Design and synthesis of novel 1,3,4-thiadiazole thioglycosides as promising antimicrobial potent structures.

Thiosemicarbazide was used as a key starting material for the building of a diversity of novel heterocyclic moieties. The heterocyclization reaction of thiosemicarbazide derivatives with carbon disulfide in basic conditions afforded novel heterocyclic 1,3,4-thiadiazolethiolate derivatives. 1,3,4-thiadiazole-2-thiol was successfully reacted with protected α-D-gluco- and galacto-pyranosyl bromides in dimethylformamide at room temperature to give the matching 1,3,4-thiadiazole S-glycosides in good yields. The latter compounds were reacted with ammonia-methanol at room temperature for 10 min, and the deprotected derivatives were obtained in good yields. The newly synthesized compounds were characterized by basic analyses and spectral information (IR,1H NMR, and 13C NMR, X-ray). All newly produced compounds were evaluated and screened for their antibacterial activities. Compound 6f proved to be the most active antimicrobial among the investigated heterocycles.

Crystal structure of (E)-N-(4-bromo-phen-yl)-2-cyano-3-[3-(2-methyl-prop-yl)-1-phenyl-1H-pyrazol-4-yl]prop-2-enamide.

The structure of the title compound, C23H21BrN4O, contains two independent mol-ecules connected by hydrogen bonds of the type Namide-H⋯N≡C to form a dimer. The configuration at the exocyclic C=C double bond is E. The mol-ecules are roughly planar except for the isopropyl groups. There are minor differences in the orientations of these groups and the phenyl rings at N1. The dimers are further linked by 'weak' hydrogen bonds, two each of the types Hphen-yl⋯O=C (H⋯O = 2.50, 2.51 Å) and Hphen-yl⋯Br (H⋯Br = 2.89, 2.91 Å), to form ribbons parallel to the b and c axes, respectively. The studied crystal was a non-merohedral twin.

Crystal structure of 5-(ß-d-gluco-pyran-osyl-thio)-N-(4-methyl-phen-yl)-1,3,4-thia-diazol-2-amine.

In the structure of the title compound, C15H19N3O5S2, the bond lengths at the linking sulfur atom are significantly different [1.7473 (17) and 1.811 (2) Å], and the angle at the exocyclic nitro-gen atom is wide at 128.45 (18)°. The inter-planar angle between the tolyl and thia-diazole rings is 9.2 (1)°. The complex hydrogen-bonding pattern, involving five donors and five acceptors, can be broken down into a one-dimensional ribbon parallel to the b axis, involving hydrogen bonds of the sugar residues only, and a two-dimensional layer structure parallel to the ab plane, based on the N-H⋯O and O-H⋯N hydrogen bonds.

Synthesis of novel pyridine and pyrimidine thioglycoside phosphoramidates for the treatment of COVID-19 and influenza A viruses.

A novel series of pyridine, cytosine, and uracil thioglycoside analogs (4a-i, 9a,b, and 13a,b, respectively) and their corresponding phosphoramidates (6a-I, 10a,b, and 14a,b, respectively) were synthesized and assessed for their antiviral inhibitory activities in a dual-pathogen screening protocol against SARS-CoV-2 and influenza A virus (IAV). MTT cytotoxicity (TC50) and plaque reduction assays were used to explore inhibition and cytotoxicity percentage values for H5N1 influenza virus strain and the half-maximal cytotoxic concentration (CC50) and inhibitory concentration (IC50) for SARS-CoV-2 virus. Most of the tested compounds demonstrated dose-dependent inhibition behavior. Both cytosine thioglycoside phosphoramidates 10a and 10b exhibited the most potent profiles with 83% and 86% inhibition at 0.25 µM concentration against H5N1 and IC50 values of 12.16 µM, 14.9 µM against SARS-CoV-2, respectively. Moreover, compounds 10a and 10b have been shown to have the highest selectivity index (SI) among all the tested compounds against SARS-CoV-2 with 28.2 and 26.9 values, respectively.

Anti-Covid-19 Drug Analogues: Synthesis of Novel Pyrimidine Thioglycosides as Antiviral Agents Against SARS-COV-2 and Avian Influenza H5N1 Viruses.

A class of pyrimidine thioglycoside analogs (6a-h) were synthesized from a reaction of 2-cyano-3,3-dimercapto-N-arylacrylamide (2a-d) and thiourea to produce the corresponding 4-amino-2-mercapto-N-arylpyrimidine-5-carboxamide derivatives (3a-d), and stirring of compounds (3a-d) with peracylated α-d-gluco- and galacto-pyranosyl bromides (4a,b) in DMF-sodium hydride gave the corresponding pyrimidine thioglycosides (5a-h). Deacetylation of the pyrimidine thioglycosides via a reaction with dry NH3/MeOH gave the corresponding free pyrimidine thioglycosides (6a-h). The compounds have been characterized by 13C NMR, 1H NMR, and IR. Pharmacological evaluation of compounds 3a-d, 5a-h, and 6a-h in vitro against SARS-COV-2 and Avian Influenza H5N1 virus strains revealed that some compounds possess interesting activity.

Synthesis of novel pyrimidine thioglycosides as structural analogs of favipiravir (avigan) and their antibird flu virus activity.

Novel class of amino pyrimidine thioglycoside derivatives were designed from sodium 2-cyano-3-(arylamino)prop-1-ene-1,1-bis(thiolate) 1a-d and guanidine hydrochloride 2 to afford the corresponding sodium 2,6-diamino-5-aryl-1,2-dihydropyrimidine-4-thiolate 3a-d, which in coupling with peracylated α-D-gluco- and galactopyranosyl bromides 5a,b in DMF gave the corresponding pyrimidine thioglycosides 6a-h. Acidification of 2,6-diamino-5-aryl-1,2-dihydropyrimidine-4-thiolate salts 3a-d with hydrochloric acid formed the corresponding pyrimidine-4-thioles 4a-d. The latter were stirred with peracetylated halo sugars α-D-gluco- and galacto-pyranosyl bromides in sodium hydride and DMF to yield the pyrimidine thioglycosides 6a-h. Deacetylation of the pyrimidine thioglycosides gave the corresponding free pyrimidine thioglycosides 7a-h. The compounds were characterized by 13C NMR, 1H NMR, and IR. The pyrimidine thioglycosides 6a-h and free pyrimidine thioglycosides 7a-h were tested against H5N1 virus strain and exhibited high to moderate activity.

Toward Developing Therapies against Corona Virus: Synthesis and Anti-Avian Influenza Virus Activity of Novel Cytosine Thioglycoside Analogues.

A series of pyrimidine and pyrimidine thioglycoside derivatives were newly synthesized using sodium 2-cyano-3-(arylamino)prop-1-ene-1,1-bis(thiolates) and urea to give the corresponding sodium 6-amino-5-aryl-2-oxo-1,2-dihydropyrimidine-4-thiolates. Stirring of the latter with peracetylated α-d-gluco- and galacto-pyranosyl bromides in DMF afforded the corresponding pyrimidine thioglycosides. On the other hand, treatment of 6-amino-5-aryl-2-oxo-1,2-dihydropyrimidine-4-thiolate salts with hydrochloric acid produced the corresponding pyrimidine-4-thioles, which on stirring with α-d-gluco- and galacto-pyranosyl bromides in sodium hydride and DMF gave the corresponding pyrimidine thioglycosides. Deacetylation of the protected pyrimidine thioglycosides gave the corresponding free pyrimidine thioglycosides. The synthesized compounds have been characterized by 13C NMR, 1H NMR, and IR spectroscopy. The pyrimidine thioglycosides and free pyrimidine thioglycosides were tested against avian influenza H5N1 virus strain and exhibited highest to moderate activity.

Crystal structure of 4,6-dimethyl-2-[(2,3,4,6-tetra-O-acetyl-ß-d-galacto-pyranos-yl)sulfan-yl]pyrimidine.

In the title com-pound, C20H26N2O9S, the S atom is attached equatorially to the sugar ring. The C-S bond lengths are unequal, with S-Cs = 1.8018 (13) Šand S-Cp = 1.7662 (13) Š(s = sugar and p = pyrimid-yl). In the crystal, a system of three weak hydrogen bonds, sharing an oxygen acceptor, links the mol-ecules to form chains propagating parallel to the b-axis direction.

Novel purine thioglycoside analogs: synthesis, nanoformulation and biological evaluation in in vitro human liver and breast cancer models.

Background: A series of novel pyrazolopyrimidine and pyrazololpyridine thioglycosides were synthesized and confirmed via their spectral analyses. Purpose: To evaluate the effect of these anti-metabolic compounds against proliferation of Huh-7 and Mcf-7 as in vitro models of human liver and breast cancers, respectively. Vero cells were used as an example of normal green monkey kidney cells. Methods: The most promising compound was subjected to a nanoformulation by its encapsulation into chitosan nanoparticles to increase its anti-cancerous activity. Nanoformulation was confirmed by TEM and FT-IR to ensure encapsulation and screened for their cytotoxicity against Huh-7 and Mcf-7 cells using MTT colorimetric assay and morphological examination. Genotoxic effect was performed by cellular DNA fragmentation assay. Simulated CompuSyn software (linear interaction effect) was conducted to predict the possible synergistic effect of nanocomposite as anticancerous activity. Apoptotic effect was further analyzed by detection of apoptotic proteins using ELISA assay. Results: The nano preparation was successfully prepared by encapsulation of compound 14 into chitosan nanoparticles, controlled to a size at 105 nm and zeta charges at 40.2 mV. Treatment of Huh-7 and Mcf-7 showed that compound 14 was the most cytotoxic compound on both cancer cell lines where IC50 was 24.59 (9.836 µg/mL) and 12.203 (4.8812 µg/mL) on Huh-7 and Mcf-7 respectively. But IC50 of the nano preparation was 37.19 and 30.68 µg/mL on Huh-7 and Mcf-7, respectively, indicating its aggressiveness on human breast cancer cells as confirmed by DNA fragmentation assay and theoretically by CompuSyn tool. Conclusion: A novel series of pyrazolopyrimidine thioglycosides and pyrazolopyridine thioglycosides were synthesized. Nanoformulation of compound 14 into chitosan nanoparticles demonstrated anticancer activity and can be used as a drug delivery system, but further studies are still required.

Novel Synthesis and Biological Evaluation of the First Pyrazole Thioglycosides as Pyrazofurin Analogues.

This study reports a novel and efficient method for the synthesis of the first reported novel class of pyrazole thioglycosides 6a-h. These series of compounds were designed through the reaction of sodium 2-cyano-3-oxo-3-(4-substitutedphenylamino)prop-1-ene-1,1-bis(thiolate) salts 2 with hydrazine hydrate in ethanol at room temperature to give the corresponding sodium 5-amino-4-(substitutedphenylcarbamoyl)-1H-pyrazole-3-thiolates 3a-d. The latter compounds were treated with protected α-D-gluco- and galacto-pyranosyl bromides 4a,b in DMF at ambient temperature to give in a high yields the corresponding pyrazole thioglycosides 6a-h. Treatment of pyrazole salts 3a-d with hydrochloric acid at amobient temperature afforded the corresponding 3-mercaptopyrazole derivatives 5. The latter compounds were treated with peracetylated sugars 4 in sodium hydride in ethanol at ambient temperature to tolerate the S-glycosyl 6a-h compounds. Ammonolysis of the pyrazole thioglycosides 6a-h afforded the corresponding free thioglycosides 7a-h. The toxicity and antitumor activities of the synthesized compounds were studied.

Novel synthesis of new pyrazole thioglycosides as pyrazomycin analogues.

This study reports a novel method for the synthesis of a new class of pyrazole thioglycosides 7a-h as pyrazomycin analogues. These series of compounds were designed through the reaction of sodium 2-cyano-3-oxo-3-(4-substitutedphenylamino)prop-1-ene-1,1-bis(thiolate) salts 2 with phenyl hydrazine in ethanol at room temperature to give the corresponding sodium 5-amino-4-(substitutedphenylcarbamoyl)-1-phenyl-1H-pyrazole-3-thiolates 3a-d. The latter compounds were treated with tetra-acetylated glycosyl bromides 4a,b in DMF at ambient temperature to give the corresponding pyrazole thioglycosides 6a-h. Treatment of pyrazole salts 3a-d with hydrochloric acid at room temperature afforded the corresponding 3-mercaptopyrazole derivatives 5. The latter compounds were treated with tetra-acetylated glycosyl bromides 4 in sodium hydride-DMF to tolerate the S-glycosyl 6a-h compounds. Ammonolysis of the latters afforded the corresponding free thioglycosides 7a-h. The structures of the reaction products were elucidated based on spectral data and elemental analysis.

First novel synthesis of triazole thioglycosides as ribavirin analogues.

This study reports a novel and efficient method for the synthesis of the first reported novel class of triazole thioglycosides. These series of compounds were designed through the reaction of potassium cyanocarbonimidodithioate 2 with hydrazine derivatives 3a-d in EtOH at room temperature to give the corresponding potassium 5-amino-1H-1,2,4-triazole-3-thiolates 4a-d. The latter compounds were treated with tetra-O-acetyl-α-D-glucopyranosyl bromide 6a and tetra-O-acetyl-α-D-galactopyranosyl bromide 6b in DMF at room temperature to give in high yields the corresponding triazole thioglycosides 7a-h. Treatment of triazole salts 4a-d with hydrochloric acid afforded the corresponding 3-mercaptotriazoles 5a-d. Compounds 5a-d were then reacted with bromoperacetylated sugars 6a,b in sodium hydride-DMF at ambient temperature to afford the thioglycosyl compounds 7a-h. Ammonolysis of the triazole thioglycosides 7a-h afforded the corresponding free thioglycosides 8a-h. The scope and limitation of the method is demonstrated. The structure of the reaction products was confirmed on the basis of their elemental analysis and spectral data (IR, 1H NMR, MS and 13C NMR).

A facile synthesis of novel pyrazolopyrimidine thioglycosides as purine thioglycoside analogues.

The easy, convenient and high yielding preparation of new thioglycosides incorporating mercaptopyrazolo[1,5-a]pyrimidine moieties from readily accessible starting materials has been reported. The main step of this protocol is the formation of 7-mercaptopyrazolo[1,5-a]pyrimidine-6-carbonitrile derivatives 4a-d by condensation of sodium 2-cyano-3-ethoxy-3-oxoprop-1-ene-1,1-bis(thiolate) 1 with 4-(aryldiazenyl)-1H-pyrazole-3,5-diamines 3a-d to form target compounds 4a-d, which coupled with tetra-O-acetyl-α-D-glycopyranosyl bromides 5a,b in the presence of basic medium to provide the corresponding product purine thioglycoside analogs 6a-h. Ammonolysis of the latter compounds 6a-d at ambient temperature for 10 minutes, led to the free glycoside derivatives 7a-h, which were obtained in approximately quantitative yields. Their structures were created based on the spectroscopic and elemental data.

Synthesis of the first novel pyrazole thioglycosides as deaza ribavirin analogues.

This study reports a novel and efficient method for the synthesis of the first reported novel class of thiopyrazoles and their corresponding thioglycosides. These series of compounds were designed through the reaction of hydrazine derivatives with sodium dithiolate salt 2 in EtOH at ambient temperature to give the corresponding sodium 5-amino-4-cyano-1H-pyrazole-3-thiolates 4a-d. The latter compounds were treated with α-acetobromoglucose 6a and α-acetobromogalactose 6b in DMF at ambient temperature to give in an excellent yields the corresponding pyrazole S-glycosides 7a-h. Ammonolysis of the pyrazole thioglycosides 7a-h afforded the corresponding free thioglycosides 8a-h.

Heterocyclic thioglycosides in carbohydrate research: Synthesis of thiophene thioglycosides.

A novel synthesis of thiophene thioglycosides is carried out via a one-pot reaction of sodium thiophenethiolates with α-halogeno sugars. The sodium thiophenethiolate salts were prepared using sodium cyanoethylene thiolate salts. The structures of the reaction products were established on the basis of their elemental analysis and spectral data (IR, 1H NMR, MS, and 13C NMR).