In vitro cytotoxicity screening of some 3-substituted-4-oxo-imidazolidin-2-(1H)-thione derivatives as anticancer drug.

Aim: This study aimed to investigate the in vitro antitumor activity of new series of 2-thiohydanotin derivatives (7 and 9) against two cancer cell lines.Materials & methods: A new series of 2-thioxoimidazolidine derivatives (3-9) were synthesized and investigated for its structure through spectral analysis and also tested against (HepG-2) and (HCT-116) cell line.Results: Among the synthesized compounds, compound 7 halted liver cancer cells at the G0/G1 phase and triggered apoptosis of liver cancer. Contrarily, compound 9 caused colon cancer cells to be arrested at the S phase and trigger apoptosis. Also, they had a good inhibitory effect on (Nrf2).Conclusion: Both compounds had attractive lead molecules for the creation of colon and liver cancer medications.

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Atropisomerism Observed in Galactose-Based Monosaccharide Inhibitors of Galectin-3 Comprising 2-Methyl-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione.

Galectin-3 (Gal-3) is a carbohydrate binding protein that has been implicated in the development and progression of fibrotic diseases. Proof-of-principal animal models have demonstrated that inhibition of Gal-3 is a potentially viable pathway for the treatment of fibrosis─with small molecule Gal-3 inhibitors advanced into clinical trials. We hereby report the discovery of novel galactose-based monosaccharide Gal-3 inhibitors comprising 2-methyl-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (compound 20) and 4-phenyl-4H-1,2,4-triazole (compound 15). Notably, hindered rotation caused by steric interaction between the 3-thione and ortho-trifluoromethyl group of compounds 20, 21 induced formation of thermodynamically stable atropisomers. Distinct X-ray cocrystal structures of 20 and 21 were obtained, which clearly demonstrated that the configuration of 21 proscribes a key halogen bonding σ-hole interaction of 3-chloro with carbonyl oxygen of Gly182, thereby leading to significant loss in potency. Ultimately, 20 and 15 were evaluated in mouse pharmacokinetic studies, and both compounds exhibited oral exposures suitable for further in vivo assessment.

Evaluation of the Ameliorative Potential of 3,5-bis(2-hydroxyethyl)-1,3,5-thiadiazinane-2-thione against Scopolamine-Induced Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, marked by cognitive impairment. Currently, the available treatment provides only symptomatic relief and there is a great need to design and formulate new drugs to stabilize AD. In the search for a new anti-Alzheimer's drug, 3,5-bis(2-hydroxyethyl)-1,3,5-thiadiazinane-2-thione (THTT), a tetrahydro-2H-1,3,5-thiadiazine-2-thione derivative, was investigated against a scopolamine-induced Alzheimer's model. The selected test compound was administered intraperitoneally in three doses (15 mg/kg, 30 mg/kg, and 45 mg/kg). The test compound exhibited an IC50 value of 69.41 µg/mL, indicating its ability to inhibit the acetylcholinesterase enzyme. An antioxidant DPPH assay revealed that the IC50 value of the test compound was 97.75 µg/mL, which shows that the test compound possesses antioxidant activity. The results of behavior tests including the Y-maze and elevated plus maze (EPM) show that the test compound improved short-term memory and spatial memory, respectively. Furthermore, in the Morris water maze (MWM) and light/dark model, the test compound shows improvements in learning and memory. Moreover, the results of histological studies show that the test compound can protect the brain against the harmful effects of scopolamine. Overall, the findings of our investigation suggest that our chosen test compound has disease-modifying and neuroprotective activities against the scopolamine-induced Alzheimer's model. The test compound may be beneficial, subject to further elaborate investigation for anti-amyloid disease-modifying properties in AD.

Synthesis of Substituted 1,2,4-Triazole-3-Thione Nucleosides Using E. coli Purine Nucleoside Phosphorylase.

1,2,4-Triazole derivatives have a wide range of biological activities. The most well-known drug that contains 1,2,4-triazole as part of its structure is the nucleoside analogue ribavirin, an antiviral drug. Finding new nucleosides based on 1,2,4-triazole is a topical task. The aim of this study was to synthesize ribosides and deoxyribosides of 1,2,4-triazole-3-thione derivatives and test their antiviral activity against herpes simplex viruses. Three compounds from a series of synthesized mono- and disubstituted 1,2,4-triazole-3-thione derivatives were found to be substrates for E. coli purine nucleoside phosphorylase. Of six prepared nucleosides, the riboside and deoxyriboside of 3-phenacylthio-1,2,4-triazole were obtained at good yields. The yields of the disubstituted 1,2,4-triazol-3-thiones were low due to the effect of bulky substituents at the C3 and C5 positions on the selectivity of enzymatic glycosylation for one particular nitrogen atom in the triazole ring. The results of cytotoxic and antiviral studies on acyclovir-sensitive wild-type strain HSV-1/L2(TK+) and acyclovir-resistant strain (HSV-1/L2/RACV) in Vero E6 cell culture showed that the incorporation of a thiobutyl substituent into the C5 position of 3-phenyl-1,2,4-triazole results in a significant increase in the cytotoxicity of the base and antiviral activity. The highest antiviral activity was observed in the 3-phenacylthio-1-(ß-D-ribofuranosyl)-1,2,4-triazole and 5-butylthio-1-(2-deoxy-ß-D-ribofuranosyl)-3-phenyl-1,2,4-triazole nucleosides, with their selectivity indexes being significantly higher than that of ribavirin. It was also found that with the increasing lipophilicity of the nucleosides, the activity and toxicity of the tested compounds increased.

Development of new chiral 1,2,4-triazole-3-thiones and 1,3,4-thiadiazoles with promising in vivo anticonvulsant activity targeting GABAergic system and voltage-gated sodium channels (VGSCs).

Antiepileptic drugs (AEDs) are used in the treatment of epilepsy, a neurodegenerative disease characterized by recurrent and untriggered seizures that aim to prevent seizures as a symptomatic treatment. However, they still have significant side effects as well as drug resistance. In recent years, especially 1,3,4-thiadiazoles and 1,2,4-triazoles have attracted attention in preclinical and clinical studies as important drug candidates owing to their anticonvulsant properties. Therefore, in this study, which was conducted to discover AED candidate molecules with reduced side effects at low doses, a series of chiral 2,5-disubstituted-1,3,4-thiadiazoles (4a-d) and 4,5-disubstituted-1,2,4-triazole-3 thiones (5a-d) were designed and synthesized starting from l-phenylalanine ethyl ester hydrochloride. The anticonvulsant activities of the new chiral compounds were assessed in several animal seizure models in mice and rats for initial (phase I) screening after their chemical structures including the configuration of the chiral center were elucidated using spectroscopic methods and elemental analysis. First, all chiral compounds were pre-screened using acute seizure tests induced electrically (maximal electroshock test, 6 Hz psychomotor seizure model) and induced chemically (subcutaneous metrazol seizure model) in mice and also their neurotoxicity (TOX) was determined in the rotorad assay. Two of the tested compounds were used for quantitative testing, and (S)-(+)5-[1-(4-fluorobenzamido)-2-phenylethyl]-4-(4-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (5b) and (S)-(+)-(5-[1-(4-fluorobenzamido)-2-phenylethyl]-4-(4-methoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (5c) emerged as the most promising anticonvulsant drug candidates and also showed low neurotoxicity. The antiepileptogenic potential of these compounds was determined using a chronic seizure induced electrically corneal kindled mouse model. Furthermore, all chiral compounds were tested for their neuroprotective effect against excitotoxic kainic acid (KA) and N-methyl-d-aspartate (NMDA) induced in vitro neuroprotection assay using an organotypic hippocampal slice culture. The KA-induced neuroprotection assay results revealed that compounds 5b and 5c, which are the leading compounds for anticonvulsant activity, also had the strongest neuroprotective effects with IC50 values of 103.30 ± 1.14 and 113.40 ± 1.20 µM respectively. Molecular docking studies conducted to investigate the molecular binding mechanism of the tested compounds on the GABAA receptor showed that compound 5b exhibits a strong affinity to the benzodiazepine (BZD) binding site on GABA. It also revealed that the NaV1.3 binding interactions were consistent with the experimental data and the reported binding mode of the ICA121431 inhibitor. This suggests that compound 5b has a high affinity for these specific binding sites, indicating its potential as a ligand for modulating GABAA and NaV1.3 receptor activity. Furthermore, the ADME properties displayed that all the physicochemical and pharmacological parameters of the compounds stayed within the specified limits and revealed a high bioavailability profile.

Anti-inflammatory action of new hybrid N-acyl-[1,2]dithiolo-[3,4-c]quinoline-1-thione.

Most of pharmaceutical agents display a number of biological activities. It is obvious that testing even one compound for thousands of biological activities is not practically possible. A computer-aided prediction is therefore the method of choice in this case to select the most promising bioassays for particular compounds. Using the PASS Online software, we determined the probable anti-inflammatory action of the 12 new hybrid dithioloquinolinethiones derivatives. Chemical similarity search in the World-Wide Approved Drugs (WWAD) and DrugBank databases did not reveal close structural analogues with the anti-inflammatory action. Experimental testing of anti-inflammatory activity of the synthesized compounds in the carrageenan-induced inflammation mouse model confirmed the computational predictions. The anti-inflammatory activity of the studied compounds (2a, 3a-3k except for 3j) varied between 52.97% and 68.74%, being higher than the reference drug indomethacin (47%). The most active compounds appeared to be 3h (68.74%), 3k (66.91%) and 3b (63.74%) followed by 3e (61.50%). Thus, based on the in silico predictions a novel class of anti-inflammatory agents was discovered.

Zinc Ionophore Pyrithione Mimics CD28 Costimulatory Signal in CD3 Activated T Cells.

Zinc is an essential trace element that plays a crucial role in T cell immunity. During T cell activation, zinc is not only structurally important, but zinc signals can also act as a second messenger. This research investigates zinc signals in T cell activation and their function in T helper cell 1 differentiation. For this purpose, peripheral blood mononuclear cells were activated via the T cell receptor-CD3 complex, and via CD28 as a costimulatory signal. Fast and long-term changes in intracellular zinc and calcium were monitored by flow cytometry. Further, interferon (IFN)-γ was analyzed to investigate the differentiation into T helper 1 cells. We show that fast zinc fluxes are induced via CD3. Also, the intracellular zinc concentration dramatically increases 72 h after anti-CD3 and anti-CD28 stimulation, which goes along with the high release of IFN-γ. Interestingly, we found that zinc signals can function as a costimulatory signal for T helper cell 1 differentiation when T cells are activated only via CD3. These results demonstrate the importance of zinc signaling alongside calcium signaling in T cell differentiation.

Synthesis of 3-sulfenylindole derivatives from 4-hydroxy-2H-chromene-2-thione and indole using oxidative cross-dehydrogenative coupling reaction and anti-proliferative activity study of some of their sulfone derivatives.

The synthesis of hitherto unreported 3-sulfenylindole derivatives is achieved from 4-hydroxy-2H-chromene-2-thione (1) and indole (2) by employing an oxidative cross-dehydrogenative coupling reaction using a combination of 10 mol% of molecular iodine and 1 equivalent of TBHP in DMSO at room temperature. Then, the 3-sulfenylindole derivatives 3a, 3b, 3d, 3f, 3 h, and 3 k were converted into their corresponding sulfone derivatives because of lead likeness properties. Subsequently, a target prediction and docking study of six sulfone derivatives (5a-f) was performed, and four sulfones, namely 5a, 5d, 5e, and 5f, were selected for further in-vitro studies. The four sulfones mentioned above exhibited prominent anti-proliferative activity on breast cancer (MCF7) cell lines. In addition, this reaction was exergonic through quantum chemical analysis of the mechanistic steps. The salient features of this reaction are mild reaction conditions, good yields, and broad substrate scope.

New imidazole-2-ones and their 2-thione analogues as anticancer agents and CAIX inhibitors: Synthesis, in silico ADME and molecular modeling studies.

The present study involves the synthesis of a series of new imidazole-2-ones derivatives and their 2-thione analogs using conventional heating and the environmentally friendly benign technique, the microwave technique. Structure of the compounds was well elucidated by considering the data of both elemental and spectral analyses. The obtained data and theoretical values of the synthesized molecules correlated with the proposed molecular structure. Moreover, all the synthesized compounds were evaluated in vitro for antitumor activity against HCT-116 and HeP2 human cancer cell panels and assessed as selective carbonic anhydrase IX isozyme (CA9/CAIX) inhibitors, thereby providing useful preliminary evidence for drug development. In addition, computational techniques were used to investigate the molecular and electronic characteristics of the investigated organic compounds. The 4b compound exhibited the best quantum chemistry features, as the highest occupied molecular orbital, softness, energy gap, and dipole moment, indicating the highest biological activity. This was supported by the experimental findings. Moreover, the in silico evaluation of drug candidates was also investigated. Thereafter, the anticancer activity of the most reactive candidate was studied via molecular docking to determine the types of interactions between this molecule and CAIX. According to the docking experiments, the 4b molecule generates five hydrogen bond interactions with active amino acid residues, Gln 92, Gln 67, and Thr 200.

Indole Derivatives Bearing Imidazole, Benzothiazole-2-Thione or Benzoxazole-2-Thione Moieties-Synthesis, Structure and Evaluation of Their Cytoprotective, Antioxidant, Antibacterial and Fungicidal Activities.

In the search for new bioactive compounds, a methodology based on combining two molecules with biological properties into a new hybrid molecule was used to design and synthesize of a series of ten indole derivatives bearing imidazole, benzothiazole-2-thione, or benzoxazole-2-thione moieties at the C-3 position. The compounds were spectroscopically characterized and tested for their antioxidant, antibacterial, and fungicidal activities. The crystal structures were determined for five of them. Comparison of the closely related structures containing either benzothiazole-2-thione or benzoxazole-2-thione clearly shows that the replacement of -S- and -O- ring atoms modify molecular conformation in the crystal, changes intermolecular interactions, and has a severe impact on biological activity. The results indicate that indole-imidazole derivatives with alkyl substituent exhibit an excellent cytoprotective effect against AAPH-induced oxidative hemolysis and act as effective ferrous ion chelating agents. The indole-imidazole compound with chlorine atoms inhibited the growth of fungal strains: Coriolus versicolor (Cv), Poria placenta (Pp), Coniophora puteana (Cp), and Gloeophyllum trabeum (Gt). The indole-imidazole derivatives showed the highest antibacterial activity, for which the largest growth-inhibition zones were noted in M. luteus and P. fluorescens cultures. The obtained results may be helpful in the development of selective indole derivatives as effective antioxidants and/or antimicrobial agents.

New Cycloadditon Reaction of 2-Chloroprop-2-enethioamides with Dialkyl Acetylenedicarboxylates: Synthesis of Dialkyl 2-[4,5-bis(alkoxycarbonyl)-2-(aryl{alkyl}imino)-3(2H)-thienylidene]-1,3-dithiole-4,5-dicarboxylates.

The 1,3-dipolar cycloaddition of 1,2-dithiole-3-thiones with alkynes to form 1,3-dithioles is one of the most studied reactions in this class of polysulfur-containing heterocycles. Nucleophilic substitution of chlorine atoms in dimethyl 2-(1,2-dichloro-2-thioxoethylidene)-1,3-dithiole-4,5-dicarboxylate, which was obtained by addition one molecules of DMAD to 4,5-dichloro-3H-1,2-dithiole-3-thione, led to a series of 2-chloro-2-(1,3-dithiol-2-ylidene)ethanethioamides. Cycloaddition reaction of 2-chloro-2-(1,3-dithiol-2-ylidene)ethanethioamides with activated alkynes led to the unexpected formation of 2-(thiophen-3(2H)-ylidene)-1,3-dithioles via new intermediate, 1-(1,3-dithiol-2-ylidene)-N-phenylethan-1-yliumimidothioate. Structure of dimethyl 2-(4,5-bis(methoxycarbonyl)-2-(phenylimino)thiophen-3(2H)-ylidene)-1,3-dithiole-4,5-dicarboxylate was finally proven by single crystal X-ray diffraction study. Optimized reaction conditions and a mechanistic rationale for the 1,3-dipolar cycloaddition of novel intermediate are presented.

Pumice as a Novel Natural Heterogeneous Catalyst for the Designation of 3,4-Dihydropyrimidine-2-(1H)-ones/thiones under Solvent-Free Conditions.

In this study, pumice is used as a novel natural heterogeneous catalyst for the synthesis of 3,4-dihydropyrimidine-2-(1H)-ones/thiones via the one-pot multi-component condensation of aromatic aldehydes, urea/thiourea, and ethyl acetoacetate or acetylacetone in excellent yields (up to 98%). The physical and chemical properties of the catalyst were studied. Their geochemical analysis revealed a basaltic composition. Furthermore, X-ray diffraction showed that it is composed of amorphous materials with clinoptilolite and heulandites zeolite minerals in its pores. Moreover, pumice has a porosity range from 78.2-83.9% (by volume) and is characterized by a mesoporous structure (pore size range from 21.1 to 64.5 nm). Additionally, it has a pore volume between 0.00531 and 0.00781 m2/g and a surface area between 0.053 and 1.47 m2/g. The latter facilitated the reaction to proceed in a short time frame as well as in excellent yields. It is worth noting that our strategy tolerates the use of readily available, cheap, non-toxic, and thermally stable pumice catalyst. The reactions proceeded smoothly under solvent-free conditions, and products were isolated without tedious workup procedures in good yields and high purity. Indeed, pumice can be reused for at least five reuse cycles without affecting its activity.

One pot domino synthesis of new 3,5-disubstituted-tetrahydro-2H-1,3,5-thiadiazine-2-thiones (THTTs) as anti-inflammatory and antinociceptive candidates: A proof from in-vivo to in-vitro and in-silico mechanistic studies.

A series of alkyl/aryl/aralkylamines or amino acids appended tetrahydro-2H-1,3,5-thiadiazine-2-thiones (4a-i, 5a-g, 6 and 7) were synthesized via one pot domino synthesis. The synthesis involved reacting alkyl/aryl/aralkylamines or amino acids with carbon disulfide employing basic aqueous medium and further cyclization with formaldehyde and alkyl/aryl/aralkylamines or amino acids. In addition, the carboxy-functionalized 1,3,5-thiadiazine-2-thione 6 was further subjected to esterification. All the structures were confirmed through spectral techniques i.e IR, 1H NMR, 13C NMR, and MS analysis. Furthermore, the newly synthesized compounds were biologically assessed via in vitro COX-2 and 5-LOX assays, in vivo anti-nociceptive and anti-inflammatory activities. Among the screened compounds, 6, 5f, and 7 exhibited highest inhibitory potency against COX-2 with IC50 values of 11.96, 13.54, and 13.93 µM, respectively. Moreover, compounds 6 and 7 exhibited excellent inhibitory potential against 5-LOX with IC50 values of 14.01 and 14.13 µM. The in-vivo anti-inflammatory bioassay studies showed that compounds 6, 7 and 5f dramatically reduced the paw edema size at 1 h and 3 h time intervals. In the anti-nociceptive activity, compound 6 showed pain protection comparative to Tramadol in all tested time intervals. In addition, studies of molecular docking revealed the compounds binding modes in the allosteric site of COX-2 and active site of 5-LOX, where these compounds exhibited higher binding scores and good binding interactions.

Solvent promoted tautomerism in thione-containing tetraazatricyclics: evidence from 1H NMR spectroscopy and transition state studies.

Tautomerism in the nitro substituted thione-containing traazatricyclics has been investigated. Evidence from 1H NMR indicating the existence of the tautomers has been augmented with computational studies providing evidence of the stability or otherwise of these tautomers. The role of water and DMSO in the formation of the tautomers has been explained. The role of the nitro group in assisting in the formation of the tautomers has been discussed.

Metal-Free Temperature-Controlled Intermolecular [3 + 2] Annulation to Access Benzo[d]thiazole-2(3H)-thiones and Benzo[d]thiazol-2(3H)-ones.

A facile access to benzo[d]thiazole-2(3H)-thiones and benzo[d]thiazol-2(3H)-ones has been developed through a temperature-controlled intermolecular [3 + 2] annulation of N,N-disubstituted arylhydrazines with CS2 in the presence of DMSO. This protocol can obviate the prefunctionalization of the starting materials. This direct C-S/C-N bond formation reaction was performed in the absence of any external catalysts, transition metals, bases, ligands, and oxidants with high step economy.

1,3,5-Thiadiazinane thione derivatives as significant urease inhibitors.

We report the promising urease inhibitory activity of four sets of tetrahydro thiadiazine thiones (THTT) namely 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine thiones: THTT 5-8 (set A) having alkyl/aryl substituents at N-3 and N-5 positions; THTT 9-12 (set B) and THTT 13-14 (set C) with 3-carboxylic acid derivatives and tetrahydro-2H-1,3,5-thiadiazine-6-thione esters 15-16 (set D). Gratifyingly, all four sets of THTT were recognized as promising inhibitors of urease enzyme. Among 12 tested compounds; THTT 6, 8, 10, 14 and 15 from each set respectively, demonstrated significant urease inhibitory activity with IC50 values between 11.2-29.8µM which is mostly found higher than that for thiourea, a standard urease inhibitor with IC50 value of 22.4µM. Furthermore, compound 7 showed almost the same level of inhibition (IC50 = 22.5µM) as of standard. In addition, molecular docking study supported the phenomenon that thiadiazinane ring itself is an active pharmacophore that binds through CH2 groups and S atom via carbon-hydrogen/π-sulfur interactions respectively to the active site of the urease enzyme. The optimistic results from this study suggest the use of thiadiazinane skeleton as a guided template for the advancement of new urease inhibitors in drug discovery.

1-Phenyl ethyl substituted tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives as promising antimicrobial agents.

Seven derivatives of 1-phenyl ethyl group containing 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine-thiones (THTT) were prepared and examined for their antibacterial and antifungal properties by using Microplate Alamar Blue Assay (MABA) and agar tube dilution protocol respectively. In vitro antifungal potential was investigated against five human pathogens and compared with the standard drugs amphotericin B and miconazole. In vitro antibacterial activity was investigated against four pathogens and compared with the ofloxacin. All compounds exhibited very promising antifungal activities against all tested pathogens. Structure activity relationship showed the importance of the presence of 1-phenyl ethyl substituent at N-3 of THTT nucleus for antifungal effects. However, these compounds showed significant antibacterial activity only against S. aureus. The compound 6c of the series was found most active compound that displayed promising antifungal potential against all tested pathogens [Growth Inhibition (GI) = 100%], and also showed promising antibacterial potential against S. aureus (GI% = 83.49) which is very much closer to the standard ofloxacin (GI% = 88.05). The study may be useful in the development of improved antimicrobial agents.

Novel transformation products from glucosinolate-derived thioglucose and isothiocyanates formed during cooking.

Glucosinolates are plant secondary metabolites occurring in Brassicaceae plants. Upon tissue disruption, these compounds can be enzymatically hydrolyzed into isothiocyanates, which are very reactive and can react with nucleophiles during thermal processes such as boiling. Here, a novel type of glucosinolate degradation product was identified resulting from the reaction of thioglucose with the isothiocyanates sulforaphane or allyl isothiocyanate during aqueous heating. The two heterocyclic compounds 4-hydroxy-3-(4-(methylsulfinyl)butyl)thiazolidine-2-thione and 3-allyl-4-hydroxythiazolidine-2-thione were isolated and their structure elucidated by NMR spectroscopy and high-resolution mass spectrometry. Based on a set of chemical experiments, a reaction mechanism was proposed. Finally, the formation of the two 3-alk(en)yl-4-hydroxythiazolidine-2-thiones was quantified in boiled cabbage samples using a standard addition method in which 92 pmol/g and 19 pmol/g fresh weight of the sulforaphane and allyl isothiocyanate derivatives were found, respectively.

Complexes of 1-(2-R(F, CH3, Cl)-phenyl)-1,4-dihydro-5H-tetrazole-5-thiones with cadmium chloride: Synthesis, molecular, crystal structures and computational investigation approach.

New complex compounds (I) - (IV) were synthesized by the reaction of 1-(2-fluorofluorophenyl) -1,4-dihydro-5H-tetrazole-5-thione (HL1), 1-(2-methylphenyl)-1,4-dihydro-5H-tetrazole-5-thione (HL2) and 1-(2-chlorochlorophenyl)-1,4-dihydro-5H-tetrazole-5-thione (HL3) with cadmium chloride. By X-ray diffraction analysis, molecular and crystal structures of complexes (I), (II), (III) and (IV) are determined. (CIF files CCDC № 2,003,797 (I), 1,993,454 (II), 2,151,359 (III), 2,098,997 (IV)). Hirshfeld surface analysis, frontier orbital analysis, atomic charges, electrostatic potential, nonlinear optical properties, and natural bond analysis of all three­cadmium metal-organic complexes were discussed. A molecular docking study was used to investigate compounds' binding and interactions with DNA molecules, which predicted compound I as the best binder at the DNA minor groove and demonstrated closed distance interactions. In a long run of molecular dynamics simulations, the compound I complex was also depicted with good dynamics.

Synthesis of 4,4-Disubstituted 3,4-Dihydropyrimidin-2(1H)-ones and -thiones, the Corresponding Products of Biginelli Reaction Using Ketone, and Their Antiproliferative Effect on HL-60 Cells.

An efficient synthetic method for novel 4,4-disubstituted 3,4-dihydropyrimidin-2(1H)-ones 5 and -thiones 6 was developed. The cyclocondensation reaction of O-methylisourea hemisulfate salt 11 with 8 gives a tautomeric mixture of dihydropyrimidines 12 and 13 following acidic hydrolysis of the cyclized products to produce 5 in high yields. Thionation reaction of 5 at the 2-position smoothly proceeds to give 2-thioxo derivatives 6. These compounds 5 and 6, corresponding to the products of a Biginelli-type reaction using urea or thiourea, a ketone and a 1,3-dicarbonyl compound, have long been inaccessible and hitherto unavailable for medicinal chemistry. These methods are invaluable for the synthesis of 5 and 6, which have been inaccessible by conventional methods. Therefore, the synthetic methods established in this study will expand the molecular diversity of their related derivatives. These compounds were also assessed for their antiproliferative effect on a human promyelocytic leukemia cell line, HL-60. Treatment of 10 µM 6b and 6d showed high inhibitory activity similarly to 1 µM all-trans retinoic acid (ATRA), indicating that the 2-thioxo group and length of two alkyl substituents at the 4-position are strongly related to activity.