DOI: 10.1002/slct.

201900814 Full Papers

1
2 z Medicinal Chemistry & Drug Discovery
3
4
5
Synthesis, Biological Evaluation and In Silico Studies of
6 1,2,4-Triazole and 1,3,4-Thiadiazole Derivatives as
7
8 Antiherpetic Agents
9
10 Hebat-Allah M. Goma’a,[a] Mariam A. Ghaly,*[b] Laila A. Abou-zeid,[a, c] Farid A. Badria,[d]
11 Ihsan A. Shehata,[b] and Mohamed M. El-Kerdawy[b]
12
13
14 Two isosteric series of 1,2,4-triazole and 1,3,4-thiadiazole interestingly, retained high selectivity compared to ACV (>
15 derivatives were designed and synthesized in this work to be 200 μM vs. 80 μM). The best effective and safe compound in
16 evaluated for their antiviral activity. Compounds 2–9 and 11– this study, 7, was further tested for its combined effects with
17 19 were synthesized and their antiviral activity was tested ACV on the anti-HSV-1 activity in the plaque reduction assay.
18 against herpes simplex virus type 1, HSV-1, using acyclovir, Compound 7 proved to improve the selectivity of ACV and
19 ACV, as a reference drug. In addition, molecular docking into reduce its effective dose that produced 100% inhibition of viral
20 the active site of HSV-1 thymidine kinase was performed to plaques. The triazolopyrimidine 7 is suggested to be a
21 interpret the data obtained from biological testing, and all promising candidate for further development as an antiherpetic
22 compounds were subjected to an in silico screening of their agent. Molecular docking into the active site of HSV-1
23 physicochemical properties to estimate their drug-likeness and thymidine kinase emphasized the superior interaction of
24 safety. The results revealed that compound 7 was able to compound 7.
25 reduce the viral plaques by 50% at a dose of 80 μM, but
26
27 1. Introduction
lated by cellular kinases to the corresponding triphosphate that
28
Herpes simplex viruses (HSV) are enveloped DNA viruses[1] inhibits DNA synthesis after incorporation into nascent DNA.[7]
29
including, among others, herpes simplex virus type 1 (HSV-1; However, resistance can occur through deletion of the viral
30
oral herpes), and herpes simplex virus type 2 (HSV-2; genital thymidine kinase gene, alteration of viral thymidine kinase
31
herpes).[2] HSV-1 is a common harmful pathogen.[3] It mainly resulting in less efficient phosphorylation of acyclovir, or
32
invades the neuronal part of the human body, and establishes alteration of viral DNA polymerase resulting in decreased
33
lifelong latent infection in the sensory neurons, with recurrent inhibition by acyclovir triphosphate.[8] Moreover, as the kidneys
34
lesions upon reactivation.[4] HSV-1 also causes genital herpes, are the principal route of ACV elimination, its dose should be
35
increasing the risk of transmission and acquisition of HIV reduced in cases of renal impairment.[8] Therefore, there is an
36
infection.[5] urgent need to develop new alternatives to ACV against HSV-
37
A number of antiviral drugs are available in the market, 1.[9]
38
among them, acyclovir, ACV, I, is the most commonly used as In our attempt to prepare new antiviral agents, two series
39
antiherpetic treatment.[6] Once phosphorylated by HSV-1 based upon 1,2,4-triazole and 1,3,4-thiadizole ring were synthe-
40
thymidine kinase, this nucleoside analog is further phosphory- sized. All prepared compounds contain an isosteric ring to the
41
five-membered imidazole ring present in ACV in order to
42
investigate the effect of this substitution on the antiviral
43
[a] H.-A. M. Goma’a, Dr. L. A. Abou-zeid activity. The unique structure of triazole ring with its three
44 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Delta nitrogen atoms and electron rich system makes triazole
45 University for Science and Technology, Gamasa City 11152, Egypt
derivatives readily bind with a variety of enzymes and
46 [b] Dr. M. A. Ghaly, Prof. I. A. Shehata, Prof. M. M. El-Kerdawy
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura receptors.[10] As for 1,3,4-thiadiazole moiety, it is characterized
47
University, Mansoura 35516, Egypt by a great in vivo stability making its derivatives biocompatible
48 Tel.: + 20 502200242 lacking toxicity.[11] Compounds 7, 8, 17, and 18 have the above
49 E-mail: mariamaghaly2@yahoo.com
mentioned rings fused as triazolopyrimidines and thiadiazolo-
50 mariamaghaly@mans.edu.eg
[c] Dr. L. A. Abou-zeid pyrimidines to attain structure similarity to purine bases and to
51
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, ACV, while in the rest of compounds, the pyrimidine ring was
52 Mansoura University, Mansoura 35516, Egypt dissected in order to test the effect of simplifying the structure
53 [d] Prof. F. A. Badria
on the antiherpetic activity. Meanwhile, the latter structures
54 Department of Pharmacognosy, Faculty of Pharmacy, Mansoura Univer-
sity, Mansoura 35516, Egypt incorporate other moieties reported to have anti-HSV-1 activity,
55
Supporting information for this article is available on the WWW under such as phenylthiourea,[12] and acid hydrazide moiety.[13]
56
https://doi.org/10.1002/slct.201900814
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2. Results and discussion 3 a,b and 13 a,b. The 1H-NMR spectra of 3 a,b showed singlet
1
signals at δ 7.28 and 7.52 ppm, respectively, each integrated
2 2.1. Chemistry
for two protons of the NH2 group attached to the triazole ring.
3
The designed compounds were synthesized as illustrated in Meanwhile, the 1H-NMR spectra of 13 a,b illustrated singlet
4
Schemes 1 and 2. The starting agents ethyl 2-((5-amino-1H- signals at δ 11.06 and 11.13 ppm, respectively, each integrated
5
for one proton of the NH-CO attached to the thiadiazole ring.
6
In addition, the aromatic protons and the proton of CONH Ar
7
appeared at the expected regions.
8
The amine functions of compounds 2 and 12 reacted with
9
phenyl isothiocyanate in dry DMF, adopting a reported
10
procedure to prepare thiourea derivatives,[17] to give com-
11
pounds 4 and 14, respectively. The structures of the latter
12
compounds were confirmed by 1H-NMR, 13C-NMR and EI-MS.
13
Compound 14 was further refluxed with chloroacetyl chloride
14
in dry toluene to give (E)-ethyl 2-((5-((4-oxo-3-phenylthiazoli-
15
din-2-ylidene)amino)-1,3,4-thiadiazol-2-yl)thio)acetate 15. For
16
compound 15, the two protons of CH2 of the thiazolidinone
17
ring were observed at δ 4.27 ppm, 13C-NMR signals correspond-
18
ing to O=C-N and CH2-CO N appeared at the expected regions.
19
20
21
22
23
24
25
26
Scheme 1. Synthesis of triazole derivatives, compounds 2–9.
27
28
29
30
31
32 Figure 1. Structure of acyclovir (I)
33
34
35
As reported for obtaining acid hydrazides,[18] treating the
36
ester groups in 2 and 12 with hydrazine hydrate in absolute
37
ethanol afforded 5 and 16, respectively. Spectral data (1H-NMR
38
and 13C-NMR) showed full agreement with their structures. The
39
disappearance of the 1H-NMR and 13C-NMR signals correspond-
40
ing to CH3-CH2-O in both 5 and 16 confirmed their structures.
41
Following a reported procedure,[19] compound 5 undergoes
42
cyclocondensation with CS2 in alcoholic KOH solution to obtain
43
the oxadiazole-thione analog 6, whose 13C-NMR spectrum
44 Scheme 2. Synthesis of thiadiazole derivatives, compounds 11–19. showed a new peak for C=S at 180.15 ppm.
45
Ethyl-2-((6-(2-chloroethyl)-5-methyl-7-oxo-1,7-dihydro-
46
[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)thio)acetate 7, and ethyl-2-
47
1,2,4-triazol-3-yl)thio)acetate 2, and ethyl 2-((5-amino-1,3,4- ((6-(2-chloroethyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-
48
thiadiazol-2-yl)thio)acetate 12 were prepared through alkyla- 2-yl)thio)acetate 17 were prepared by the cyclocondensation of
49
tion of the thiol functional group of 1 and 11 respectively using 2 and 12, respectively, with α-acetyl-γ-butyrolactone in POCl3
50
ethyl chlolroacetate, in the presence of either anhydrous K2CO3 in accordance with the method described in the literature.[20]
51
in dry dimethyl formamide to obtain 2,[14] or KOH in absolute New 1H-NMR and 13C-NMR signals for CH3, CH2CH2Cl, N-CO and
52
ethanol to obtain 12.[15] N-C=C-NH appeared at the expected regions approving the
53
The phenylurea derivatives 3 a,b and 13 a,b were obtained structures of 7 and 17. The mass spectral data of the
54
analogously to the method described in the literature[16] synthesized compound 7 displayed molecular ion peak con-
55
through refluxing 2 and 12 with the appropriate phenyl firming its structure.
56
isocyanate in methylene chloride to correspondingly obtain
57

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Furthermore, following a reported procedure to cyclize Table 1. Antiviral and cytotoxicity results.
1
aminoheterocycles,[21,22] the amine groups of 2 and 12 were
2 Compound % Reduction of plaques Cytotoxicity (μg/mL)
treated with diethyl ethoxymethylenemalonate (DEEM) in No. (μM)* (CD50)
3
glacial acetic acid under reflux to cyclize and correspondingly
4 2 ……. 30 + 0.031 μM
produce compounds 8 and 18. Both structures were assured by
5 3a …………. 100 + 0.016 μM
the spectral data (1H-NMR, 13C-NMR and EI-MS). 3b 8% at 80 + 0.063 μM 120 + 0.024 μM
6
In addition, compounds 9 and 19 were correspondingly 4 20% at 80 + 0.043 μM 160 + 0.014 μM
7
provided by the reaction of 2 and 12 with chloroacetyl chloride 5 …………. > 200 + 0.015 μM
8 6 …………. 70 + 0.018 μM
in dry toluene in the presence of anhydrous K2CO3. Both
9 7 50% at 80 + 0.006 μM > 200 + 0.008 μM
structures were established on the basis of spectral data. For 8 20% at 80 + 0.009 μM > 200 + 0.002 μM
10
example, new signals, each integrated for one proton, 9 10% at 80 + 0.014 μM 160 + 0.070 μM
11
appeared in the 1H-NMR spectra of 9 and 19 at δ 13.6 and 12 ……… 80 + 0.011 μM
12 13a ………. > 200 + 0.320 μM
13.04, respectively, corresponding to NH-C=O. Also, 1H and 13C
13 13b ………. > 200 + 0.020 μM
signals of CH2-Cl appeared at the expected regions. 14 ………. > 200 + 0.042 μM
14
Reagents and conditions: (i) ClCH2COOC2H5, anhydrous 15 ……… 160 + 0.017 μM
15
K2CO3, dry DMF, reflux. (ii) R Ph-NCO, CH2Cl2, reflux. (iii) Ph- 16 5% at 80 + 0.033 μM > 200 + 0.072 μM
16 17 ……… > 200 + 0.072 μM
NCS, dry DMF, reflux. (iv) H2N-NH2, absolute EtOH, reflux. (v)
17 18 16.5% at 80 + 0.061 μM 160 + 0.024 μM
CS2, KOH, absolute EtOH, reflux. (vi) α-acetyl-γ-butyrolactone, 19 …….. > 200 + 0.052 μM
18
POCl3, reflux. (vii) C2H5OCH2CH(COOC2H5)2, gl. HOAc, reflux. (viii) Acyclovir 100% at 12.2 + 0.062 μM 80 + 0.016 μM
19
ClCH2COCl, anhydrous K2CO3, dry toluene, reflux. (ACV)
20
Reagents and conditions: (i) CS2, KOH, absolute EtOH, reflux. * Concentrations range 2–200 μM
21
(ii) ClCH2COOC2H5, KOH, absolute EtOH, reflux. (iii) R Ph-NCO,
22
CH2Cl2, reflux. (iv) Ph-NCS, dry DMF, K2CO3, reflux. (v)
23
ClCH2COCl, anhydrous K2CO3, dry toluene, reflux. (vi) H2N-NH2,
24
absolute EtOH, reflux. (vii) α-acetyl-γ-butyrolactone, POCl3, the third nitrogen of the triazole ring in hydrogen-binding
25
reflux. (viii) C2H5OCH2CH(COOC2H5)2, gl. HOAC, reflux. (ix) with the effector enzyme, reflecting its superiority over
26
ClCH2COCl, anhydrous K2CO3, dry toluene, reflux. thiadiazole.
27
6. Even though compound 7 was able to reduce the viral
28
plaques by 50% at a relatively high concentration (80 μM), it
29
2.2. Biological evaluation retained high selectivity compared to ACV (> 200 μM vs.
30
80 μM).
31 2.2.1. Antiviral and cytotoxicity assay
32
All synthesized compounds were subjected to in vitro evalua-
33 2.2.2. Antiviral sensitization assay of compound 7
tion of their antiviral activity against HSV-1 grown on Vero
34
African green monkey kidney cells.[13,23,24] The results, presented The most active compound, 7, revealed to have high safety
35
in Table 1, showed very interesting information about the margin with 50% activity on HSV-1 and considered as a good
36
tested compounds and can be summarized as follows: candidate to be used with ACV with hope to improve the
37
1. The synthesis protocols of both starting materials-triazole selectivity of ACV and reduce the latter effective dose which
38
and thiadiazole derivatives 1 and 11-resulted in decreasing produced 100% inhibition of viral plaques. Therefore, sensitiza-
39
the cytotoxicity of all produced compounds towards normal tion assay was set up to test the combined effect of compound
40
cells, i. e. host Vero monkey kidney cells, increasing their 7 with serial dilutions of ACV less than 12.2 μM.
41
selectivity. The results of sensitization assay proved that the best
42
2. Some compounds showed weak antiviral activity, however, effective and safe compound in this study, 7, was able to
43
they exhibited high selectivity as represented by com- reduce the effective dose of ACV that produced 100%
44
pounds 7, 8, 4, 18, 9, 3 b, and 16. inhibition of viral plaques from 12.2 μM to 5.7 μM, as presented
45
3. The most active compound in the two series is compound in Figure 2.
46
7, having triazolopyrimidine ring system.
47
4. Conserving the triazole ring in compound 8, but changing
48
the side chain at position 6 from chloroethyl to ethoxycar- 2.3. In silico studies
49
bonyl, dramatically decreased the antiviral activity, from
50 2.3.1. Molecular docking
50% plaque reduction in compound 7 to 20% in 8. This
51
might be due to differences in either or all steric, electronic, Docking study of all synthesized compounds was performed
52
or hydrophobicity properties between these two triazolo- using the crystal structure of HSV-1 thymidine kinase in
53
pyrimidine derivatives caused by side chain variation. complex with ACV (PDB code: 2KI5),[25] Figure 3. The Dock
54
5. Replacement of the triazole ring in compound 7 by module implemented in MOE[26] was used for comparison
55
thiadiazole in compound 8 caused complete disappearance between the modes of binding to thymidine kinase of the
56
of the antiviral activity. This may be due to a role played by
57

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1
2
3
4
5
6
7
8
9
10
11
Figure 2. Sensitization of Vero cells infected with HSV-1 and treated with compound 7.
12
13
14
Table 2. Docking interactions with HSV-1 thymidine kinase (2KI5).
15
16 Compound Binding No. Amino acid
No. energy (kcal/ of
17
mol) HB
18
19 3a -12.473 2 HB: Tyr101, Arg176 Hydrophobic
interaction: Tyr101, Tyr172
20
3b -15.182 2 HB: Tyr101, Arg176
21 4 -27.707 1 HB: Ala168 Hydrophobic interaction:
22 Ile100, Met121, Arg176, Pro173
23 5 0.622 1 HB: Glu225
6 -4.390 1 HB: Gln125
24
7 -6.502 4 HB: Gln125, Ile100, Tyr101, Arg226
25 Hydrophobic interaction: Met231
26 8 -8.182 2 HB: Ile100, Arg226 Hydrophobic
27 interaction: Tyr 101, His58, Met231
9 -23.015 2 HB: Gln125, Glu225 Hydrophobic
28
interaction: Ile100, Tyr172
29 13a -42.929 2 HB: Tyr101, Arg176
30 13b -43.576 2 HB: Tyr101, Arg176
31 14 -33.617 1 HB: Arg176 Hydrophobic interac-
tion: Ile100, Pro173
32
15 -23.819 1 HB: Tyr172
33 16 2.927 2 HB: Arg176, Glu225
34 Figure 3. Interaction of ACV with 2KI5. 17 -17.700 1 HB: Arg176 Hydrophobic interac-
35 tion: Tyr101
18 -18.21 1 HB: Arg163
36
19 -19.574 1 HB: Arg176
37 ACV -33.58 3 HB: Gln125, Arg176, Glu83 Hydro-
various ligands as shown in Table 2, from which the following
38 phobic interaction: Tyr172
could be summarized:
39
1. Compounds 7, 8, and 17 are similarly located in a region of
40
the site rich in polar groups. The ester oxygen mimics the
41
terminal hydroxyl oxygen of ACV, Figures 4–6. hydrophobic interaction between Met231 and the fused
42
2. These guanine-like bases occupy distinct locations on heterorings.
43
approximately the same geometric plane. With van der 4. However, in case of compound 8, the presence of a second
44
Waals interactions, guanine-like fused rings showed their terminal ester and absence of 5-methyl function allowed
45
own specific modes of binding to neighboring residues, the ethyl to turn around to avoid clashing with and
46
reflecting the particular volume the bases occupy. deviation of the surrounding amino acid, and in turn, lack of
47
3. Compound 7, the highest HSV-1 inhibitor, showed the binding the carbonyl pyrimidino function with the fronting
48
largest number of hydrogen bonds with conserved amino conserved Gln125, Figure 5. These conformational changes
49
acid residues, Figure 4. Conserved amino acids are involved and difference in substitution give proper explanation about
50
in the lead recognition; Gln125 from the terminal side of the the experimental antiviral difference.
51
pocket held the carbonyl oxygen of the triazolopyrimidine 5. In case of compound 17, the presence of two sulfur atoms
52
ring. From the opening groove, both Tyr101 and Arg226 of the thiadiazole and the mercapto-methyl bridge caused
53
hocked the oxygen of the ester carbonyl expressing super the intensive repulsive interactions with the facing amino
54
recognition. Thiomethyl bridge stabilized the recognition by acid residues. Lack of NH-function in the guanido-like ring
55
one unique hydrogen bond with Ile100, in addition to a impaired the hydrophobic interaction with the correspond-
56
ing residues, Figure 6.
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1
2
3
4
5
6
7
8
9
10
11
12
13
14 Figure 6. Interaction of the least active compound, 17, with 2KI5.
15
16
17
2.3.2. In silico physicochemical evaluation
18
19
“Drug-likeness” evaluates qualitatively the chance for a mole-
20
cule to become an oral drug with respect to bioavailability.
21
Drug-likeness was established from physicochemical inspec-
22
tions of compounds based upon their absorption, distribution,
23
metabolism, and excretion (ADMET) properties.[27,28]
24
In the current study, the ADMET properties were calculated
25
using Osiris Property Explorer server, and analyzed by applying
26
Lipinski’s rule of five which is widely used for selecting lead
27 Figure 4. Interaction of the most active compound, 7, with 2KI5. Top; 2D, and
bottom; 3D presentation.
compounds promising for advanced drug design programs. As
28
shown in Table 3, the tested compounds exhibited proper
29
physicochemical properties that are important for a new drug‘s
30
pharmacokinetics.[29] All the tested compounds have molecular
31
weights less than 500 g/mol, and logP in the acceptable range.
32
The absorption percentage was calculated based upon the
33
values of polar surface area, PSA.[30] All the synthesized
34
compounds showed no violation from Lipinski’s rule of five.
35
The bioavailability radar enables a first glance at the drug-
36
likeness of a molecule. The pink area represents the optimal
37
range for each property. Lipophilicity: logP between 0.7 and
38
+ 5.0, size: MW between 150 and 500 g/mol, polarity: TPSA
39
between 20 and 130, solubility: logS not higher than 6,
40
saturation: fraction of carbons in the sp3 hybridization not less
41
than 0.25 and flexibility: no more than 9 rotatable bonds. The
42
values invariably imply that these molecules are potential drug
43
candidates and can be further optimized for better activity.
44
45
46 3. Conclusion
47 Figure 5. Interaction of the moderately active compound, 8, with 2KI5. In this study, two isosteric series of 1,2,4-triazole and 1,3,4-
48
thiadiazole derivatives were synthesized and subjected to
49
antiherpetic evaluation. The obtained results revealed that the
50
6. In conclusion, it is clear that missing the guanido-like core most active compound was 7, having a triazolopyrimidine core.
51
interferes with complementarity, and in turn, dramatically It attains structure similarity to ACV. Compound 7 revealed to
52
lowers the degree of recognition with the conserved amino be more safe than ACV against normal cells with IC50 < 200 μM.
53
acid residues and consequently lowers the corresponding Furthermore, compound 7 was able to reduce the effective
54
antiherpetic potency. dose of ACV which produced 100% inhibition in viral plaques
55
from 12.2 to 5.7 μM. In silico screening of the drug-likeness of
56
all compounds was performed. Docking simulation of com-
57

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1 Table 3. In silico physicochemical properties.

2 Compound No. TPSA MW milogP nrotb HBA HBD Bioavailability Radar
3
4
5
6 3a 112.14 321.36 1.77 8 5 2
7
8
9
10
11
12
13 3b 137.43 355.81 1.94 8 5 2
14
15
16
17
18
19
4 91.93 337.43 1.98 9 4 3
20
21
22
23
24
25
26 5 149.32 337.42 1.11 9 4 3

27
28
29
30
31
32 6 100.89 232.29 -0.12 6 4 3
33
34
35
36
37
38 7 114.65 330.80 1.56 7 5 1
39
40
41
42
43
44
8 140.95 326.35 0.72 8 7 1
45
46
47
48
49
50
51 9 96.98 278.72 0.65 8 5 2
52
53
54
55
56
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1 Table 3. continued
2 Compound No. TPSA MW milogP nrotb HBA HBD Bioavailability Radar
3
4
5
6 13a 93.21 338.41 2.82 7 5 2
7
8
9
10
11
12 13b 93.21 372.86 3.50 7 5 2
13
14
15
16
17
18
14 76.14 354.48 2.72 9 4 2
19
20
21
22
23
24
25 15 163.59 394.50 1.96 7 6 0
26
27
28
29
30
31 16 106.93 205.27 1.37 3 4 3
32
33
34
35
36
37
17 127.10 347.85 1.54 7 7 0
38
39
40
41
42
43
44 18 153.40 343.39 0.69 8 7 0

45
46
47
48
49
50 19 134.72 295.77 0.33 8 5 1
51
52
53
54
55
56
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1 Table 3. continued
2 Compound No. TPSA MW milogP nrotb HBA HBD Bioavailability Radar
3
4
5
6 ACV 119.05 225.20 1.56 4 5 3
7
8
9
10
TPSA: Topological polar surface area; MW: Molecular weight; milogP: Logarithm of octanol-water partition coefficient developed by Molinspiration; nrotb:
11 Number of rotatable bonds; HBA: Number of hydrogen bond acceptors, HBD: Number of hydrogen bond donors; Bioavailability Radar: enables a first glance at
12 the drug-likeness of a molecule
13
14
15 [10] M. Asif, Chem. Int. 2015, 1, 71–80.
pound 7 into thymidine kinase 2KI5 active site suggested that [11] A. M. Rabie, A. S. Tantawy, S. M. I. Badr, Researcher 2018, 10, 21–43.
16
it could exert its anti-HSV-1 activity through thymidine kinase [12] I. Küçükgüzel, E. Tatar, S. G. Küçükgüzel, S. Rollas, E. De Clercq, Eur. J.
17
interaction. Moreover, comparison between the most active (7) Med. Chem. 2008, 43, 381–392.
18 [13] K. M. Dawood, H. Abdel-Gawad, H. A. Mohamed, F. A. Badria, Med. Chem.
and the least active (17) compounds was applied showing
19 Res. 2011, 20, 912–919.
different profiles, explaining their sharp difference in activity [14] S. M. El-Feky, L. A. Abou-zeid, M. A. Massoud, S. G. Shokralla, H. M. Eisa,
20
though having similar structure. Modeling studies showed a Acta Pharm. Sci. 2010, 52, 353–364.
21
fairly good agreement with preliminary biological experimental [15] A. M. Al-Azzawi, A. S. Hamd, Int. J. Res. Pharm. Chem. 2013, 3, 890–897.
22 [16] C. Fotsch, J. D. Sonnenberg, N. Chen, C. Hale, W. Karbon, M. H. Norman,
data.
23 J. Med. Chem. 2001, 44, 2344–2356.
24 [17] S. Kubota, K. Horie, H. Misra, K. Toyooka, M. Uda, M. Shibuya, H. Terada,
Chem. Pharm. Bull. 1985, 33, 662–666.
25 4. Supporting information summary [18] S. A. El-Feky, Z. K. A. El-Samii, N. A. Osman, J. Lashine, M. A. Kamel, H. K.
26 Thabet, Bioorg. Chem. 2015, 58, 104–116.
The detailed experimental protocols, IR, 1H-NMR, 13C-NMR, and
27 [19] H. Bayrak, A. Demirbas, N. Demirbas, S. A. Karaoglu, Eur. J. Med. Chem.
EI-MS spectra are provided in the supporting information. 2009, 44, 4362–4366.
28
[20] F. M. Awadallah, Sci. Pharm. 2008, 76, 415–438.
29
[21] N. S. El-Sayed, E. R. El-Bendary, S. M. El-Ashry, M. M. El-Kerdawy, Eur. J.
30 Conflict of Interest Med. Chem. 2011, 46, 3714–3720.
31 [22] M. A. Ghaly, E. R. El-Bendary, I. A. Shehata, S. M. Bayomi, S. Habib, J. Am.
The authors declare no conflict of interest. Sci. 2012, 8, 617–628.
32
[23] H. I. El-Subbagh, S. M. Abu-Zaid, M. A. Mahran, F. A. Badria, A. M. Al-
33
Obaid, J. Med. Chem. 2000, 43, 2915–2921
34 Keywords: anti-HSV-1; in silico studies; synthesis; thiadiazole; [24] M. A. El-Sherbeny, M. B. El-Ashmawy, H. I. El-Subbagh, A. A. El-Emam,
35 triazole. F. A. Badria, Eur. J. Med. Chem. 1995, 30, 445–449.
36 [25] M. S. Bennett, F. Wien, J. N. Champness, T. Batuwangala, T. Rutherford,
[1] G. H. Alsayed, A. M. Alzohairy, R. B. Amer, M. M. Saleh, O. M. Abdo, Int. J. W. C. Summers, H. Sun, G. Wright, M. R. Sanderson, FEBS Lett. 1999, 443,
37
Comp. Appl. 2014, 87, 5–13. 121–125.
38 [2] C. R. Santos, R. Capela, C. S. Pereira, E. Valente, L. Gouveia, C. [26] Molecular Operating Environment software 10.2008 (MOE) provided
39 Pannecouque, E. De Clercq, R. Moreira, P. Gomes, Eur. J. Med. Chem. with chemical computing group, Canada.
40 2009, 44, 2339–2346. [27] E. Pontiki, D. Hadjipavlou-Litina, K. Litinas, G. Geromichalos, Molecules
[3] J. S. Smith, N. J. Robinson, J. Infect. Dis. 2002, 186, S3-S28. 2014, 19, 9655–9674.
41
[4] J. L. Umbach, M. F. Kramer, I. Jurak, H. W. Karnowski, D. M. Coen, B. R. [28] S. Kauthale, S. Tekale, M. Damale, J. Sangshetti, R. Pawar, Bioorg. Med.
42 Cullen, Nature 2008, 454, 780–785. Chem. Lett. 2017, 27, 3891–3896.
43 [5] R. Al-Salahi, I. Alswaidan, H. A. Ghabbour, E. Ezzeldin, M. Elaasser, M. [29] C. A. Lipinski, F. Lombardo, B. W. Dominy, P. J. Feeney, Adv. Drug Deliv.
44 Marzouk, Molecules 2015, 20, 5099–5111. Rev. 1997, 23, 3–26.
[6] K. Benci, T. Suhina, L. Mandić, S. K. Pavelić, A. T. Paravić, K. Pavelić, J. [30] P. Ertl, B. Rohde, P. Selzer, J. Med. Chem. 2000, 43, 3714–3717.
45
Balzarini, K. Wittine, M. Mintas, Antivir. Chem. Chemother. 2011, 21, 221–
46 230.
47 [7] M. S. Kokoris, M. E. Black, Protein Sci. 2002, 11, 2267–2272.
[8] A. J. Wagstaff, D. Faulds, K. Goa, Drugs 1994, 47, 153–205. Submitted: March 3, 2019
48
[9] E. Wintersberger, Biochem. Soc. Trans. 1997, 25, 303–308. Accepted: May 20, 2019
49
50
51
52
53
54
55
56
57

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