl)-2-
Sulfonyl-1,3,4-Oxadiazole Derivatives. Bioorg. Med. Chem. 2007, 15, 3981–3989. DOI: 10.
1016/j.bmc.2007.04.014.
[12] Zuo, X.; Mi, N.; Fan, Z. J.; Zheng, Q. X.; Zhang, H. K.; Wang, H.; Yang, Z. K. Synthesis
of 4-Methyl-1,2,3-Thiadiazole Derivatives via Ugi Reaction and Their Biological Activities.
J. Agric. Food Chem. 2010, 58, 2755–2762. DOI: 10.1021/jf902863z.
ꢁ
ꢂ
[13] Zoumpoulakis, P.; Camoutsis, C.; Pairas, G.; Sokovic, M.; Glamoclija, J.; Potamitis, C.;
Pitsas, A. Synthesis of Novel Sulfonamide-1,2,4-Triazoles, 1,3,4-Thiadiazoles and 1,3,4-
Oxadiazoles, as Potential Antibacterial and Antifungal Agents. Biological Evaluation and
Conformational Analysis Studies. Bioorg. Med. Chem. 2012, 20, 1569–1583. DOI: 10.1016/
j.bmc.2011.12.031.
[14] Zhang, L.-J.; Yang, M.-Y.; Sun, Z.-H.; Tan, C.-X.; Weng, J.-Q.; Wu, H.-K.; Liu, X.-H.
Synthesis and Antifungal Activity of 1,3,4-Thiadiazole Derivatives Containing Pyridine
Group. Lddd. 2014, 11, 1107–1111. DOI: 10.2174/1570180811666140610212731.
[15] Othman, A. A.; Kihel, M.; Amara, S. 1,3,4-Oxadiazole, 1,3,4-Thiadiazole and 1,2,4-Triazole
Derivatives as Potential Antibacterial Agents. Arab. J. Chem 2019, 12, 1660–1675, DOI:
10.1016/j.arabjc.2014.09.003.
[16] Li, P.; Shi, L.; Gao, M. N.; Yang, X.; Xue, W.; Jin, L. H.; Hu, D. Y.; Song, B. A.
Antibacterial Activities against Rice Bacterial Leaf Blight and Tomato Bacterial Wilt of

16
A. M. M. MOHAMED ET AL.
2-Mercapto-5-Substituted-1,3,4-Oxadiazole/Thiadiazole Derivatives. Bioorg. Med. Chem.
Lett. 2015, 25, 481–484. DOI: 10.1016/j.bmcl.2014.12.038.
[17] Yu, P.; Hu, J.; Zhou, T. Y.; Wang, P.; Xu, Y. H. Synthesis, Insecticidal Evaluation of Novel
1,3,4-Thiadiazole Chrysanthemamide Derivatives Formed by EDCI/HOBt Condensation.
J. Chem. Res. (S). 2011, 35, 703–706. DOI: 10.3184/174751911X13230201951890.
[18] Wan, R.; Zhang, J. Q.; Han, F.; Wang, P.; Yu, P.; He, Q. Synthesis and Insecticidal
Activities of Novel 1,3,4-Thiadiazole 5-Fluorouracil Acetamides Derivatives: An RNA
Interference Insecticide. Nucleosides Nucleotides Nucleic Acids. 2011, 30, 280–292. DOI:
10.1080/15257770.2011.580811.
[19] Hu, Y.; Li, C. Y.; Wang, X. M.; Yang, Y. H.; Zhu, H. L. 1,3,4-Thiadiazole: Synthesis,
Reactions, and Applications in Medicinal, Agricultural, and Materials Chemistry. Chem.
Rev. 2014, 114, 5572–5610. DOI: 10.1021/cr400131u.
[20] Fadda, A. A.; El Salam, M. A.; Tawfik, E. H.; Anwar, E. M.; Etman, H. A. Synthesis and
Insecticidal Assessment of Some Innovative Heterocycles Incorporating a Thiadiazole
Moiety against the Cotton Leafworm. RSC Adv. 2017, 7, 39773–39785. DOI: 10.1039/
C7RA06087D.
[21] Dai, H.; Li, G.; Chen, J.; Shi, Y.; Ge, S.; Fan, C.; He, H. Synthesis and Biological Activities
of Novel 1,3,4-thiadiazole-containing pyrazole oxime derivatives. Bioorg. Med. Chem. Lett.
2016, 26, 3818–3821. DOI: 10.1016/j.bmcl.2016.04.094.
[22] Li, Z. S.; Wang, W. M.; Lu, W.; Niu, C. W.; Li, Y. H.; Li, Z. M.; Wang, J. G. Synthesis
and Biological Evaluation of Nonsymmetrical Aromatic Disulfides as Novel Inhibitors of
Acetohydroxyacid Synthase. Bioorg. Med. Chem. Lett. 2013, 23, 3723–3727. DOI: 10.1016/
j.bmcl.2013.05.013.
_
[23] Juszczak, M.; Matysiak, J.; Szeliga, M.; Pozarowski, P.; Niewiadomy, A.; Albrecht, J.;
Rzeski, W. 2-amino-1,3,4-Thiadiazole Derivative (FABT) Inhibits the Extracellular Signal-
Regulated Kinase Pathway and Induces Cell Cycle Arrest in Human Non-Small Lung
Carcinoma Cells. Bioorg. Med. Chem. Lett. 2012, 22, 5466–5469. DOI: 10.1016/j.bmcl.
2012.07.036.
[24] Aliabadi, A.; Eghbalian, E.; Kiani, A. Synthesis and Evaluation of the Cytotoxicity of a
Series of 1,3,4-Thiadiazole Based Compounds as Anticancer Agents. Iran. J. Basic Med.
Sci. 2013, 16, 1133–1138.
[25] Mohammadi-Farani, A.; Heidarian, N.; Aliabadi, A. N-(5-Mercapto-1,3,4-Thiadiazol-2-yl)-
2-Phenylacetamide Derivatives: Synthesis and In-Vitro Cytotoxicity Evaluation as Potential
Anticancer Agents. Iran. J. Pharm. Res. 2014, 13, 487–492.
[26] Polkam, N.; Rayam, P.; Anireddy, J. S.; Yennam, S.; Anantaraju, H. S.; Dharmarajan, S.;
Perumal, Y.; Kotapalli, S. S.; Ummanni, R.; Balasubramanian, S. Synthesis, in Vitro
Anticancer and Antimycobacterial Evaluation of New 5-(2,5-Dimethoxyphenyl)-1,3,4-
Thiadiazole-2-Amino Derivatives. Bioorg. Med. Chem. Lett. 2015, 25, 1398–1402. DOI: 10.
1016/j.bmcl.2015.02.052.
[27] Dawood, K. M.; Gomha, S. M. Synthesis and Anticancer Activity of 1,3,4-Thiadiazole
Derivatives Having 1,3,4-Oxadiazole Moiety. J. Heterocyclic Chem. 2015, 52, 1400–1405.
DOI: 10.1002/jhet.2250.
[28] Sunil, D.; Isloor, A. M.; Shetty, P.; Satyamoorthy, K.; Prasad, A. S. B. 6-[3-(4-
Fluorophenyl)-1H-Pyrazol-4-yl]-3-[(2-Naphthyloxy)Methyl][1,2,4]Triazolo[3,4-
b][1,3,4]Thiadiazole as a Potent Antioxidant and an Anticancer Agent Induces Growth
Inhibition Followed by Apoptosis in HepG2 Cells. Arabian. J. Chem. 2010, 3, 211–217.
DOI: 10.1016/j.arabjc.2010.06.002.
ꢀ
€
[29] Gu€r, M.; Muglu, H.; C¸avu¸s, M. S.; Guder, A.; Sayıner, H. S.; Kandemirli, F. Synthesis,
Characterization, Quantum Chemical Calculations and Evaluation of Antioxidant
Properties of 1,3,4-Thiadiazole Derivatives Including 2- and 3-Methoxycinnamic Acids.
J. Mol. Struct. 2017, 1134, 40–50. DOI: 10.1016/j.molstruc.2016.12.041.
[30] Chen, Z.; Xu, W.; Liu, K.; Yang, S.; Fan, H.; Bhadury, P. S.; Hu, D.-Y.; Zhang, Y.
Synthesis and Antiviral Activity of 5-(4-chlorophenyl)-1,3,4-thiadiazole sulfonamides.
Molecules. 2010, 15, 9046–9056. DOI: 10.3390/molecules15129046.

R
SYNTHETIC COMMUNICATIONSV
17
[31] Ragab, F. A.; Heiba, H. I.; El-Gazzar, M. G.; Abou-Seri, S. M.; El-Sabbagh, W. A.; El-
Hazek, R. M. Anti-Inflammatory, Analgesic and COX-2 Inhibitory Activity of Novel
Thiadiazoles in Irradiated Rats. J. Photochem. Photobiol. B. Biol. 2017, 166, 285–300. DOI:
10.1016/j.jphotobiol.2016.12.007.
[32] Kadi, A. A.; Al-Abdullah, E. S.; Shehata, I. A.; Habib, E. E.; Ibrahim, T. M.; El-Emam,
A. A. Synthesis, Antimicrobial and Anti-Inflammatory Activities of Novel 5-(1-
Adamantyl)-1,3,4-Thiadiazole Derivatives. Eur. J. Med. Chem. 2010, 45, 5006–5011. DOI:
10.1016/j.ejmech.2010.08.007.
[33] Alegaon, S. G.; Alagawadi, K. R.; Sonkusare, P. V.; Chaudhary, S. M.; Dadwe, D. H.; Shah,
A. S. Novel Imidazo[2,1-b][1,3,4]Thiadiazole Carrying Rhodanine-3-Acetic Acid as
Potential Antitubercular Agents. Bioorg. Med. Chem. Lett. 2012, 22, 1917–1921. DOI: 10.
1016/j.bmcl.2012.01.052.
[34] Bhatia, R.; Sharma, A.; Kaundal, A. A. Review on 1, 3, 4-Thiadiazole Derivatives. Indian J.
Pharm. Sci. Res. 2014, 4, 165–172.
[35] Raj, V.; Rai, A.; Singh, M.; Kumar, A.; Kumar, V.; Sharma, S. K. Recent Update on 1,3,4-
Thiadiazole Derivatives: As Anticonvulsant Agents. EC. Pharm. Sci. 2015, 2, 202–229.
ꢁ
[36] Luszczki, J. J.; Karpinska, M.; Matysiak, J.; Niewiadomy, A. Characterization and
Preliminary Anticonvulsant Assessment of Some 1,3,4-Thiadiazole Derivatives. Pharmacol.
Rep. 2015, 67, 588–592. DOI: 10.1016/j.pharep.2014.12.008.
[37] Pattan, S. R.; Kekare, P.; Dighe, N. S.; Nirmal, S. A.; Musmade, D. S.; Parjane, S. K.;
Daithankar, A. V. Synthesis and Biological Evaluation of Some 1,3,4-Thiadiazoles.
J. Chem. Pharm. Res. 2009, 1, 191–198.
[38] Yusuf, M.; Khan, R. A.; Ahmed, B. Syntheses and anti-Depressant Activity of 5-Amino-
1,3,4-Thiadiazole-2-Thiol Imines and Thiobenzyl Derivatives. Bioorg. Med. Chem. 2008,
16, 8029–8034. DOI: 10.1016/j.bmc.2008.07.056.
[39] Clerici, F.; Pocar, D.; Guido, M.; Loche, A.; Perlini, V.; Brufani, M. Synthesis of 2-Amino-
5-Sulfanyl-1,3,4-Thiadiazole Derivatives and Evaluation of Their Antidepressant and
Anxiolytic Activity. J. Med. Chem. 2001, 44, 931–936. DOI: 10.1021/jm001027w.
[40] Kaur, H.; Kumar, S.; Vishwakarma, P.; Sharma, M.; Saxena, K. K.; Kumar, A. Synthesis
and Antipsychotic and Anticonvulsant Activity of Some New Substituted Oxa/
Thiadiazolylazetidinonyl/Thiazolidinonylcarbazoles. Eur. J. Med. Chem. 2010, 45,
2777–2783. DOI: 10.1016/j.ejmech.2010.02.060.
[41] Hasui, T.; Matsunaga, N.; Ora, T.; Ohyabu, N.; Nishigaki, N.; Imura, Y.; Igata, Y.; Matsui,
H.; Motoyaji, T.; Tanaka, T.; et al. Identification of Benzoxazin-3-One Derivatives as
Novel, Potent, and Selective Nonsteroidal Mineralocorticoid Receptor Antagonists. J. Med.
Chem. 2011, 54, 8616–8631. DOI: 10.1021/jm2011645.
[42] Gupta, J. K.; Yadav, R. K.; Dudhe, R.; Sharma, P. K. Recent Advancements in the
Synthesis and Pharmacological Evaluation of Substituted 1,3,4-Thiadiazole Derivatives. Int.
J. Pharmtech. Res. 2010, 2, 1493–1507.
[43] Balaji, K.; Bhatt, P.; Mallika, D.; Jha, A. Design, Synthesis and Antimicrobial Evaluation of
Some Mannich Base Derivative of 2(2-Substituted)-5-Aminothiadiazoles. Int. J. Pharm.
Pharm. Sci. 2015, 7, 145–149.
[44] Yadagiri, B.; Gurrala, S.; Bantu, R.; Nagarapu, L.; Polepalli, S.; Srujana, G.; Jain, N.
Synthesis and Evaluation of Benzosuberone Embedded with 1,3,4-Oxadiazole, 1,3,4-
Thiadiazole and 1,2,4-Triazole Moieties as New Potential anti Proliferative Agents. Bioorg.
Med. Chem. Lett. 2015, 25, 2220–2224. DOI: 10.1016/j.bmcl.2015.03.032.
[45] Gomha, S. M.; Kheder, N. A.; Abdelhamid, A. O.; Mabkhot, Y. N. One Pot Single Step
Synthesis and Biological Evaluation of Some Novel Bis(1,3,4-Thiadiazole) Derivatives as
Potential Cytotoxic Agents. Molecules. 2016, 21, 1532–1839. DOI: 10.3390/
molecules21111532.
[46] Zhong, X.; Wang, X.; Chen, L.; Ruan, X.; Li, Q.; Zhang, J.; Chen, Z.; Xue, W. Synthesis
and Biological Activity of Myricetin Derivatives Containing 1,3,4-Thiadiazole Scaffold.
Chem. Cent. J. 2017, 11, 106DOI: 10.1186/s13065-017-0336-7.

18
A. M. M. MOHAMED ET AL.
[47] Xu, W. M.; Han, F. F.; He, M.; Hu, D. Y.; He, J.; Yang, S.; Song, B. A. Inhibition of
Tobacco Bacterial Wilt with Sulfone Derivatives Containing an 1,3,4-oxadiazole moiety. J.
Agric. Food Chem. 2012, 60, 1036–1041. DOI: 10.1021/jf203772d.
[48] Wang, P. Y.; Zhou, L.; Zhou, J.; Wu, Z. B.; Xue, W.; Song, B. A.; Yang, S. Synthesis and
Antibacterial Activity of Pyridinium-Tailored 2,5-Substituted-1,3,4oxadiazole Thioether/
Sulfoxide/Sulfone Derivatives. Bioorgan. Med. Chem. Lett 2016, 26, 1214–1217. DOI: 10.
1016/j.bmcl.2016.01.029.
[49] Wang, X.; Li, P.; Li, Z.; Yin, J.; He, M.; Xue, W.; Chen, Z.; Song, B. Synthesis and
Bioactivity Evaluation of Novel Arylimines Containing
a
3-Aminoethyl-2[(q-
Trifluoromethoxy)Anilino]-4(3H)-Quinazolinone Moiety. J. Agric. Food. Chem. 2013, 61,
9575–9582. DOI: 10.1021/jf403193q.
[50] Chen, M. H.; Wang, X. B.; Tang, B. C.; Zhang, X. Synthesis and Antibacterial Evaluation
of Novel Schiff Base Derivatives Containing 4(3H)-Quinazolinone Moiety. Chem. Pap.
2016, 70, 1521–1528.
[51] Abu El-Azm, F. S. M.; El-Shahawi, M. M.; Elgubbi, A. S.; Madkour, H. M. F. Design,
Synthesis, anti-Proliferative Activity, and Molecular Docking Studies of Novel
Benzo[f]Chromene,
Chromeno
[2,3-d]Pyrimidines
and
Chromenotriazolo[1,5-
c]Pyrimidines. Synth. Commun. 2020, 50, 669–683. DOI: 10.1080/00397911.2019.1710850.
[52] Khlosy, T. A.; Salem, M. S.; Ali, A. T.; Madkour, H. M. F. Synthesis and Cytotoxic
Activity against Human Tumor Cells of Heterocyclic Systems Derived from 2-Thioxo-1,2-
Dihydro-4H-3,1-Benzothazin-4-One. J. Heterocyclic Chem. 2020, 57, 60–68. DOI: 10.1002/
jhet.3745.
[53] Salem, M. S.; Hussein, R. A.; El-Sayed, W. M. Substitution at Phenyl Rings of Chalcone
and Schiff Base Moieties Accounts for Their Antiproliferative Activity. Anticancer Agents
Med. Chem. 2019, 19, 620–626. DOI: 10.2174/1871520619666190225122338.
[54] Madkour, H. M. F.; El-Hashash, M. A. E. M.; Salem, M. S.; Mahmoud, A.-S. O. A.
Synthesis, Antileishmanial and Cytotoxicity Activities of Fused and Nonfused
Tetrahydroquinoline Derivatives. Res. Chem. Intermed. 2018, 44, 3349–3364. DOI: 10.
1007/s11164-018-3311-6.
[55] Zarei, M. One-Pot Synthesis of 1,3,4-Thiadiazoles Using Vilsmeier Reagent as a Versatile
Cyclodehydration Agent. Tetrahedron. 2017, 73, 1867–1872. DOI: 10.1016/j.tet.2017.02.
042.
[56] Shahcheragh, S. M.; Habibi, A.; Khosravi, S. Straightforward Synthesis of Novel
Substituted 1,3,4-Thiadiazole Derivatives in Choline Chloride-Based Deep Eutectic
Solvent. Tetrahedron. Lett. 2017, 58, 855–859. DOI: 10.1016/j.tetlet.2017.01.057.
[57] Ali, Y. M.; Ismail, M. F.; Abu El-Azm, F. S. M.; Marzouk, M. I. Design, Synthesis and
Pharmacological Assay of Novel Compounds Based on Pyridazine Moiety as Potential
Antitumor Agents. J. Heterocyclic Chem. 2019, 56, 2580–2591. DOI: 10.1002/jhet.3662.
[58] Ismail, M. F.; Elsayed, G. A. Dodecanoyl Isothiocyanate and N’-(2-
Cyanoacetyl)Dodecanehydrazide as Precursors for the Synthesis of Different Heterocyclic
Compounds with Interesting Antioxidant and Antitumor Activity. Synth. Commun. 2018,
48, 892–905. DOI: 10.1080/00397911.2018.1428345.
[59] Mahmoud, M. R.; El-Ziaty, A. K.; Abu El-Azm, F. S. M.; Ismail, M. F.; Shiba, S. A. Utility
of cyano-N-(2-Oxo-1,2-Dihydroindol-3-Ylidene)Acetohydrazide in the Synthesis of Novel
Heterocycles. J. Chem. Res. 2013, 37, 80–85. DOI: 10.3184/174751912X13567100793191.
[60] Ismail, M. F.; El-Sayed, A. A. Synthesis and in-Vitro Antioxidant and Antitumor
Evaluation of Novel Pyrazole-Based Heterocycles. J. Iran. Chem. Soc. 2019, 16, 921–937.
DOI: 10.1007/s13738-018-1566-x.
[61] Hamed, N. A.; Marzouk, M. I.; Ismail, M. F.; Hekal, M. H. N’-(1-([1,1’-Biphenyl]-4-
yl)Ethylidene)-2-Cyanoacetohydrazide as Scaffold for the Synthesis of Diverse Heterocyclic
Compounds as Prospective Antitumor and Antimicrobial Activities. Synth. Commun.
2019, 49, 1–3029. DOI: 10.1080/00397911.2019.1655578.

R
SYNTHETIC COMMUNICATIONSV
19
[62] Salman, A. S.; Mahmoud, N. A.; Abdel-Aziem, A.; Mohamed, M. A.; Elsisi, D. M.
Synthesis, Reactions and Antimicrobial Activity of Some New 3-Substituted Indole
Derivatives. IJOC. 2015, 05, 81–99. DOI: 10.4236/ijoc.2015.52010.
[63] Madkour, H. M. F.; Azab, M. E.; Aly, A. F.; Khamees, M. S. M. Novel Heterocycles Based
on 1,3,4-Thiadiazole Scaffold as Insecticides. J. Environ. Sci. 2017, 40, 19–44. DOI: 10.
21608/jes.2017.20047.
[64] Ali, H. A.; Kordy, A. M.; Khaled, A. E.; Hassan, N. A.; Abdelsalam, N. R. Efficiency of
Using Some New Insecticides against Cotton Leaf Worm (Spodopteralittoralis) Based on
Biochemical and Molecular Markers. Alexandria Sci. Exchange. J. 2015, 36, 303–313.
[65] Eldefrawi, M. E.; Toppozada, A. T.; Salama, A.; ElKishen, S. A. Toxicological Studies on
the Egyptian Cotton Leaf Worm, Prodenia Litura FII. Reversion of Toxaphene Resistance
in the Egyptian Cotton Leafworm. J. Econ. Entomol. 1964, 57, 593–595. DOI: 10.1093/jee/
57.4.593.
[66] Abbott, W. S. A Method of Computing the Effectiveness of an Insecticide. J. Econ.
Entomol. 1925, 18, 265–267. DOI: 10.1093/jee/18.2.265a.
[67] Finney, D. J. Probit Analysis. 3rd ed.; Cambridge University Press: Cambridge, England,
1971.
[68] Sun, Y.-P.; Hyman, J.; Denver, C. Toxicity Index-An Improved Method of Comparing
the Relative Toxicity of Insecticides. J. Econ. Entomol 1950, 43, 45–53. DOI: 10.1093/jee/
43.1.45.