Next Article in Journal
Biodegradability of Dental Care Antimicrobial Agents Chlorhexidine and Octenidine by Ligninolytic Fungi
Previous Article in Journal
γ-Tocotrienol and α-Tocopherol Ether Acetate Enhance Docetaxel Activity in Drug-Resistant Prostate Cancer Cells
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 25
Issue 2
10.3390/molecules25020399
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Synthesis and Cytotoxic Activity of New Thiazolopyrimidine Sugar Hydrazones and Their Derived Acyclic Nucleoside Analogues

by
Ebtesam A. Basiony
1,
Allam A. Hassan
2,3,
Zahra M. Al-Amshany
4,
Ahmed A. Abd-Rabou
5,6,
Adel A.-H. Abdel-Rahman
1,
Nasser A. Hassan
7,8,* and
Wael A. El-Sayed
8,9,*
1
Faculty of Science, Chemistry Department, Menoufia University, Shibin EL-Kom 32511, Egypt
2
Faculty of Science, Chemistry Department, Suez University, Suez 43511, Egypt
3
Applied Medical Science, Medical Laboratories Department, Shaqra University, Shaqra 11961, Saudi Arabia
4
Department of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah 21551, Saudi Arabia
5
Hormones Department, Medical Research Division, National Research Centre, Giza 12511, Egypt
6
Stem Cells Lab, Center of Excellence for Advanced Sciences, National Research Centre, Giza 12511, Egypt
7
Pharmaceutical Science Department, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia
8
Photochemistry Department, National Research Centre, Giza 12511, Egypt
9
Department of Chemistry, College of Science, Qassim University, Buraidah 51452, Saudi Arabia
*
Authors to whom correspondence should be addressed.
Molecules 2020, 25(2), 399; https://doi.org/10.3390/molecules25020399
Submission received: 14 December 2019 / Revised: 15 January 2020 / Accepted: 16 January 2020 / Published: 18 January 2020
Browse Figures
Versions Notes

Abstract

:
New thienyl- or chlorophenyl-substituted thiazolopyrimidine derivatives and their derived sugar hydrazones incorporating acyclic d-galactosyl or d-xylosyl sugar moieties in addition to their per-O-acetylated derivatives were synthesized. Heterocyclization of the formed sugar hydrazones afforded the derived acyclic nucleoside analogues possessing the 1,3,4-oxadiazoline as modified nucleobase via acetylation followed by the cyclization process. The cytotoxic activity of the synthesized compounds was studied against human breast cancer MCF7 and MDA-MB-231 cell lines as well as human colorectal cancer HCT 116 and Caco-2 cell lines. High activities were revealed by compounds 1, 8, 10, 11, and 13 against Caco-2 and MCF7 cells in addition to moderate activities exhibited by other compounds against HCT116 or MDA-MB-231 cells.

Graphical Abstract

1. Introduction

The increased risk of cancer leading to a high mortality rate is one of the important factors that stimulates scientific research in the field of medicinal chemistry for achieving distinct results able to face such threat. Chemotherapy represents an important strategy [1] that is frequently applied for treatment of cancer. The main objective associated with numerous approved chemotherapeutic agents [2] is the apoptosis induction of cancer cells. The research for developing novel anticancer candidates, with no or minimal side effects, is of considerable interest due to the observed toxicity of current drugs towards normal cells, the suppressed drug activity and the induced drug resistance which usually lead to insufficiency in the treatment process.
Thiazolopyrimidine is one of the most interesting heterocyclic scaffolds possessing structural similarity to 5-fluorouracil (5-FU)—the well-known cancer metabolite. In addition, they have been reported to possess various important potent activities such as antimicrobial, antipsychotic, anti-inflammatory, anti-Parkinson’s, analgesic, antidepressant, anti-HIV, and anticancer activities [3,4,5,6,7,8,9,10,11]. In addition, they have been revealed with their bioactivities as transient receptor potential vanilloid–receptor 1 (TRPV1) modulators [12,13], antioxidants [14,15], pesticides [16], phosphate inhibitors [17,18], acetylcholinesterase inhibitors [19,20], and antimicrobial activities [21,22,23].
1,3,4-Oxadiazole is a prominent scaffold which was found to possess opulent interesting applications in drug development and designing important agrochemicals [24]. Many compounds incorporating 1,3,4-oxadiazole system showed potent bioactivities such as antiviral, anticancer, antiproliferative, antimicrobial, anti-inflammatory activities in addition to their activities as potential antifibrotic agents and monoamine oxidase B inhibitors [24,25,26,27,28,29,30,31,32]. On the other hand, acyclic and C-nucleoside analogs, as modified forms of natural nucleosides, have revealed important bioactivities as antibiotic, antiviral, and antitumor activities [25,26,27,33,34,35,36,37,38]. Figure 1 displays a number of thiazolopyrimidine and their incorporating sugar derivatives in addition to pyrimidine and oxadiazole hybrids possessing reported potent anticancer activities [39,40,41,42]. Recent strategies of combining various pharmacophoric scaffolds in a new hybrid structure (molecular hybridization) for constructing potent drugs have been reported to result in the formation of more potent bioactive candidates. These significances and our ongoing interest in synthesizing new active carbohydrate based heterocycles [38,43,44,45,46] prompted us to synthesize new hybrid compounds comprising thiazolopyrimidine system, aryl or thienyl moiety, and acyclic sugar or oxadiazolyl linked to sugar moiety as modified acyclic C-nucleoside analogs and studying their anticancer activity against a number of cancer cell lines.

2. Results and Discussion

2.1. Chemistry

In the present study, two types of targeted hybrid heteroaryl sugar derivatives were synthesized. The first possesses either a thienyl or chlorophenyl moiety and a thiazolopyrimidine system linked to an acyclic sugar moiety and the second incorporates an additional 1,3,4-oxadiazole system linked to acyclic sugar moiety. The substituted thiazolopyrimidine system was first prepared via a multicomponent reaction (one pot Biginelli reaction) of the aldehyde (namely; p-chlorobenzaldehyde or thiophen-2-carbaldehyde) with ethyl acetoacetate and thiourea to afford the corresponding substituted pyrimidine derivatives 1 or 2, respectively as previously reported [47,48]. Reaction of the pyrimidine substituted ester derivatives 1 or 2 with 1,2-dibromoethane and potassium carbonate gave the corresponding thiazolopyrimidine derivatives 3 or 4, respectively, which is similar to previously reported work [49]. Their 1H-NMR spectra showed the presence of the two methylene groups in addition to the characteristic triplet and quartet signals assigned for the ethyl group in addition to the aryl protons. The reaction of thiazolopyrimidine derivative 3 or 4 with hydrazine hydrate [33] gave the corresponding acyl hydrazide compound 5 or 6, respectively (Scheme 1). Their IR spectra showed the presence of NH2 and NH in the region 3425–3325 cm−1 in addition to the characteristic carbonyl band for the amidic carbonyl group.
The sugar hydrazone derivatives 7–10 were formed via the reaction of acyl hydrazides with d-galactose or d-xylose in the presence of catalytic acetic acid amount. The IR spectra of the latter sugar hydrazones revealed the bands of sugar-hydroxyl groups at 3434–3338 cm−1. Their 1H-NMR spectra revealed, in addition to the characteristic signals of the protons in the assigned structures, the H-1 methine proton at 7.20–7.45 ppm with coupling constant 8.5 Hz. The latter observed chemical shift values showed the sp2 hybridization of the sugar C-1 which indicates that the sugar moiety is present in the acyclic form.
Acetylation of the thiazolopyrimidine hydrazonyl sugar compounds 7–10 was achieved by means of acetic anhydride in the presence of pyridine resulting in the formation of the per-O-acetylated sugar hydrazones 11–14, respectively. The IR spectra of the produced acetylated products revealed the existence of the C=O band of the acetyl group at 1749–1735 cm−1 in addition to the disappearance of OH group bands. Furthermore, their 1H-NMR spectra displayed the assigned signals for the protons of the five methyl groups in the CH3C=O group at 1.95–2.26 ppm in addition to the H-1 proton at 7.32–8.05 ppm with 7.6–7.8 Hz coupling constant, indicating the acyclic sugar form of the sugar part.
On the other hand, performing the acetylation reaction of the sugar hydrazones 7–10 was further carried out in acetic anhydride at 100 °C and resulted in a heterocyclization process in addition to the acetylation step affording the derived 1,3,4-oxadiazoline compounds linked to acetylated acyclic sugar units 15–18, respectively (Scheme 2). Formation of these oxadiazoline acyclic C-nucleoside analogs was consistent with the previous reported studies of the hydrazine derivatives under these conditions [24,33,38,46,50,51]. The infrared spectra of the resulting oxadiazoline sugar derivatives displayed the absorption bands attributed to the carbonyl groups of the acetyl parts at 1740–1735 and 1680–1670 cm−1. The signals that were afforded in their 1H-NMR spectra were in accordance with the assigned structures. Thus, the doublet signal at 5.70–5.72 ppm with J coupling 7.2–7.4 Hz corresponds to H-2 of the formed oxadiazoline ring (originally H-1 in the reacted acyclic sugar moiety) which is attached to an sp3 carbon atom indicating the heterocyclization process. In acyclic hydrazine forms the latter proton should be at higher chemical shift values due to the sp2 character of the assumed C-1 (methylenic proton). The remaining protons in the acyclic sugar skeleton were displayed at their characteristic assigned values. Furthermore, the 13C-NMR spectra of these products showed a signal at 81.3–82.5 ppm corresponding to the C-2 in the oxadiazoline ring (originally C-1 of the acyclic sugar part) in addition to the signals corresponding to the acetyl-carbonyl carbons and aryl carbons confirming the assigned structures.

2.2. Cytotoxic Activity

In the current study, the newly synthesized compounds were examined in vitro for their cytotoxic activities against human breast cancer MCF7 and MDA-MB-231 cell lines, as well as human colorectal cancer HCT 116 and Caco-2 cell lines [52]. In addition, it will be also of interest in the present investigation to see the effect of the introduction of an acyclic sugar or oxadiazolyl linked to sugar moiety on the activity. The current results demonstrated that there was a gradual significant decrease (p > 0.05) of cell proliferation after treating human colorectal cancerous cell lines (HCT 116 and Caco-2) and human breast cancerous cell lines (MDA-MB-231 and MCF-7) with the synthesized compounds using different dosages started from 0 to 100 µg/mL.
From Table 1, it has been suggested that the lower the IC50, the highest the cytotoxic effect against the cancer cells. Compounds which showed 100% inhibition and revealed IC50 values less than 100 µg/mL against at least one cancer cell line are listed in Table 1. The remaining compounds revealed undetectable IC50 (more than 100 ug/mL) upon all tested cancer cell lines.
The observed results showed that compounds 1 and 9 exhibited the lowest IC50 with the highest cytotoxic effect against HCT 116 cell line with IC50 values 25.28 and 27.95 µg/mL, respectively. In addition, compound 11 revealed moderate cytotoxic effect against the latter cancer cell line as illustrated in (Figure 2 and Table 1). Regarding the activity against Caco-2 cell line, compounds 10, 8, and 13 showed the lowest IC50 with the highest cytotoxic effect against this cancer cell line as illustrated in Figure 3 and Table 1.
On the other hand, compound 11 was shown to possess the lowest IC50 with the highest cytotoxic effect against MDA-MB-231 cell line as illustrated in Figure 4 and Table 1. The results also showed that compounds 10 and 4 showed moderate activities against such cancer cell line. The activity results against MCF7 cancer cell revealed that compounds 11 and 10 displayed the lowest IC50 with the highest cytotoxic effect as illustrated in Figure 5 and Table 1.
By correlating of the obtained bioactivity results with the main structural features of the compounds exhibiting the highest activities, it was found that thiazolopyrimidine linked to 4-chlorophenyl or thienyl hybrid compounds incorporating acyclic sugar parts were the most active candidates. These derivatives incorporated the sugar part linked via a hydrazinyl linkage to either free hydroxyl or acetylated acyclic moiety. Thus, attachment of a hydrazinyl sugar moiety to the thiazolopyrimidine ring system (compounds 7–14) resulted in higher activities compared to their starting precursors. The thiazolopyrimidine linked to acetylated galactose moiety were found higher in activities than their analogs with the five carbon xylose sugar unit. However, this was not the case for the deacetylated analogs since the free hydroxyl xylose products (8 and 10) were higher than those possessing galactose unit (the hydrazones 7 and 9). The sugar hydrazones 8 and 10 with free hydroxyl xylosyl group were found higher in activities than their derived acetylated products 12 and 14, respectively. When the sugar part was a galactosyl moiety, the acetylated derivative 11 was found higher in activity than its deacetylated analogue 7. Furthermore, the substituted pyrimidine compound 1 was higher in its activity against HCT116 cells than the derived thiazolopyrimidine product 4 which did not incorporate sugar part. Such observations may account for the importance of the -NH linked to the thione group for the cytotoxic activity against the HCT116 cell line. However, the thiazolopyrimidine ester derivative 4 was found to be higher in the cytotoxic activity against Caco-2 cells than the substituted pyrimidine 1.

3. Experimental

3.1. Synthesis

General Procedures

Melting points were determined on a Böetius PHMK (Veb Analytik Dresden) apparatus. Thin Layer Chromatography (TLC) was performed using aluminum plates pre-coated with silica gel 60 or 60 F254 (Merck) and visualized by iodine or UV light (254 nm). The NMR spectra were recorded on a Varian Gemini 300 and Bruker DRX 400 spectrometer at 25 °C. 1H- and 13C-NMR signals were referenced to TMS and the solvent shift ((CD3)2SO δ H 2.50 and δ C 39.5). Coupling constants are given in Hz and without sign. The IR spectra (ν, cm−1) were recorded (KBr) on a Jasco FT/IR-410 instrument. Microanalyses were operated using Perkin Elmer 240 instrument and satisfactory results within the accepted range (±0.40) of the calculated values were obtained. All reagents and solvents were of commercial grade. The cytotoxic activity against cancer cell lines was studied at National Research Center (NRC), Dokki, Cairo, Egypt. Compounds 1 and 2 were prepared as reported previously [47,48].

3.2. Ethyl 7-(Aryl)-5-methyl-2,3-dihydro-7H-thiazolo[3,2-a]pyrimidine-6-carboxylate (3, 4)

A mixture of the ester compounds 1 or 2 (10 mmol), 1,2-dibromoethane (10 mmol), and K2CO3 (20 mmol) in DMF (12 mL) was heated in a water bath at 90 °C for 3 h, and poured on ice and cooled with water. The afforded precipitate was filtered, dried, and recrystallized from acetone–water (1:1) to give the thiazolopyrimidine derivatives 3 or 4, respectively.

3.2.1. Ethyl 7-(4-Chlorophenyl)-5-methyl-2,3-dihydro-7H-thiazolo[3,2-a]pyrimidine-6-carboxylate (3)

Yield: 88%; 136–137 °C. IR spectrum: 3060 (C-H aromatic), 2975 (CH-aliphatic), 1695 (C=O), 1605 (C=N). 1H-NMR (500 MHz, DMSO-d6) δ 1.39 (t, 3H, J = 5.8 Hz, CH3), 2.11 (s, 3H, CH3), 3.34 (t, 2H, J = 5.8 Hz, CH2), 3.41 (t, 2H, J = 5.8 Hz, CH2), 4.12 (q, 2H, J = 5.8 Hz, CH2), 5.69 (s, 1H, H-7), 7.52 (d, 2H, J = 7.8 Hz, Ar–H), 7.79 (d, 2H, J = 7.8 Hz, Ar-H). 13C-NMR (DMSO-d6) δ 14.3 (CH3), 29.2 (CH3), 53.2 (CH2), 54.8 (CH2), 58.9 (CH2), 60.9 (pyrimidine-C), 129.6 (pyrimidine-C), 130.5 (Ar-2C), 132.5 (Ar-2C), 133.0 (Ar-C), 134.8 (Ar-C), 164.3 (pyrimidine-C), 165.5 (pyrimidine-C), 169.1(C=O). EI-MS (m/z, %): 336 (M+, 69). Anal. calcd. for C16H17ClN2O2S (336.83): C, 57.05; H, 5.09; N; 8.32. Found: C, 56.90; H, 5.02; N, 8.47.

3.2.2. Ethyl 5-Methyl-7-(thiophen-2-yl)-2,3-dihydro-7H-thiazolo[3,2-a]pyrimidine-6-carboxylate (4)

Yield: 79%; 131–132 °C. IR spectrum: 3060 (C–H aromatic), 2970 (CH-aliphatic), 1670 (C=O), 1603 (C=N). 1H-NMR (500 MHz, DMSO-d6) δ 1.37 (t, 3H, J = 5.8 Hz, CH3), 2.10 (s, 3H, CH3), 3.35 (t, 2H, J = 5.8 Hz, CH2), 3.41 (t, 2H, J = 5.8 Hz, CH2), 4.12 (q, 2H, J = 5.8 Hz, CH2), 4.60 (s, 1H, H-7), 6.95–7.15 (m, 3H, thienyl-H). 13C-NMR (DMSO-d6) δ 14.6 (CH3), 20.3 (CH3), 52.5 (CH2), 53.9 (CH2), 57.9 (CH2), 60.5 (pyrimidine-C), 117.0 (pyrimidine-C), 127.8 (thienyl C-5), 143.2 (thienyl C-3), 143.8 (thienyl C-4), 162.9 (thienyl C-2), 165.1 (pyrimidine-C), 166.5 (pyrimidine-C), 173.3 (C=O). EI-MS (m/z, %): 308 (M+, 85). Anal. calcd. for C14H16N2O2S2(308.41): C, 54.52; H, 5.23; N, 9.08. Found: C, 54.36; H, 5.32; N, 8.95.

3.3. 5-Methyl-7-(aryl)-2,3-dihydro-7H-thiazolo[3,2-a]pyrimidine-6-carbohydrazide (5, 6)

A solution of the thiazolopyrimidine ester compound 3 or 4 (10 mmol) and hydrazine hydrate (30 mmol) in ethanol (25 mL) was heated under reflux for 8 h. The solution was cooled, and the resulting precipitate was filtered and recrystallized from ethanol to give 5 or 6, respectively.

3.3.1. 7-(4-Chlorophenyl)-5-methyl-2,3-dihydro-7H-thiazolo[3,2-a]pyrimidine-6-carbohydrazide (5)

Yield: 66%; 169–170 °C. IR spectrum: 3412, 3325 (NH2 and NH), 3065 (CH-aromatic), 2927 (CH-aliphatic), 1655 (C=O), 1605 (C=N). 1H-NMR (500 MHz, DMSO-d6) δ 2.01 (s, 3H, CH3), 3.34 (t, 2H, J = 5.8 Hz, CH2), 3.41 (t, 2H, J = 5.8 Hz, CH2), 4.02 (brs, 2H, NH2), 4.61 (s, 1H, H-7), 7.56 (d, 2H, J = 7.8 Hz, Ar–H), 7.88 (d, 2H, J = 7.8 Hz, Ar–H), 10.90 (brs, 1H, NH). 13C-NMR (DMSO-d6) δ 21.3 (CH3), 55.9 (CH2), 56.9 (CH2), 60.5 (pyrimidine-C), 115.0 (pyrimidine-C), 123.9 (Ar–C), 134.9 (Ar-2C), 140.4 (Ar-2C), 149.9 (Ar-C), 157.4 (pyrimidine-C), 168.4 (pyrimidine-C), 172.2 (C=O). EI-MS (m/z, %): 322 (M+, 73). Anal. calcd. for C14H15ClN4OS (322.81): C, 52.09; H, 4.68; N; 17.36. Found: C, 52.27; H; 4.59; N; 17.51.

3.3.2. 5-Methyl-7-(thiophen-2-yl)-2,3-dihydro-7H-thiazolo[3,2-a]pyrimidine-6-carbohydrazide (6)

Yield: 76%; 162–163 °C. IR spectrum: 3425–3390 (NH2 and NH), 3060 (CH-aromatic), 2925 (CH-aliphatic), 1660 (C=O), 1610 (C=N). 1H-NMR (500 MHz, DMSO-d6) δ 1.65 (s, 3H, CH3), 3.20 (t, 2H, J = 5.8 Hz, CH2), 3.50 (t, 2H, J = 5.8 Hz, CH2), 3.89-4.15 (brs, 3H, NH2, H-7), 7.15 (m, 1H, thienyl-H), 7.40 (d, 1H, J = 7.2 Hz, thienyl-H), 7.60 (d, 1H, J = 6.8 Hz, thienyl-H), 8.49 (brs, 1H, NH). 13C-NMR (DMSO-d6) δ 22.3 (CH3), 55.6 (CH2), 57.7 (CH2), 79.7 (pyrimidine-C), 120.2 (pyrimidine-C), 121.9 (thienyl-C5), 132.9 (thienyl-C3), 154.4 (thienyl-C4), 154.9 (thienyl-C2), 157.5 (pyrimidine-C), 158.2 (pyrimidine-C), 172.4 (C=O). EI-MS (m/z, %): 294 (M+, 70). Anal. calcd. for C12H14N4OS2 (294.39): C, 48.96; H; 4.79, N; 19.03. Found: C, 49.07; H, 4.71; N, 19.17.

3.4. Sugar-5-(aryl)-7-methyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carbohydrazone (7–10)

General procedure: a solution of the acyl hydrazide 5 or 6 (10 mmol) in ethanol (10 mL) was added to a solution of d-galactose or d-xylose (10 mmol) in water (2 mL) followed by addition of glacial acetic acid (0.2 mL). The reaction mixture was heated at reflux temperature for 5 h and then the solvent was removed under reduced pressure. Dry diethyl ether was added to the remaining residue with stirring for 15 min and the formed product was washed with dry ethanol then dried to give the sugar hydrazone derivatives 7–10.

3.4.1. d-Galactose 7-(4-chlorophenyl)-5-methyl-2,3-dihydro-7H-thiazolo[3,2-a]pyrimidine-6-carbohydrazone (7)

Yield: 71%; brownish foam; IR spectrum: 3425–3421 (OH), 3070 (CH-aromatic), 2930 (CH-aliphatic), 1645 (C=O), 1626 (C=N). 1H-NMR (500 MHz, DMSO-d6) δ 2.40 (s, 3H, CH3), 3.36 (t, 2H, J = 5.6 Hz, CH2), 3.40–3.49 (m, 4H, CH2, H-6′,6″), 3.60–3.63 (m, 1H, H-5′), 3.89–4.05 (m, 2H, H-4′,3′), 4.65–4.71 (m, 2H, H-2′, OH), 5.15–5.19 (m, 1H, OH), 5.30–5.33 (m, 1H, OH), 5.40–5.44 (m, 1H, OH), 5.60–5.66 (m, 2H, OH, H-7), 7.45 (d, 1H, J = 8.5 Hz, H-1′), 7.60 (d, 2H, J = 8.2 Hz, Ar–H), 7.88 (d, 2H, J = 8.2 Hz, Ar-H), 9.02 (s, 1H, NH). 13C-NMR (DMSO-d6) δ 18.8 (CH3), 45.1 (CH2), 55.4 (CH2), 60.6 (pyrimidine-C), 64.7 (C6′), 70.7 (C5′), 75.1 (C4′), 77.1 (C3′), 82.9 (C2′), 121.4 (pyrimidine-C), 121.9 (Ar-C), 126.9 (Ar-2C), 127.9 (Ar-2C), 139.4 (Ar-C), 140.6 (pyrimidine-C), 141.5 (C1′), 158.0 (pyrimidine-C), 167.9 (C=O). Anal. calcd. for C20H25ClN4O6S (484.95): C, 49.53; H, 5.20; N, 11.55. Found: C; 49.37; H; 5.28; N; 11.41.

3.4.2. d-Xylose 7-(4-chlorophenyl)-5-methyl-2,3-dihydro-7H-thiazolo[3,2-a]pyrimidine-6-Carbohydrazone (8)

Yield: 62%; brownish foam; IR spectrum: 3420–3416 (OH), 3060 (CH-aromatic), 2922 (CH-aliphatic), 1665 (C=O), 1612 (C=N). 1H-NMR (500 MHz, DMSO-d6) δ 2.38 (s, 3H, CH3), 3.37 (t, 2H, J = 5.6 Hz, CH2), 3.52-3.65 (m, 4H, CH2, H-5′,5″), 3.92-4.05 (m, 2H, H-4′,3′), 4.67–4.72 (m, 2H, H-2′, OH), 5.15–5.18 (m, 1H, OH), 5.29–5.40 (m, 2H, 2OH), 5.60 (s, 1H, H-7), 7.40 (d, 1H, J = 8.5 Hz, H-1′), 7.60 (d, 2H, J = 8.2 Hz, Ar–H), 7.88 (d, 2H, J = 8.2 Hz, Ar-H), 9.02 (s, 1H, NH). 13C-NMR (DMSO-d6) δ 18.8 (CH3), 45.1 (CH2), 55.4 (CH2), 62.6 (pyrimidine-C), 64.5 (C5′), 72.7 (C4′), 77.1 (C3′), 85.9 (C2′), 121.4 (pyrimidine-C), 121.9 (Ar–C), 126.9 (Ar-2C), 127.9 (Ar-2C), 139.4 (Ar-C), 140.6 (pyrimidine-C), 141.5 (C1′), 158.0 (pyrimidine-C), 167.9 (C=O). Anal. calcd. for C19H23ClN4O5S (454.93): C, 50.16; H; 5.10, N; 12.32. Found: C, 50.41; H, 5.03; N, 12.15.

3.4.3. d-Galactose 5-methyl-7-(thiophen-2-yl)-2,3-dihydro-7H-thiazolo[3,2-a]pyrimidine-6-carbohydrazone (9)

Yield: 75%; brownish foam. IR spectrum: 3417–3413 (OH), 3074 (CH-aromatic), 2923 (CH-aliphatic), 1650 (C=O), 1605 (C=N). 1H-NMR (500 MHz, DMSO-d6) δ 2.30 (s, 3H, CH3), 3.40 (t, 2H, J = 5.6 Hz, CH2), 3.46–3.52 (m, 4H, CH2, H-6′,6‴), 3.60–3.63 (m, 1H, H-5′), 3.94-4.10 (m, 2H, H-4′,3′), 4.68–4.72 (m, 2H, H-2′, OH), 5.18–5.21 (m, 1H, OH), 5.29–5.33 (m, 1H, OH), 5.39–5.43 (m, 1H, OH), 5.55–5.61 (m, 2H, OH, H-7), 7.35–742 (m, 2H, H-1′, thienyl-H), 7.40 (d, 1H, J = 7.2 Hz, thienyl-H), 7.6 (d, 1H, J = 6.8 Hz, thienyl-H), 8.92 (brs, 1H, NH). 13C NMR (DMSO-d6) δ 18.8 (CH3), 45.1 (CH2), 55.4 (CH2), 60.6 (pyrimidine-C), 64.7 (C6′), 70.7 (C5′), 75.1 (C4′), 77.1 (C3′), 82.9 (C2′), 121.4 (pyrimidine-C), 124.9 (thienyl-C5), 126.4 (thienyl-C3), 127.0 (thienyl-C4), 139.4 (thienyl-C2), 140.6 (pyrimidine-C), 141.5 (C1′), 158.0 (pyrimidine-C), 167.9 (C=O). Anal. calcd. for C18H24N4O6S2 (456.53): C; 47.36; H; 5.30, N, 12.27. Found: C; 47.17; H; 5.42; N; 12.04.

3.4.4. d-Xylose 5-methyl-7-(thiophen-2-yl)-2,3-dihydro-7H-thiazolo[3,2-a]pyrimidine-6-Carbohydrazone (10)

Yield: 70%; brownish foam. IR spectrum: 3415–3411 (OH), 3055 (CH-aromatic), 2919 (CH-aliphatic), 1655 (C=O), 1523 (C=N). 1H-NMR (500 MHz, DMSO-d6) δ 2.38 (s, 3H, CH3), 3.32 (t, 2H, J = 5.6 Hz, CH2), 3.54–3.66 (m, 4H, CH2, H-5′,5‴), 3.95-4.12 (m, 2H, H-4′,3′), 4.97–5.11 (m, 3H, H-2′, 2OH), 5.15–5.18 (m, 1H, OH), 5.29–5.40 (m, 2H, OH, H-7), 7.20 (d, 1H, J = 8.5 Hz, H-1′), 7.34–7.38 (m, 1H, thienyl-H), 7.41 (d, 1H, J = 8.2 Hz, thienyl-H), 7.88 (d, 1H, J = 8.2 Hz, thienyl-H), 9.05 (s, 1H, NH). 13C-NMR (DMSO-d6) δ 18.8 (CH3), 45.1 (CH2), 55.4 (CH2), 60.6 (pyrimidine-C), 62.22 (C5′), 70.1 (C4′), 76.1 (C3′), 83.9(C2′), 121.4 (pyrimidine-C), 124.9 (thienyl-C5), 126.4 (thienyl-C3), 127.0 (thienyl-C4), 139.4 (thienyl-C2), 140.6 (pyrimidine-C), 141.5 (C1′), 158.0 (pyrimidine-C), 167.9 (C=O). Anal. calcd. for C17H22N4O5S2 (426.10): C, 47.87; H; 5.20, N; 13.14. Found: C; 48.02; H; 5.08; N; 13.04.

3.5. General Procedure for the Preparation of Compounds (11–14)

To a solution of the sugar hydrazones 7–10 (10 mmol) in pyridine (5 mL), acetic anhydride (3 mL) was added and the mixture was stirred at room temperature for 20 h. The resulting solution was poured onto crushed ice and the product was extracted by ethyl acetate (15 × 3 mL), washed with a saturated solution of sodium hydrogen carbonate (10 mL) followed by water and then the solvent was evaporated to afford the acetylated products 11–14.

3.5.1. Penta-O-acetyl-d-galactopentitolyl-7-(4-chlorophenyl)-5-methyl-2,3-dihydro-7H-thiazolo[3,2-a]pyrimidine-6-carbohydrazone (11)

Yield: 70%; Brownish foam. IR spectrum: 3421 (NH), 3055 (CH-aromatic), 2933 (CH-aliphatic), 1735 (C=O), 1624 (C=N). 1H-NMR (500 MHz, DMSO-d6) δ 2.01 (s, 3H, CH3), 2.03 (s, 3H, CH3), 2.05 (s, 3H, CH3), 2.10 (s, 3H, CH3), 2.12 (s, 3H, CH3), 2.43 (s, 3H, CH3), 3.41–3.45 (m, 4H, 2CH2), 3.88–3.95 (m, 2H, H-6′,6″), 4.08–4.16 (m, 1H, H-5′), 4.68–4.80 (m, 2H, H-4′, H-3′), 4.82–4.86 (m, 1H, H-2′), 5.32 (s, 1H, H-7), 7.35 (d, 2H, J = 8.4 Hz, Ar–H), 7.41 (d, 2H, J = 8.4 Hz, Ar-H), 7.48 (d, 1H, J = 7.8 Hz, H-1′), 9.07 (s, 1H, NH). 13C-NMR (DMSO-d6) δ 18.8, 19.9, 20.2, 20.4, 20.7, 21.1 (6CH3), 45.1 (CH2), 55.4 (CH2), 60.6 (pyrimidine-C), 65.7 (C6′), 72.7 (C5′), 76.14 (C4′), 79.5 (C3′), 83.2(C2′), 121.4 (pyrimidine-C), 121.9 (Ar–C), 126.9 (Ar-2C), 127.9 (Ar-2C), 139.4 (Ar-C), 140.6 (pyrimidine-C), 141.5 (C1′), 158.0 (pyrimidine-C), 167.9, 169.8, 170.1, 170.3, 170.6, 170.8 (6C=O). Anal. calcd. for C30H35ClN4O11S (695.14): C; 51.84; H; 5.08, N, 8.06. Found: C; 51.56; H; 5.12; N; 7.92.

3.5.2. Tetra-O-acetyl-d-xylotetritolyl-7-(4-chlorophenyl)-5-methyl-2,3-dihydro-7H-thiazolo[3,2-a]- pyrimidine-6-carbohydrazone (12)

Yield: 61%; Brownish foam. IR spectrum: 3431 (NH), 3048 (CH-aromatic), 2925 (CH-aliphatic), 1749 (C=O), 1630 (C=N). 1H-NMR (500 MHz, DMSO-d6) δ 2.04 (s, 3H, CH3), 2.06 (s, 3H, CH3), 2.08 (s, 3H, CH3), 2.10 (s, 3H, CH3), 2.48 (s, 3H, CH3), 2.98 (t, 2H, J = 5.8 Hz, CH2), 3.25-3.45 (m, 4H, CH2, H-5′,5″), 3.90 (m, 1H, H-4′), 4.35–4.58 (m, 2H, H-3′, H-2′), 5.56 (s, 1H, H-7), 7.32 (d, 1H, J = 7.6 Hz, H-1′), 7.64 (d, 2H, J = 8.4 Hz, Ar-H), 7.78 (d, 2H, J = 8.4 Hz, Ar-H), 9.12 (s, 1H, NH). 13C-NMR (DMSO-d6) δ 18.8, 19.8, 20.1, 20.3, 21.2 (5CH3), 45.1 (CH2), 55.4 (CH2), 60.6 (pyrimidine-C), 72.4 (C5′), 75.23 (C4′), 78.5 (C3′), 83.4 (C2′), 121.4 (pyrimidine-C), 121.9 (Ar–C), 126.9 (Ar-2C), 127.9 (Ar-2C), 139.4 (Ar-C), 140.6 (pyrimidine-C), 141.5 (C1′), 158.0 (pyrimidine-C), 168.1, 170.2, 170.4, 170.7, 170.9 (5C=O). Anal. calcd. for C27H31ClN4O9S (623.07): C, 52.05; H; 5.02, N; 8.99. Found: C, 51.88; H, 5.09; N, 9.11.

3.5.3. Penta-O-acetyl-d-galactopentitolyl-5-methyl-7-(thiophen-2-yl)-2,3-dihydro-7H-thiazolo[3,2-a]- pyrimidine-6-carbohydrazone (13)

Yield: 74%; Brownish foam. IR spectrum: 3424 (NH), 3066 (CH-aromatic), 2928 (CH-aliphatic), 1740 (C=O), 1615 (C=N). 1H-NMR (500 MHz, DMSO-d6) δ 1.95 (s, 3H, CH3), 1.99 (s, 3H, CH3), 2.04 (s, 3H, CH3), 2.17 (s, 3H, CH3), 2.26 (s, 3H, CH3), 2.46 (s, 3H, CH3), 2.92 (t, 2H, J = 5.6 Hz, CH2), 3.39–3.60 (m, 4H, CH2, H-6′,6″), 4.11–4.15 (m, 1H, H-5′), 4.25-4.34 (m, 2H, H-4′, H-3′), 4.83 (m, 1H, H-2′), 5.34 (s, 1H, H-7), 7.35-7.43 (m, 3H, thienyl-H), 8.05 (d, 1H, J = 7.8 Hz, H-1′), 9.12 (brs, 1H, NH). 13C-NMR (DMSO-d6) δ 18.8, 20.1, 20.4, 20.6, 20.9, 21.1 (6CH3), 45.1 (CH2), 55.4 (CH2), 60.6 (pyrimidine-C), 62.7 (C6′), 70.2 (C5′), 74.1 (C4′), 76.1 (C3′), 81.9 (C2′), 121.4 (pyrimidine-C), 124.9 (thienyl-C5), 126.4 (thienyl-C3), 127.0 (thienyl-C4), 139.4 (thienyl-C2), 140.6 (pyrimidine-C), 141.5 (C1′), 158.0 (pyrimidine-C), 167.5, 169.9, 170.2, 170.4, 170.6, 170.9 (6C=O). Anal. calcd. for C28H34N4O11S2 (666.72): C, 50.44; H, 5.14; N; 8.40. Found: C, 50.21; H; 5.18; N; 8.27.

3.5.4. Tetra-O-acetyl-d-xylotetritolyl-5-methyl-7-(thiophen-2-yl)-2,3-dihydro-7H-thiazolo[3,2-a]- pyrimidine-6-carbohydrazone (14)

Yield: 65%; Brownish foam. IR spectrum: 3407 (NH), 3060 (CH-aromatic), 2928 (CH-aliphatic), 1740 (C=O), 1626 (C=N). 1H-NMR (500 MHz, DMSO-d6) δ 2.01 (s, 3H, CH3), 2.03 (s, 3H, CH3), 2.05 (s, 3H, CH3), 2.11 (s, 3H, CH3), 2.44 (s, 3H, CH3), 3.39 (t, 2H, J = 5.6 Hz, CH2), 3.54-3.73 (m, 4H, CH2, H-5′,5″), 4.15–4.18 (m, 1H, H-4′), 4.70–4.75 (m, 1H, H-3′), 4.88–4.94 (m, 1H, H-2′), 5.55 (s, 1H, H-7), 7.35–7.38 (m, 1H, thienyl-H), 7.46 (d, 1H, J = 7.4 Hz, thienyl-H), 7.55–7.61 (m, 2H, thienyl-H, H-1′), 9.05 (brs, 1H, NH). 13C-NMR (DMSO-d6) δ 18.8, 19.9, 20.2, 20.4, 20.8 (5CH3), 45.1 (CH2), 55.4 (CH2), 60.6 (pyrimidine-C), 66.2 (C5′), 73.1 (C4′), 76.1 (C3′), 81.9 (C2′), 121.4 (pyrimidine-C), 124.9 (thienyl-C5), 126.4 (thienyl-C3), 127.0 (thienyl-C4), 139.4 (thienyl-C2), 140.6 (pyrimidine-C), 141.5 (C1′), 158.0 (pyrimidine-C), 167.7, 169.9, 170.2, 170.5, 170.9 (5C=O). Anal. calcd. for C25H30N4O9S2 (594.65): C; 50.50; H; 5.09, N; 9.42. Found: C, 50.35; H; 5.26; N; 9.25.

3.6. General Procedure for the Preparation of the Oxadiazoline Substituted Sugar Derivatives (15–18)

A solution of sugar hydrazones 7–10 (10 mmol) in acetic anhydride (15 mL) was heated at 100 °C with stirring for 1.5 h. The resulting solution was poured onto crushed ice, and the product was extracted by ethyl acetate, washed with a solution of sodium hydrogen carbonate followed by water and then dried after evaporation of ethyl acetate. The product was washed two times with diethyl ether–pet. ether mixture (1:1) then dried to give compounds 15–18.

3.6.1. 1-(5-(7-(4-Chlorophenyl)-5-methyl-2,3-dihydro-7H-thiazolo[3,2-a]pyrimidin-6-yl)-2-(penta-O-acetyl-d-galactopentitolyl)-1,3,4-oxadiazol-3(2H)-yl)ethan-1-one (15)

Yield: 72%; Brownish foam. IR spectrum: 3048 (CH-aromatic), 2962 (CH-aliphatic), 1735 (C=O), 1675 (C=O), 1618 (C=N). 1H-NMR (500 MHz, DMSO-d6) δ 2.30 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.41 (s, 3H, CH3), 2,42 (s, 3H, CH3), 2.43 (s, 3H, CH3), 3.41 (t, 2H, J = 6.2 Hz, CH2), 3.67–3.88 (m, 4H, CH2, H-5′,5″), 4.38–4.42 (m, 1H, H-4′), 4.68–4.72 (m, 1H, H-3′), 4.86-4.92 (m, 1H, H-2′), 4.99-5.04 (m, 1H, H-1′), 5.32 (s, 1H, H-7), 5.70 (d, 1H, J = 7.4 Hz, oxadiazoline-H), 7.35 (d, 2H, J = 8.4 Hz, Ar-H), 7.41 (d, 2H, J = 8.4 Hz, Ar-H). 13C-NMR (DMSO-d6) 18.6, 19.8, 20.1, 20.7, 21.0, 21.5, 23.4 (7CH3), 31.5, 52.8, (2CH2), 55.9 (pyrimidine-C), 61.9 (C5′), 62.8 (C4′), 67.7 (C3′), 68.9 (C2′), 75.0 (C1′), 82.5 (oxadiazoline-C), 118.1 (pyrimidine-C), 127.5 (ArC), 128.9 (Ar-2C), 134.5 (Ar-2C), 135.9 (Ar–C), 141.1 (pyrimidine-C), 151.5 (oxadiazoline-C), 158.2 (pyrimidine-C), 169.9, 170.1, 170.4, 170.7, 170.9, 171.2 (6C=O). Anal. calcd. for C32H37ClN4O12S (737.17): C, 52.14; H, 5.06; N; 7.60. Found: C, 52.39; H; 5.14; N, 7.79.

3.6.2. 1-(5-(7-(4-Chlorophenyl)-5-methyl-2,3-dihydro-7H-thiazolo[3,2-a]pyrimidin-6-yl)-2-(tetra-O-acetyl-d-xylotetritolyl)-1,3,4-oxadiazol-3(2H)-yl)ethan-1-one (16)

Yield: 66%; Brownish foam. IR spectrum: 3053 (CH-aromatic), 2916 (CH), 1735 (C=O), 1680 (C=O) 1616 (C=N). 1H-NMR (500 MHz, DMSO-d6) δ 2.36 (s, 3H, CH3), 2.38 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.41 (s, 3H, CH3), 2.42 (s, 3H, CH3), 2.49 ((s, 3H, CH3), 3.07 (t, 2H, J = 5.8 Hz, CH2), 3.43-3.54 (m, 3H, CH2, H-4″), 3.92–3.97 (m, 1H, H-4′), 4.35–4.38 (m, 1H, H-3′), 4.77–4.81 (m, 1H, H-2′), 4.90-4.94 (m, 1H, H-1′), 5.35 (s, 1H, H-7), 5.72 (d, 1H, J = 7.4 Hz, oxadiazoline-H), 7.29 (d, 2H, J = 8.5 Hz, Ar–H), 7.52 (d, 2H, J = 8.5 Hz, Ar–H). 13C-NMR (DMSO-d6) 19.1, 20.5, 20.8, 21.1, 21.5, 23.2 (6CH3), 31.4 (CH2), 52.7 (CH2), 59.30 (pyrimidine-C), 61.8 (C4′), 65.2 (C3′), 68.7 (C2′), 76.4 (C1′), 81.3 (oxadiazoline-C), 118.4 (pyrimidine-C), 128.5 (Ar-C), 130.0 (Ar-2C), 134.4(Ar-2C), 136.0 (Ar-C), 141.0 (pyrimidine-C), 150.7 (oxadiazoline-C), 158.6 (pyrimidine-C), 17.0, 170.3, 170.9, 171.2, 171.5 (5C=O). Anal. calcd. for C29H33ClN4O10S (665.11): C, 52.37; H; 5.00, N; 8.42. Found: C, 52.08; H; 5.14; N; 8.31.

3.6.3. 1-(5-(5-Methyl-7-(thiophen-2-yl)-2,3-dihydro-7H-thiazolo[3,2-a]pyrimidin-6-yl)-2-(penta-O-acetyl-d-galactopentitolyl)-1,3,4-oxadiazol-3(2H)-yl)ethan-1-one (17)

Yield: 76%; Brownish foam. IR spectrum: 3050 (CH-aromatic), 2929 (CH-aliphatic), 1739 (C=O), 1672 (C=O), 1612 (C=N); 1H-NMR (500 MHz, DMSO-d6) δ 2.30 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.36 (s, 3H, CH3), 2.39 (s, 3H, CH3), 2.43 (s, 3H, CH3), 2.46 (s, 3H, CH3), 2.49 (s, 3H, CH3), 3.23 (t, 2H, J = 5.8 Hz, CH2), 3.39–3.51 (m, 3H, CH2, H-5″), 3.82–4.01 (m, 1H, H-5′), 4.32–4.35 (m, 1H, H-4′), 4.64–4.79 (m, 2H, H-3′, H-2′), 4.98–5.05 (m, 1H, H-1′), 5.21 (s, 1H, H-7), 5.71 (d, 1H, J = 7.2 Hz, oxadiazoline-H), 7.81-7.93 (m, 3H, thiophen-H). 13C-NMR (DMSO-d6) 18.6, 20.1, 20.7, 21.0, 21.4, 21.5, 23.4 (7CH3), 31.5 (CH2), 52.8 (CH2), 40.9 (pyrimidine-C), 61.9 (C5′), 62.8 (C4′), 67.7 (C3′), 68.9 (C2′), 75.0 (C1′), 82.5 (oxadiazoline-C), 118.1 (pyrimidine-C), 127.5 (thienyl-C5),128.9 (thienyl-C3), 136.5 (thienyl-C4), 139.9 (thienyl-C2), 141.1 (pyrimidine-C), 151.5 (oxadiazoline-C), 158.2 (pyrimidine-C), 169.9, 170.1, 170.4, 170.7, 170.9, 171.2 (6C=O). Anal. calcd. for C30H36N4O12S2 (708.75): C, 50.84; H; 5.12, N; 7.91. Found: C, 50.62; H; 5.04; N; 8.02.

3.6.4. 1-(5-(5-Methyl-7-(thiophen-2-yl)-2,3-dihydro-7H-thiazolo[3,2-a]pyrimidin-6-yl)-2-(tetra-O-acetyl-d-xylotetritolyl)-1,3,4-oxadiazol-3(2H)-yl)ethan-1-one (18)

Yield: 68%; Brownish foam. IR spectrum: 3072 (CH-aromatic), 2935 (CH-aliphatic), 1740 (C=O), 1670 (C=O), 1631 (C=N). 1H-NMR (500 MHz, DMSO-d6) δ 2.30 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.41 (s, 3H, CH3), 2.46 (s, 3H, CH3), 2.55 (s, 3H, CH3), 3.24–3.27 (m, 4H, 2CH2), 3.93–3.97 (m, 1H, H-4″), 4.02–4.08 (m, 1H, H-4′), 4.43–4.47 (m, 1H, H-3′), 4.85–4.88 (m, 1H, H-2′), 5.12–5.17 (m, 2H, H-1′), 5.25 (s, 1H, H-7), 5.70 (d, 1H, J = 7.4 Hz, oxadiazoline-H), 7.83–7.92 (m, 3H, thiophen-H). 13C-NMR (DMSO-d6): 19.1, 20.5, 20.8, 21.1, 21.5, 23.2 (6CH3), 31.4 (CH2), 52.7 (CH2), 47.2 (pyrimidine-C), 61.8 (C4′), 65.2 (C3′), 68.7 (C2′), 76.4 (C1′), 81.3 (oxadiazoline-C), 118.4 (pyrimidine-C), 127.5 (thienyl C-5), 129.5 (thienyl C-3), 134.4 (thienyl C-4), 135.9 (thienyl C-2), 141.0 (pyrimidine-C), 150.7 (oxadiazoline-C), 158.6 (pyrimidine-C), 170.3, 170.5, 170.9, 171.2, 171.5 (5C=O); Anal. calcd. for C27H32N4O10S2 (636.69): C, 50.93; H; 5.07, N; 8.80. Found: C; 51.05; H; 5.11; N; 8.68.

3.7. Materials of the Cell Lines Assay

3.7.1. Cell Culture, Maintenance, and Sub-Culture

Human sensitive and resistant cell lines were purchased from American Type Culture Collection (ATCC, Gaithersburg, MD, USA) as well as human breast cancer MCF7 and MDA-MB-231 cell lines and human colorectal cancer HCT 116 and Caco-2 cell lines. They were cultured using Dulbecco’s modified Eagle’s medium (DMEM) and Roswell Park Memorial Institute (RPMI-1640) medium. All media were supplemented with 4.5g/L glucose w/L-glutamine (Lonza Bioproducts, Belgium) and 10% fetal bovine serum (FBS) (Seralab, UK). The cells were incubated in 5% CO2 humidified at 37 °C for growth maintenance.

3.7.2. Cell Proliferation by MTT Assay

The percentages of viable human colorectal cancer HCT 116 and Caco-2 cells as well as human breast cancer MCF7 and MDA-MB-231 cell lines after treatment with different concentrations of the synthesized compounds. These compounds were evaluated by the 3-(4,5-methylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay, as reported previously [38], with slight modification. In brief, after evaluation of cell count and viability by trypan blue dye-based method, A549 cells (1 × 104 cells/well) were seeded in a 96 well plate and then kept overnight for attachment. The next day, the complete medium was replaced with fresh one, and then various concentrations of the formulations were investigated on each cell line. After that, cells were allowed to grow for 24 h. Four hours before completion of the incubation period, 10 μL of the MTT (5 mg/mL) was added in each well. After completing the incubation, 100 μL of dimethyl sulfoxide (DMSO) was added to each well and left for 20 min to dissolve the formazan crystals. After the reaction, color development was measured at 450 nm using Bio-Tek microplate reader.

3.7.3. IC50 Measurement

The half-maximal inhibitory concentrations (IC50) values, which are the concentrations that inhibit 50% of cancer cell viabilities, were obtained by plotting the percentages of cancer cell viabilities versus the concentrations of the sample using polynomial concentration–response curve fitting models (OriginPro 8 software).

4. Conclusions

New hybrid compounds of aryl or heteroaryl substituted thiazolopyrimidine system incorporating acyclic sugar moiety derivatives and their derived oxadiazoline compounds were prepared from simple starting compounds. The cytotoxic activities against four cancer cell lines were studied and the prepared compounds that had either an acetylated or deprotected acyclic sugar part were the most active. The results showed the importance of attachment of certain sugar moieties to the thiazolopyrimidine system. The highest activities by the most active candidates were revealed against human colorectal cancer Caco-2 cell lines with the lowest IC50 values.

Author Contributions

The research group including E.A.B. and A.A.-H.A.-R. (Menoufia University), W.A.E.-S. (Qassim university), A.A.H. and N.A.H. (Shaqra University) conceived the research project, conceptualization, participation in the research steps, interpreted the results, discussed the experimental data and prepared the manuscript. Z.M.A.-A. (King Abdulaziz University) participated in discussion of the experimental data and supported funding acquisition. A.A.A.-R. conducted the biological assays and provided the experimental procedures and results of biological analysis. All authors have read and agreed to the published version of the manuscript.

Funding

This project was funded by the Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah, under grant No. (D-222-247-1441).

Acknowledgments

The authors gratefully acknowledge DSR’s technical and financial support.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. De Martino, J.K.; Boger, D.L. Glycinamide ribonucleotide transformylase (GAR TFase) as a target for cancer therapy. Drug Future 2008, 33, 969–979. [Google Scholar] [CrossRef]
  2. Curran, W.J. New chemotherapeutic agents: Update of major chemoradiation trials in solid tumors. Oncology 2002, 63, 29–38. [Google Scholar] [CrossRef] [PubMed]
  3. Mohamed, A.M.; Amr, A.E.G.; Alsharari, M.A.; Al-Qalawi, H.R.M.; Germoush, M.O.; Al-Omar, M.A. Anticancer Activities of Some New Synthesized Thiazolo[3,2-a]Pyrido[4,3-d]Pyrimidine Derivatives. Am. J. Biochem. Biotechnol. 2011, 7, 43–54. [Google Scholar] [CrossRef]
  4. Hammam, A.G.; El-Salam, O.I.A.; Mohamed, A.M.; Hafez, N.A. Novel fluoro substituted benzo[o]pyranwith anti-lung cancer activity. Ind. J. Chem. 2005, 44B, 1887–1893. [Google Scholar]
  5. Flefel, E.E.; Salama, M.A.; El-Shahat, M.; El-Hashash, M.A.; El-Farargy, A.F. A novel synthesis of some new pyrimidine and thiazolopyrimidine derivatives for anticancer evaluation. Phosphorus Sulfur Silicon Relat. Elem. 2007, 182, 1739–1756. [Google Scholar] [CrossRef]
  6. Cai, D.; Zhang, Z.-H.; Chen, Y.; Yan, X.-J.; Zou, L.-J.; Wang, Y.-X.; Liu, X.-Q. Synthesis, Antibacterial and Antitubercular Activities of Some 5H-Thiazolo[3,2-a]pyrimidin-5-ones and Sulfonic Acid Derivative. Molecules 2015, 20, 16419–16434. [Google Scholar] [CrossRef] [PubMed]
  7. Wichmann, J.; Adam, G.; Kolczewski, S.; Mutel, V.; Woltering, T. Structure-activity relationships of substituted 5H-thiazolo[3,2-a]pyrimidines as group 2 metabotropic glutamate receptor antagonists. Bioorg. Med. Chem. Lett. 1999, 9, 1573–1576. [Google Scholar] [CrossRef]
  8. Al-Omary, F.A.; Hassan, G.S.; El-Messery, S.M.; ElSubbagh, H.I. Substituted thiazoles V. Synthesis and antitumor activity of novel thiazolo[2,3-b]quinazoline and pyrido[4,3-d] thiazolo[3,2-a] pyrimidine analogues. Eur. J. Med. Chem. 2012, 47, 65–72. [Google Scholar] [CrossRef]
  9. Fatima, S.; Sharma, A.; Saxena, R.; Tripathi, R.; Shukla, S.K.; Pandey, S.K.; Tripathi, R.; Tripathi, R.P. One pot efficient diversity oriented synthesis of polyfunctional styryl thiazolopyrimidines and their bio-evaluation as antimalarial and anti-HIV agents. Eur. J. Med. Chem. 2012, 55, 195–204. [Google Scholar] [CrossRef]
  10. Yıldırım, A.B.; Mutlu, E.; Yıldırım, M. Cytotoxic Effects of Thiazolo[3,2-C]Pyrimidines Against Mcf-7 And Hepg2/C3a Carcinoma Cell Lines. Hacet. J. Biol. Chem. 2018, 46, 237–246. [Google Scholar] [CrossRef]
  11. Amr, A.-E.-G.; Maigali, S.S.; Abdulla, M.M. Synthesis, and analgesic and antiparkinsonian activities of thiopyrimidine, pyrane, pyrazoline, and thiazolopyrimidine derivatives from 2-chloro-6-ethoxy-4-acetylpyridine. Mon. Chem. 2008, 139, 1409–1415. [Google Scholar] [CrossRef]
  12. Branstetter, B.J.; Breitenbucher, J.G.; Lebsack, A.D.; Xiao, W. Thiazolopyrimidine Modulators of TRPV1. U.S. Patent WO 005303, 10 January 2008. [Google Scholar]
  13. Said, M.; Abouzid, K.; Mouneer, A.; Ahmedy, A.; Osman, A.-M. Synthesis and biological evaluation of new thiazolopyrimidines. Arch. Pharm. Res. 2004, 27, 471–477. [Google Scholar] [CrossRef] [PubMed]
  14. Ackova, D.G.; Kotur-Stevuljevic, J.; Mishra, C.B.; Luthra, P.M.; Saso, L. Antioxidant Properties of Synthesized Bicyclic Thiazolopyrimidine Derivatives as Possible Therapeutic Agents. Appl. Sci. 2019, 9, 113. [Google Scholar] [CrossRef] [Green Version]
  15. Youssef, M.M.; Amin, M.A. Microwave Assisted Synthesis of Some New Thiazolopyrimidine, Thiazolodipyrimidine and Thiazolopyrimidothiazolopyrimidine Derivatives with Potential Antioxidant and Antimicrobial Activity. Molecules 2012, 17, 9652–9667. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Linder, W.; Brandes, W. Pesticidal Thiazolopyrimidine Derivatives. U.S. Patent 4,996,208, 26 February 1991. [Google Scholar]
  17. Duval, R.; Kolb, S.; Braud, E.; Genest, D.; Garbay, C. Rapid discovery of triazolobenzylidenethiazolopyrimidines (TBTP) as CDC25 phosphatase inhibitors by parallel click chemistry and in situ screening. J. Comb. Chem. 2009, 11, 947–950. [Google Scholar] [CrossRef] [PubMed]
  18. Kolb, S.; Mondésert, O.; Goddard, M.L.; Jullien, D.; Villoutreix, B.O.; Ducommun, B.; Garbay, C.; Braud, E. Development of novel thiazolopyrimidines as CDC25B phosphatase inhibitors. ChemMedChem 2009, 4, 633–648. [Google Scholar] [CrossRef] [PubMed]
  19. Mahgoub, M.Y.; Elmaghraby, A.M.; Harb, A.A.; da Silva, J.L.F.; Justino, G.C.; Marques, M.M. Synthesis, Crystal Structure, and Biological Evaluation of Fused Thiazolo[3,2-a]Pyrimidines as New Acetylcholinesterase Inhibitors. Molecules 2019, 24, 2306. [Google Scholar] [CrossRef] [Green Version]
  20. Liu, S.-J.; Yang, L.; Jin, Z.; Huang, E.F.; Wan, D.C.C.; Lin, H.-Q.; Hu, C. Design, synthesis, and biological evaluation of 7H-thiazolo[3,2-b]- 1,2,4-triazin-7-one derivatives as novel acetylcholinesterase inhibitors. Arkivoc 2009, 10, 333–348. [Google Scholar]
  21. Rashad, A.E.; Shamroukh, A.H.; Abdel-Megeid, R.E.; El-Sayed, W.A. Synthesis, reactions and antimicrobial evaluation of some polycondensedthieno-pyrimidine derivatives. Synth. Commun. 2010, 40, 1149–1160. [Google Scholar] [CrossRef]
  22. El-Emary, T.I.; Abdel-Mohsen, S.A. Synthesis and antimicrobial activity of some new 1,3-diphenylpyrazoles bearing pyrimidine, Pyrimidinethione, thiazolopyrimidine, triazolopyrimidine, thio- and alkylthiotriazolopyrimidinone moieties at the 4-position. Phosphorus Sulfur Silicon Relat. Elem. 2006, 181, 2459–2474. [Google Scholar] [CrossRef]
  23. Maddila, S.; Damu, G.L.V.; Oseghe, E.O.; Abafe, O.A.; Venakata, R.C.; Lavanya, P. Synthesis and biological studies of novel biphenyl-3,5-dihydro-2H-thiazolo-pyrimidines derivatives. J. Korean Chem. Soc. 2012, 56, 334–340. [Google Scholar] [CrossRef]
  24. Khalilullah, H.; Ahsan, M.J.; Hedaitullah, M.; Khan, S.; Ahmad, B. 1,3,4-Oxadiazole: A Biologically Active Scaffold. Mini-Rev. Med. Chem. 2012, 12, 789–801. [Google Scholar] [CrossRef] [PubMed]
  25. Kassem, A.F.; Nassar, I.F.; Abdel-Aal, M.T.; Awad, H.M.; El-Sayed, W.A. Synthesis and Anticancer Activity of New ((Furan-2-yl)-1,3,4-thiadiazolyl)-1,3,4-oxadiazole Acyclic Sugar Derivatives. Chem. Pharm. Bull. 2019, 67, 888–895. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Nassar, I.F.; El kady, D.S.; Awad, H.M.; El-Sayed, W.A. Design, Synthesis, and Anticancer Activity of New Oxadiazolyl-Linked and Thiazolyl-Linked Benzimidazole Arylidines, Thioglycoside, and Acyclic Analogs. J. Heterocycl. Chem. 2019, 56, 1086–1100. [Google Scholar] [CrossRef]
  27. El-Sayed, W.A.; Khalaf, H.S.; Osman, D.A.A.; Abbas, H.S.; Ali, M.M. Synthesis and Anticancer Activity of New Pyrazolyl and Oxadiazolyl Glycosides Based on Theinopyrimidine Nucleus and Their Acyclic Analogs. Acta Polonea Pharm. Drug Res. 2017, 74, 1739–1751. [Google Scholar]
  28. Gamal El-Din, M.M.; El-Gamal, M.I.; Abdel-Maksoud, M.S.; Yoo, K.H.; Oh, C.H. Synthesis and in vitro antiproliferative activity of new 1,3,4-oxadiazole derivatives possessing sulfonamide moiety. Eur. J. Med. Chem. 2015, 90, 45–52. [Google Scholar] [CrossRef]
  29. El-Sadek, M.M.; Hassan, S.Y.; Abd El-Dayem, N.S.; Yacout, G.A. 5-(5-Aryl-1,3,4-oxadiazole-2-carbonyl)furan-3-carboxylate and New Cyclic C-Glycoside Analogues from Carbohydrate Precursors with MAO-B, Antimicrobial and Antifungal Activities. Molecules 2012, 17, 7010–7027. [Google Scholar] [CrossRef] [Green Version]
  30. Glomb, T.; Szymankiewicz, K.; Swiatek, P. Anti-Cancer Activity of Derivatives of 1,3,4-Oxadiazole. Molecules 2018, 23, 336. [Google Scholar] [CrossRef] [Green Version]
  31. El Sayed, W.A.; Abbas, H.-A.S.; Ewais, A.M. C-Furyl glycosides, III: Synthesis and antimicrobial evaluation of C-furyl glycosides bearing substituted 1,3,4-oxadiazoles and their sugar hydrazone derivatives. J. Heterocycl. Chem. 2011, 48, 1006–1013. [Google Scholar] [CrossRef]
  32. Kahl, D.; Hutchings, K.; Lisabeth, E.M.; Larsen, S.D. 5-Aryl-1,3,4-oxadiazol-2-ylthioalkanoic Acids: A Highly Potent New Class of Inhibitors of Rho/Myocardin-Related Transcription Factor (MRTF)/Serum Reponse Factor (SRF)-Mediated Gene Transcription as Potential Antifibrotic Agents for Scleroderma. J. Med. Chem. 2019, 62, 4350–4369. [Google Scholar] [CrossRef]
  33. El-Sayed, W.A.; El-Sofany, W.I.; Hussein, H.A.; Fathi, N.M. Synthesis and Anticancer Activity of New [(Indolyl)pyrazolyl]-1,3,4-oxadiazole Thioglycosides and Acyclic Nucleoside Analogs. Nucleosides Nucleotides Nucleic Acids 2017, 36, 474–495. [Google Scholar] [CrossRef] [PubMed]
  34. El Ashry, E.S.H.; El Kilany, Y. Acyclonucleosides: Part 1. Seco-Nucleosides. Adv. Heterocycl. Chem. 1996, 67, 391–438. [Google Scholar]
  35. El Ashry, E.S.H.; El Kilany, Y. Acyclonucleosides: Part 3. tri-, tetra-, and pentaseco-Nucleosides. Adv. Heterocycl. Chem. 1998, 69, 129–215. [Google Scholar]
  36. Kassem, A.F.; Abbas, E.M.H.; El-Kady, D.S.; Awad, H.M.; El-Sayed, W.A. Synthesis, Docking Studies and Anticancer Activity of New Tetrazolyl- and (Triazolyl)thiazole Glycosides and Acyclic Analogs. Mini-Rev. Med. Chem. 2019, 19, 933–948. [Google Scholar] [CrossRef]
  37. Abdel Rahman, A.A.H.; Nassar, I.F.; Shaban, A.K.F.; EL-Kady, D.S.; Awad, H.M.; El Sayed, W.A. Synthesis, Docking Studies into CDK-2 and Anticancer Activity of New Derivatives Based Pyrimidine Scaffold and Their Derived Glycosides. Mini-Rev. Med. Chem. 2019, 19, 1093–1110. [Google Scholar] [CrossRef]
  38. Abdel-Aal, M.T.; El-Sayed, W.A.; El-Kosy, S.M.; El-Ashry, E.S.H. Synthesis and Antiviral Evaluation of Novel 5-(N-Aryl-aminomethyl-1,3,4-oxadiazol-2-yl)hydrazines and their Sugars, 1,2,4-triazoles, tetrazoles and pyrazolyl Derivatives. Arch. Pharm. Chem. Life Sci. 2008, 341, 307–313. [Google Scholar] [CrossRef]
  39. Yousif, M.N.M.; El-Sayed, W.A.; Abbas, H.S.; Awad, H.M.; Yousif, N.M. Anticancer Activity of New Substituted Pyrimidines, Their Thioglycosides and Thiazolopyrimidine Derivatives. J. Appl. Pharm. Sci. 2017, 7, 021–032. [Google Scholar]
  40. Iftikhar, F.; Yaqoob, F.; Tabassum, N.; Jan, M.S.; Sadiq, A.; Tahir, S.; Batool, T.; Niaz, B.; Ansari, F.L.; Choudhary, M.I.; et al. Design, Synthesis, in-Vitro Thymidine Phosphorylase Inhibition, In-Vivo Antiangiogenic and in-Silico Studies of C-6 Substituted Dihydropyrimidines. Bioorg. Chem. 2018, 80, 99–111. [Google Scholar] [CrossRef]
  41. Flefel, E.M.; El-Sayed, W.A.; El-Sofany, W.; Mohamed, A.M.; Awad, H.M. Synthesis and Anticancer Activity of New 1-Thia-4-azaspiro[4.5]decane, Their Derived Thiazolopyrimidine and 1,3,4-Thiadiazole Thioglycosides. Molecules 2017, 22, 170. [Google Scholar] [CrossRef]
  42. Fahmy, H.T.Y.; Rostom, S.A.F.; Saudi, M.N.; Zjawiony, J.K.; Robins, D.J. Synthesis and in vitro evaluation of the anticancer activity of novel fluorinated thiazolo[4,5-d]pyrimidines. Arch. Pharm. Pharm. Med. Chem. 2003, 336, 216–225. [Google Scholar] [CrossRef]
  43. El-Sayed, W.A.; Khalaf, H.S.; Mohamed, S.F.; Hssien, H.A.; Kutkat, O.M.; Amr, A.E.E. Synthesis and Antiviral Activity of 1,2,3-Triazole Glycosides Based Substituted Pyridine Via Click Cycloaddition. Russ. J. Gen. Chem. 2017, 87, 2444–2453. [Google Scholar] [CrossRef]
  44. Nassar, I.F.; El-Sayed, W.A.; Ragab, T.I.M.; Shalaby, A.S.G.; Mehany, A.B.M. Design, Synthesis of New Pyridine and Pyrimidine Sugar Compounds as Antagonists Targeting the ERα via Structure-Based Virtual Screening. Mini-Rev. Med. Chem. 2019, 19, 395–409. [Google Scholar] [CrossRef] [PubMed]
  45. Alminderej, F.M.; Elganzory, H.H.; El-Bayaa, M.N.; Awad, H.M.; El-Sayed, W.A. Synthesis and Cytotoxic Activity of New 1,3,4-Thiadiazole Thioglycosides and 1,2,3-Triazolyl-1,3,4-Thiadiazole N-glycosides. Molecules 2019, 24, 3738. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Abdel-Aal, M.T.; El-Sayed, W.A.; El-Ashry, E.S.H. Synthesis and Antiviral Evaluation of Some Sugar Arylglycinoylhydrazones and Their Oxadiazoline Derivatives. Arch. Pharm. Chem. Life Sci. 2006, 339, 656–663. [Google Scholar] [CrossRef]
  47. Attri, P.; Bhatia, R.; Gaur, J.; Arora, B.; Gupta, A.; Kumar, N.; Choi, E.H. Triethylammonium acetate ionic liquid assisted one-pot synthesis of dihydropyrimidinones and evaluation of their antioxidant and antibacterial activities. Arab. J. Chem. 2017, 10, 206–214. [Google Scholar]
  48. Chen, L.; Jin, Y.; Fu, W.; Xiao, S.; Feng, C.; Fang, B.; Gu, Y.; Li, C.; Zhao, Y.; Liu, Z.; et al. Design, Synthesis, and Structure–Activity Relationship Analysis of Thiazolo[3,2-a]pyrimidine Derivatives with Anti-inflammatory Activity in Acute Lung Injury. ChemMedChem 2017, 12, 1022–1032. [Google Scholar] [CrossRef]
  49. Mobinikhaledi, A.; Forughifar, N.; Goodarzi, F. Synthesis of Some Bicyclic Thiazolopyrimidine Derivatives. Phosphorus Sulfur Silicon Relat. Elem. 2003, 178, 2539–2543. [Google Scholar] [CrossRef]
  50. Abdel Rahman, M.M.; El Ashry, E.S.H.; Abdalla, A.A.; Rashed, N. C-(Polyacetoxy)alkyloxadiazolines and related compounds. Carbhydr. Res. 1979, 73, 103–111. [Google Scholar] [CrossRef]
  51. Somogyi, L. Structure and reactions of L-rhamnose benzoylhydrazone tetra-acetates. Carbohydr. Res. 1978, 64, 289–292. [Google Scholar] [CrossRef]
  52. Van Meerloo, J.; Kaspers, G.J.; Cloos, J. Cell sensitivity assays: The MTT assay. J. Methods Mol. Biol. 2011, 731, 237–245. [Google Scholar]
Sample Availability: Samples of the synthesized compounds are available from the authors.
Molecules 25 00399 g001 550
Figure 1. Anticancer thiazolopyrimidine, pyrinidinyl-sugar, and pyrimidinyl-oxadiazole compounds.
Figure 1. Anticancer thiazolopyrimidine, pyrinidinyl-sugar, and pyrimidinyl-oxadiazole compounds.
Molecules 25 00399 g001
Molecules 25 00399 sch001 550
Scheme 1. Synthesis of aryl- or heteroaryl-substituted thiazolopyrimidine derivatives.
Scheme 1. Synthesis of aryl- or heteroaryl-substituted thiazolopyrimidine derivatives.
Molecules 25 00399 sch001
Molecules 25 00399 sch002 550
Scheme 2. Synthesis of thiazolopyrimidine sugar hydrazones and their oxadiazolyl sugar derivatives.
Scheme 2. Synthesis of thiazolopyrimidine sugar hydrazones and their oxadiazolyl sugar derivatives.
Molecules 25 00399 sch002
Molecules 25 00399 g002 550
Figure 2. Anti-proliferative activities of compounds against human colorectal cancer HCT 116 cells. The MTT assay was performed three independent times (n = 3) using different concentrations of the mentioned compounds.
Figure 2. Anti-proliferative activities of compounds against human colorectal cancer HCT 116 cells. The MTT assay was performed three independent times (n = 3) using different concentrations of the mentioned compounds.
Molecules 25 00399 g002
Molecules 25 00399 g003 550
Figure 3. Anti-proliferative activities of compounds against human colorectal cancer Caco-2 cells. The MTT assay was performed three independent times (n = 3) using different concentrations of the mentioned compounds.
Figure 3. Anti-proliferative activities of compounds against human colorectal cancer Caco-2 cells. The MTT assay was performed three independent times (n = 3) using different concentrations of the mentioned compounds.
Molecules 25 00399 g003
Molecules 25 00399 g004 550
Figure 4. Anti-proliferative activities of compounds against human breast cancer MDA-MB-231 cells. The MTT assay was performed three independent times (n = 3) using different concentrations of the mentioned compounds.
Figure 4. Anti-proliferative activities of compounds against human breast cancer MDA-MB-231 cells. The MTT assay was performed three independent times (n = 3) using different concentrations of the mentioned compounds.
Molecules 25 00399 g004
Molecules 25 00399 g005 550
Figure 5. Anti-proliferative activities of compounds against human breast cancer MCF7 cells. The MTT assay was performed three independent times (n = 3) using different concentrations of the mentioned compounds.
Figure 5. Anti-proliferative activities of compounds against human breast cancer MCF7 cells. The MTT assay was performed three independent times (n = 3) using different concentrations of the mentioned compounds.
Molecules 25 00399 g005
Table
Table 1. IC50s of the compounds against different colorectal and breast cancerous cell lines.
Table 1. IC50s of the compounds against different colorectal and breast cancerous cell lines.
CompoundHCT116 CellsCaco-2 CellsMDA-MB-231 CellsMCF7 Cells
125.2858.3140.78ND
463.6130.8436.55ND
866.759.6346.9969.90
927.95NDNDND
1065.894.7930.5816.85
1134.8083.0123.3512.47
1344.0416.8246.3034.83
IC50 values are in µg/mL. ND = IC50 undetectable (i.e., IC50 more than 100 µg/mL).

Share and Cite

MDPI and ACS Style

Basiony, E.A.; Hassan, A.A.; Al-Amshany, Z.M.; Abd-Rabou, A.A.; Abdel-Rahman, A.A.-H.; Hassan, N.A.; El-Sayed, W.A. Synthesis and Cytotoxic Activity of New Thiazolopyrimidine Sugar Hydrazones and Their Derived Acyclic Nucleoside Analogues. Molecules 2020, 25, 399. https://doi.org/10.3390/molecules25020399

AMA Style

Basiony EA, Hassan AA, Al-Amshany ZM, Abd-Rabou AA, Abdel-Rahman AA-H, Hassan NA, El-Sayed WA. Synthesis and Cytotoxic Activity of New Thiazolopyrimidine Sugar Hydrazones and Their Derived Acyclic Nucleoside Analogues. Molecules. 2020; 25(2):399. https://doi.org/10.3390/molecules25020399

Chicago/Turabian Style

Basiony, Ebtesam A., Allam A. Hassan, Zahra M. Al-Amshany, Ahmed A. Abd-Rabou, Adel A.-H. Abdel-Rahman, Nasser A. Hassan, and Wael A. El-Sayed. 2020. "Synthesis and Cytotoxic Activity of New Thiazolopyrimidine Sugar Hydrazones and Their Derived Acyclic Nucleoside Analogues" Molecules 25, no. 2: 399. https://doi.org/10.3390/molecules25020399

Article Metrics

Back to TopTop