Copper-mediated cyclization of thiosemicarbazones leading to 1,3,4-thiadiazoles: Structural elucidation, DFT calculations, in vitro biological evaluation and in silico evaluation studies.

Cancer's global impact necessitates innovative and less toxic treatments. Thiosemicarbazones (TSCs), adaptable metal chelators, offer such potential. In this study, we have synthesized N (4)-substituted heterocyclic TSCs from syringaldehyde (TSL1, TSL2), and also report the unexpected copper-mediated cyclization of the TSCs to form thiadiazoles (TSL3, TSL4), expanding research avenues. This work includes extensive characterization and studies such as DNA/protein binding, molecular docking, and theoretical analyses to demonstrate the potential of the as-prepared TSCs and thiadiazoles against different cancer cells. The DFT results depict that the thiadiazoles exhibit greater structural stability and reduced reactivity compared to the corresponding TSCs. The docking results suggest superior EGFR inhibition for TSL3 with a binding constant value of - 6.99 Kcal/mol. According to molecular dynamics studies, the TSL3-EGFR complex exhibits a lower average RMSD (1.39 nm) as compared to the TSL1-EGFR complex (3.29 nm) suggesting that both the thiadiazole and thiosemicarbazone examined here can be good inhibitors of EGFR protein, also that TSL3 can inhibit EGFR better than TSL1. ADME analysis indicates drug-likeness and oral availability of the thiadiazole-based drugs. The DNA binding experiment through absorption and emission spectroscopy discovered that TSL3 is more active towards DNA which is quantitatively calculated with a Kb value of 4.74 × 106 M-1, Kq value of 4.04 × 104 M-1and Kapp value of 5 × 106 M-1. Furthermore, the BSA binding studies carried out with fluorescence spectroscopy showed that TSL3 shows better binding capacity (1.64 × 105 M-1) with BSA protein. All the compounds show significant cytotoxicity against A459-lung, MCF-7-breast, and HepG2-liver cancer cell lines; TSL3 exhibits the best cytotoxicity, albeit less effective than cisplatin. Thiadiazoles demonstrate greater cytotoxicity than the TSCs. Overall, the promise of TSCs and thiadiazoles in cancer research is highlighted by this study. Furthermore, it unveils unexpected copper-mediated cyclization of the TSCs to thiadiazoles.

Systematic review of neurokinin-3 receptor antagonists for the management of vasomotor symptoms of menopause.

IMPORTANCE: Vasomotor symptoms (VMS) affect many postmenopausal persons and impact sleep and quality of life. OBJECTIVE: This systematic review examines the literature describing the safety and efficacy of neurokinin-3 receptor antagonists approved and in development for postmenopausal persons with VMS. EVIDENCE REVIEW: A search of MEDLINE, EMBASE, and International Pharmaceutical Abstracts was conducted using the search terms and permutations of neurokinin-3 receptor antagonist, elinzanetant, fezolinetant, and osanetant. Inclusion criteria of reporting on efficacy or safety of fezolinetant, elinzanetant, or osanetant; studies in participants identifying as female; full record in English; and primary literature were applied. Abstract-only records were excluded. Extracted data were synthesized to allow comparison of reported study characteristics, efficacy outcomes, and safety events. Eligible records were evaluated for risk of bias via the Cochrane Risk of Bias 2 tool for randomized studies and the Grading of Recommendations Assessment, Development and Evaluation system was used. This study was neither funded nor registered. FINDINGS: The search returned 191 records; 186 were screened after deduplication. Inclusion criteria were met by six randomized controlled trials (RCT), four reported on fezolinetant, and two reported on elinzanetant. One record was a post hoc analysis of a fezolinetant RCT. An additional study was identified outside the database search. Three fezolinetant RCT demonstrated a reduction in VMS frequency/severity, improvement in Menopause-Specific Quality of Life scores, and improvement in sleep quality at weeks 4 and 12 compared with placebo without serious adverse events. The two RCT on elinzanetant also showed improvements in VMS frequency and severity. All eight records evaluated safety through treatment-emergent adverse events; the most common adverse events were COVID-19, headache, somnolence, and gastrointestinal. Each record evaluated had a low risk of bias. There is a strong certainty of evidence as per the Grading of Recommendations Assessment, Development and Evaluation system. CONCLUSIONS AND RELEVANCE: Because of the high-quality evidence supporting the efficacy of fezolinetant and elinzanetant, these agents may be an effective option with mild adverse events for women seeking nonhormone treatment of VMS.

Synthesis of Indole-Linked Thiadiazoles and their Anticancer Action against Triple-Negative Breast Cancer.

With a lack of targeted therapy and significantly high metastasis, heterogeneity, and relapse rates, Triple-Negative Breast Cancer (TNBC) offers substantial treatment challenges and demands more chemotherapeutic interventions. In the present study, indole-endowed thiadiazole derivatives have been synthesized and screened for antiproliferative potency against the triple-negative breast cancer MDA-MB-231 cell line. Compound 4 h, possessing chlorophenyl moiety, displays the best anticancer potency (IC50: 0.43 µM) in the cell viability assay. The title compounds demonstrate substantial docking competency against the EGFR receptor (PDB ID: 3POZ), validating their in-vitro ant proliferative action. With a high docking score (-9.9 to -8.7 kcal/mol), the indole hybrids display significant binding propensity comparable to the co-crystallized ligand TAK-285 and occupy a similar strategic position in the active domain of the designated receptor. The quantum and electronic properties of the integrated templates are evaluated through DFT, and optimal values of the deduced global reactivity indices, such as energy gap, electronegativity, ionization potential, chemical potential, electrophilicity, etc., suggest their apt biochemical reactivity. The indole hybrids show near-appropriate pharmacokinetic efficacy and bioavailability in the in-silico studies, indicating their candidacy for potential drug usage. Promising in-vitro anticancer action and binding interfaces project indole conjugates as potential leads in addressing the TNBC dilemma.

Emerging synthetic strategies and pharmacological insights of 1,3,4-thiadiazole derivatives: a comprehensive review.

This review meticulously examines the synthesis techniques for 1,3,4-thiadiazole derivatives, focusing on cyclization, condensation reactions and functional group transformations. It enhances the understanding of these chemical methods that re crucial for tailoring derivative properties and functionalities. This study is considered to be vital for researchers, detailing established effects such as antioxidant, antimicrobial and anticancer activities, and revealing emerging pharmacological potentials such as neuroprotective, antiviral and antidiabetic properties. It also discusses the molecular mechanisms underlying these effects. In addition, this article covers structure-activity relationship studies and computational modelling that are essential for designing potent, selective 1,3,4-thiadiazole compounds. This work lays a foundation for future research and targeted therapeutic development.

Highly Stretchable Conjugated Polymer/Elastomer Blend Films with Sandwich Structure.

The physical blending of high-mobility conjugated polymers with ductile elastomers provides a simple way to realize high-performance stretchable films. However, how to control the morphology of the conjugated polymer and elastomer blend film and its response to mechanical fracture processes during stretching are not well understood. Herein, a sandwich structure is constructed in the blend film based on a conjugated polymer poly[(5-fluoro-2,1,3-benzothiadiazole-4,7-diyl)(4,4-dihexadecyl-4H-cyclopenta[2,1-b:3,4-b″]dithiophene-2,6-diyl)(6-fluoro-2,1,3-benzothiadiazole-4,7-diyl)(4,4-dihexadecyl-4H-cyclopenta[2,1-b:3,4-b″]dithiophene-2,6-diyl)] (PCDTFBT) and an elastomer polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene (SEBS). The sandwich structure is composed of a PCDTFBT:SEBS mixed layer laminated with a PCDTFBT-rich layer at both the top and bottom surfaces. During stretching, the external strain energy can be effectively dissipated by the deformation of the crystalline PCDTFBT domains and amorphous SEBS phases and the recrystallization of the PCDTFBT chains. This endows the blend film with excellent ductility, with a large crack onset strain exceeding 1100%, and minimized the electrical degradation of the blend film at a large strain. This study indicates that the electrical and mechanical performance of conjugated polymer/elastomer blend films can be improved by manipulating their microstructure.

Unveiling the chemistry of 1,3,4-oxadiazoles and thiadiazols: A comprehensive review.

Oxadiazoles and thiadiazoles are malleable heterocycles that have recently generated major interest in the field of medicinal chemistry. Compounds based on these moieties have versatile biological applications such as anticonvulsant, anticancer, antidiabetic, and antioxidant agents. Due to the versatile nature and stability of the oxadiazole and thiadiazole nucleus, medicinal chemists have changed the structural elements of the ring in numerous ways. These compounds have shown significant anticonvulsant effects, demonstrating their potential in the management of epileptic disorders. In this review, we have covered numerous biological pathways and in silico targeted proteins of oxadiazole and thiadiazole derivatives for treating various biological disorders. The data compiled in this article will be helpful for researchers, research scientists, and research chemists who work in the field of drug discovery and drug development.

Synthesis, X-ray Crystal Structure, and Antimicrobial Studies of New Quinazolin-4(3H)-one Derivatives Containing the 1,2,4-Triazolo[3,4-b][1,3,4]thiadiazole Moiety and 4-Piperidinyl Linker.

A total of 35 new quinazolinone derivatives bearing the 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole scaffold and the 4-piperidinyl linker were designed, prepared, and assessed for their antibacterial and antifungal activities. Among these derivatives, the chemical structure of compound F5 was clearly verified via single-crystal X-ray diffraction analysis. The experimental results revealed that some of the compounds displayed good even excellent inhibitory effects toward the tested phytopathogenic bacteria. For instance, compound F33 was capable of strongly inhibiting Xanthomonas oryzae pv. oryzae (Xoo) in vitro with an EC50 (half-maximal effective concentration) value of 4.1 µg/mL, about 16-fold more effective than the commercialized bactericide bismerthiazol. Significantly, this compound also effectively suppressed the proliferation of Xoo in the potted rice plants, showing a good in vivo protection efficacy of 47.6% at 200 µg/mL. Subsequently, the antibacterial mechanisms of compound F33 were explored by means of different biophysical and biochemical methods. Last, some of the compounds were found to possess relatively good antifungal activities in vitro, like compound F19 against Phytophthora nicotianae (with an inhibition rate of 67.2% at 50 µg/mL). In a word, the current experimental results imply that the 4-piperidinyl-bridged quinazolinone-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole derivatives possess potential as lead compounds for developing more efficient anti-Xoo bactericides.

Synthesis of 1,3,4-Thiadiazole Derivatives and Their Anticancer Evaluation.

Thiadiazole derivatives have garnered significant attention in the field of medicinal chemistry due to their diverse pharmacological activities, including anticancer properties. This article presents the synthesis of a series of thiadiazole derivatives and investigates their chemical characterization and potential anticancer effects on various cell lines. The results of the nuclear magnetic resonance (NMR) analyses confirmed the successful formation of the target compounds. The anticancer potential was evaluated through in silico and in vitro cell-based assays using LoVo and MCF-7 cancer lines. The assays included cell viability, proliferation, apoptosis, and cell cycle analysis to assess the compounds' effects on cancer cell growth and survival. Daphnia magna was used as an invertebrate model for the toxicity evaluation of the compounds. The results revealed promising anticancer activity for several of the synthesized derivatives, suggesting their potential as lead compounds for further drug development. The novel compound 2g, 5-[2-(benzenesulfonylmethyl)phenyl]-1,3,4-thiadiazol-2-amine, demonstrated good anti-proliferative effects, exhibiting an IC50 value of 2.44 µM against LoVo and 23.29 µM against MCF-7 after a 48-h incubation and little toxic effects in the Daphnia test.

Therapeutic charisma of imidazo [2,1-b] [1,3,4]-thiadiazole analogues: a patent review.

Imidazothiadiazole was discovered around the 1950s era, containing an imidazole ring fused to a thiadiazole ring. Imidazothiadiazole exhibit versatile pharmacological properties including anticonvulsant, cardiotonic, anti-inflammatory, diuretic, antifungal, antibacterial and anticancer. Despite of the being discovered in 1950s, the imidazothiadiazole derivatives are unable to being processed to clinical trials because of lack of bioavailability, efficacy and cytotoxicity. The recent patent literature focused on structural modification of imidazothiadiazole core to overcome these problems. This review limelight a disease-centric perspective on patented imidazothiadiazole from 2015-2023 and to understand their mechanism of action in related diseases. The relevant granted patent applications were located using patent databases, Google Patents, USPTO, EPO, WIPO, Espacenet and Lens.

Synthesis, biological evaluation and in silico studies of novel thiadiazole-hydrazone derivatives for carbonic anhydrase inhibitory and anticancer activities.

Thiadiazole and hydrazone derivatives (5a-5i) were synthesized and their chemical structures were verified and described by 1H NMR, 13C NMR, and HRMS spectra. Three cancer cell lines (MCF-7, MDA, and HT-29) and one healthy cell line (L929) were used to test the cytotoxicity activity of synthesized compounds as well as their inhibitory activity against carbonic anhydrase I, II and IX isoenzymes. Compound 5d (29.74 µM) had a high inhibitory effect on hCA I and compound 5b (23.18 µM) had a high inhibitory effect on hCA II. Furthermore, compound 5i was found to be the most potent against CA IX. Compounds 5a-5i, 5b and 5i showed the highest anticancer effect against MCF-7 cell line with an IC50 value of 9.19 and 23.50 µM, and compound 5d showed the highest anticancer effect against MDA cell line with an IC50 value of 10.43 µM. The presence of fluoro substituent in the o-position of the phenyl ring increases the effect on hCA II, while the methoxy group in the o-position of the phenyl ring increases the activity on hCA I as well as increase the anticancer activity. Cell death induction was evaluated by Annexin V assay and it was determined that these compounds cause cell death by apoptosis. Molecular docking was performed for compounds 5b and 5d to understand their biological interactions. The physical and ADME properties of compounds 5b and 5d were evaluated using SwissADME.

Design and structural optimization of thiadiazole derivatives with potent GLS1 inhibitory activity.

GLS1 is an attractive target not only as anticancer agents but also as candidates for various potential pharmaceutical applications such as anti-aging and anti-obesity treatments. We performed docking simulations based on the complex crystal structure of GLS1 and its inhibitor CB-839 and found that compound A bearing a thiadiazole skeleton exhibits GLS1 inhibition. Furthermore, we synthesized 27 thiadiazole derivatives in an effort to obtain a more potent GLS1 inhibitor. Among the synthesized derivatives, 4d showed more potent GLS1 inhibitory activity (IC50 of 46.7 µM) than known GLS1 inhibitor DON and A. Therefore, 4d is a very promising novel GLS1 inhibitor.

Benzimidazolone-piperazine/triazole/thiadiazole/furan/thiophene conjugates: Synthesis, in vitro urease inhibition, and in silico molecular docking studies.

This study describes the synthesis, in vitro urease inhibition, and molecular docking studies of benzimidazolone derivatives incorporating the piperazine, triazole, thiadiazole, furan, thiophene, and thiosemicarbazide moieties. All newly synthesized compounds demonstrated varying degrees of urease inhibitory activity, with IC50 values ranging between 0.64 ± 0.099 and 0.11 ± 0.017 µM, when compared with the standard drug thiourea (IC50 value of 0.51 ± 0.028 µM). To confirm the experimental urease inhibition results and elucidate the mode of interaction of the synthesized compounds with the binding site of the urease enzyme, molecular docking studies were performed using the Schrödinger Suite package. Molecular docking studies showed that compounds with high in vitro urease inhibition interacted with key residues of the urease active site such as His221, Glu222, Asp223, His322, Arg338, and Ni2+ cations via hydrogen bonding, metal coordination, salt bridge, π-π stacking, and π-cation interactions.

Synthesis of bile acid-thiadiazole conjugates as antibacterial and antioxidant agents.

The synthesis, characterization, and antibacterial and antioxidant activity of thiadiazole-deoxycholic/lithocholic acid conjugates are described in this communication. The structures of the synthesised bile acid-thiadiazole conjugates were studied using 1H NMR, 13C NMR and FTIR. Compounds 4c (IC50; 15.34 ± 0.07 µM) and 5c (IC50; 13.45 ± 0.25 µM) demonstrated greater antioxidant activity than the reference compound ascorbic acid (IC50; 20.72 ± 1.02 µM) in DPPH assay. The most effective conjugates against P. vulgarise were 4c (IC50; 24 ± 2.3 µM), 4 g (IC50; 29 ± 2.5 µM), and 5c (IC50; 93 ± 3.6 µM), whereas the most effective conjugates against E. coli were 4e (IC50; 55 ± 2.1 µM) and 4f (IC50; 52 ± 3.5 µM). Conjugates 4c and 5c were the most effective against B. megaterium of all the synthesised conjugates, with IC50 values of 15 ± 1.08 and 20 ± 1.1 µM, respectively. Thus, a large library of compounds derived from bile acid can be easily synthesised for extensive structure-activity relationship studies in order to identify the most appropriate antibacterial agents and antioxidant activity.

[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives as new therapeutic candidates against urease positive microorganisms: design, synthesis, pharmacological evaluations, and in silico studies.

Regarding the important role of the urease enzyme as a virulence factor in urease-positive microorganisms in this study, new series of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives were designed and synthesized. All compounds evaluated against urease enzyme exhibiting IC50 values of 0.87 ± 0.09 to 8.32 ± 1.21 µM as compared with thiourea as the positive control (IC50 = 22.54 ± 2.34 µM). The kinetic evaluations of 6a as the most potent derivative recorded a competitive type of inhibition. Molecular dynamic simulations of the 6a derivative were also conducted, showing that 6a occupied the active site with closed state. Antimicrobial activities of all derivatives were performed, and 6f (R = 3-Cl), 6g (R = 4-Cl), and 6h (R = 3,4-diCl) analogs demonstrated significant antifungal activities with MIC values of 1, 2, and 0.5 µg/mL compared with fluconazole with MIC = 2 µg/mL. Synthesized analogs also exhibited potent urease inhibitory activities against C. neoformans (IC50 = 83.7-118.7 µg/mL) and P. mirabilis (IC50 = 74.5-113.7 µg/mL), confirming their urease inhibitory potential. The results demonstrated that the designed scaffold could be considered a suitable pharmacophore to develop potent urease inhibitors.

Design and synthesis of thiadiazole-oxadiazole-acetamide derivatives: Elastase inhibition, cytotoxicity, kinetic mechanism, and computational studies.

Considering the biological significance of 1,3,4-thiadiazole/oxadiazole heterocyclic scaffolds, a novel series of 1,3,4-thiadiazole-1,3,4-oxadiazole-acetamide derivatives (7a-j) was designed and synthesized using molecular hybridization. The inhibitory effects of the target compounds on elastase were evaluated, and all of these molecules were found to be potent inhibitors compared to the standard reference oleanolic acid. Compound 7f exhibited the excellent inhibitory activity (IC50 = 0.06 ± 0.02 µM), which is 214-fold more active than oleanolic acid (IC50 = 12.84 ± 0.45 µM). Kinetic analysis was also performed on the most potent compound (7f) to determine the mode of binding with the target enzyme, and it was discovered that 7f inhibits the enzyme in a competitive manner. Furthermore, the MTT assay method was used to assess their toxicity on the viability of B16F10 melanoma cell lines, and all compounds did not display any toxic effect on the cells even at high concentrations. The molecular docking studies of all compounds also justified with their good docking score and among them, compound 7f had a good conformational state with hydrogen bond interactions within the receptor binding pocket, which is consistent with the experimental inhibition studies.

Benzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole) and Its Bromo Derivatives: Molecular Structure and Reactivity.

Benzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole) (isoBBT) is a new electron-withdrawing building block that can be used to obtain potentially interesting compounds for the synthesis of OLEDs and organic solar cells components. The electronic structure and delocalization in benzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole), 4-bromobenzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole), and 4,8-dibromobenzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole) were studied using X-ray diffraction analysis and ab initio calculations by EDDB and GIMIC methods and were compared to the corresponding properties of benzo[1,2-c:4,5-c']bis[1,2,5]thiadiazole (BBT). Calculations at a high level of theory showed that the electron affinity, which determines electron deficiency, of isoBBT was significantly smaller than that of BBT (1.09 vs. 1.90 eV). Incorporation of bromine atoms improves the electrical deficiency of bromobenzo-bis-thiadiazoles nearly without affecting aromaticity, which increases the reactivity of these compounds in aromatic nucleophilic substitution reactions and, on the other hand, does not reduce the ability to undergo cross-coupling reactions. 4-Bromobenzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole) is an attractive object for the synthesis of monosubstituted isoBBT compounds. The goal to find conditions for the selective substitution of hydrogen or bromine atoms at position 4 in order to obtain compounds containing a (het)aryl group in this position and to use the remaining unsubstituted hydrogen or bromine atoms to obtain unsymmetrically substituted isoBBT derivatives, potentially interesting compounds for organic photovoltaic components, was not set before. Nucleophilic aromatic and cross-coupling reactions, along with palladium-catalyzed C-H direct arylation reactions for 4-bromobenzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole), were studied and selective conditions for the synthesis of monoarylated derivatives were found. The observed features of the structure and reactivity of isoBBT derivatives may be useful for building organic semiconductor-based devices.

5-Membered Heterocyclic Compounds as Antiviral Agents.

Viral infections range from self-limiting to more serious and fatal infections; therefore, some viral infections are of great public health concern worldwide, e.g., Hepatitis B virus, Hepatitis C virus, and HIV. Recently, the world faced a new infection due to the coronavirus, COVID-19, which was announced as a pandemic in early 2020. This virus infected more than 500 million people, killing around 6 million people worldwide. On the other hand, the increase in drug-resistant strains is also creating serious health problems. Thus, developing new selective antiviral agents with a different mode of action to fight against mutated and novel viruses is a primary goal of many researchers. Taking into account the role of heterocyclic compounds in drug discovery as a key structural component of most of the bioactive molecules; herein, we report an extensive review of the antiviral activity of five-membered heterocyclic compounds reported from 2015 to date. In this review, the antiviral activities of the agents containing the specified ring systems thiadiazoles, triazoles, oxadiazoles, and thiazoles are discussed.

Inhibition of α-glucosidase enzyme by 'click'-inspired pharmacophore framework 1,3,4-thiadiazole-1,2,3-triazole hybrids.

Aim: α-Glucosidase inhibitors are important oral antidiabetic drugs that are used alone or in combination therapy. Materials & methods: In this regard, 1,3,4-thiadiazoles-1,2,3-triazoles were designed, synthesized and evaluated for α-glucosidase enzyme inhibition. Results: The applied synthesis protocol involved a 'click' reaction between a novel alkyne derived from a 1,3,4-thiadiazole derivative and phenylacetamide azides. The hybrid (9n) bearing 2-methyl and 4-nitro substituents was the best inhibitor with an IC50 value of 31.91 µM (acarbose IC50 = 844.81 µM). The blind molecular docking study of the best derivative (9n) showed that it interacted with the allosteric site's amino acid residues of α-glucosidase. Conclusion: 'Click'-inspired potential α-glucosidase inhibitors (1,3,4-thiadiazole-1,2,3-triazole hybrids) were identified and structure-activity relationship and kinetic and molecular docking studies accomplished.

Oral antidiabetic drugs such as α-glucosidase inhibitors are used alone or in combination therapy. α-Glucosidase inhibitors are considered important for their localized site of action and limited side effects compared with other antidiabetic medications. In this regard, 1,3,4-thiadiazoles­1,2,3-triazoles were designed and synthesized and their antidiabetic potential (α-glucosidase enzyme inhibition) evaluated. The synthesis involved a 'click', or copper-catalyzed 1,3-dipolar cycloaddition, reaction between a novel alkyne derived from a 1,3,4-thiadiazole derivative and phenylacetamide azides. The synthesis was simple, easy and free of tedious separation processes. All synthesized thiadiazole­triazole hybrids were found to be active toward α-glucosidase (yeast origin). One of the thiadiazole­triazole hybrids showed excellent activity that was approximately 26-times greater than the standard drug acarbose. This study was further supported by computational analysis.

First X-ray Crystal Structure Characterization, Computational Studies, and Improved Synthetic Route to the Bioactive 5-Arylimino-1,3,4-thiadiazole Derivatives.

N-arylcyanothioformamides are useful coupling components for building key chemical intermediates and biologically active molecules in an expedited and efficient manner. Similarly, substituted (Z)-2-oxo-N-phenylpropanehydrazonoyl chlorides have been utilized in numerous one-step heteroannulation reactions to assemble the structural core of several different types of heterocyclic compounds. Herein, we demonstrate the effectiveness of the reaction of N-arylcyanothioformamides with various substituted (Z)-2-oxo-N-phenylpropanehydrazonoyl chlorides to produce, stereoselectively and regioselectively, a range of 5-arylimino-1,3,4-thiadiazole derivatives decorated with a multitude of functional groups on both aromatic rings. The synthetic methodology features mild room-temperature conditions, large substrate scope, wide array of functional groups on both reactants, and good to high reaction yields. The products were isolated by gravity filtration in all cases and structures were confirmed by multinuclear NMR spectroscopy and high accuracy mass spectral analysis. Proof of molecular structure of the isolated 5-arylimino-1,3,4-thiadiazole regioisomer was obtained for the first time by single-crystal X-ray diffraction analysis. Crystal-structure determination was carried out on (Z)-1-(5-((3-fluorophenyl)imino)-4-(4-iodophenyl)-4,5-dihydro-1,3,4-thiadiazol-2-yl)ethan-1-one and (Z)-1-(4-phenyl-5-(p-tolylimino)-4,5-dihydro-1,3,4-thiadiazol-2-yl)ethan-1-one. Similarly, the tautomeric structures of the N-arylcyanothioformamides and (Z)-geometries of the 2-oxo-N-phenylpropanehydrazonoyl chloride coupling partners were proven by X-ray diffraction studies. As representative examples, crystal-structure determination was carried out on (4-ethoxyphenyl)carbamothioyl cyanide and (Z)-N-(2,3-difluorophenyl)-2-oxopropanehydrazonoyl chloride. Density functional theory calculations at the B3LYP-D4/def2-TZVP level were carried out to rationalize the observed experimental findings.

Synthesis, Biological Evaluation, and Molecular Modeling Studies of New 1,3,4-Thiadiazole Derivatives as Potent Antimicrobial Agents.

In this work, the synthesis, characterization, and biological activities of a new series of 1,3,4-thiadiazole derivatives were investigated. The structures of final compounds were identified using 1 H-NMR, 13 C-NMR, elemental analysis, and HRMS. All the new synthesized compounds were then screened for their antimicrobial activity against four types of pathogenic bacteria and one fungal strain, by application of the MIC assays, using Ampicilin, Gentamycin, Vancomycin, and Fluconazole as standards. Among the compounds, the MIC values of 4 and 8 µg/mL of the compounds 3f and 3g, respectively, are remarkable and indicate that these compounds are good candidates for antifungal activity. The docking experiments were used to identify the binding forms of produced ligands with sterol 14-demethylase to acquire insight into relevant proteins. The MD performed about 100 ns simulations to validate selected compounds' theoretical studies. Finally, using density functional theory (DFT) to predict reactivity, the chemical characteristics and quantum factors of synthesized compounds were computed. These results were then correlated with the experimental data. Furthermore, computational estimation was performed to predict the ADME properties of the most active compound 3f.