Diether derivatives of homo- or substituted piperidines as non-imidazole histamine H3 receptor ligands

Synthesis and biological activities of a series of homo- or substituted piperidine unsymmetrical diethers are described. The novel compounds were evaluated for histamine H₃ receptor binding affinities at recombinant human H₃ receptor stably expressed in HEK-293 cells. All diethers showed in vitro affinities in nanomolar concentration range. The most potent compounds are 1-[3-(3-(4-chlorophenoxy)propoxy)propyl]-3-methylpiperidine 11 (K_i = 3.2 nM) and 1-[3-(3-(4-chlorophenoxy)propoxy)propyl]azepane 13 (K_i = 3.5 nM).     

Large conductance Ca2+-activated K+ channel (BKCa) activating properties of a series of novel N-arylbenzamides: Channel subunit dependent effects

Large conductance calcium activated potassium channels (BK_Ca) are fundamental in the control of cellular excitability. Thus, compounds that activate BK_Ca channels could provide potential therapies in the treatment of pathologies of the cardiovascular and central nervous system. A series of novel N-arylbenzamide compounds, and the reference compound NS1619, were evaluated for BK_Ca channel opener properties in Human Embryonic Kidney (HEK293) cells expressing the human BK_Ca channel α-subunit alone or α + β1-subunit complex.Channel activity was determined using a non-radioactive Rb⁺ efflux assay to construct concentration effect curves for each compound. All N-arylbenzamide compounds and NS1619 evoked significant (p <0.05) concentration related increases in Rb⁺ efflux both in cells expressing α-subunit alone or α + β1-subunits. Co-expression of the β1-subunit modified the Rb⁺ efflux responses, relative to that obtained in cells expressing the α-subunit alone, for most of the N-arylbenzamide compounds, in contrast to NS1619. The EC₄₀ values of NS1619, BKMe1 and BKOEt1 were not significantly affected by the co-expression of the BK_Ca channel α + β1-subunits. In contrast, 5 other N-arylbenzamides (BKPr2, BKPr3, BKPr4, BKH1 and BKVV) showed a significant (p <0.05) 2- to 10-fold increase in EC₄₀ values when tested on the BK_Ca α + β1-subunit expressing cells compared to BK_Ca α-subunit expressing cells. Further, the E_max values for BKPr4, BKVV and BKH1 were lower in the BK_Ca channel α + β1-subunit expressing cells.In conclusion, the N-arylbenzamides studied, like NS1619, were able to activate BK_Ca channels formed of the α-subunit only. The co-expression of the β1-subunit, however, modified the ability of certain compounds to active the channel leading to differentiated pharmacodynamic profiles.     

Synthesis of novel 7-imino-2-thioxo-3,7-dihydro-2H-thiazolo [4,5-d] pyrimidine derivatives as adenosine A2A receptor antagonists

Novel bicyclic thiazolopyrimidine compounds (15–26) were synthesized to develop adenosine A_2A receptor (A_2AR) antagonist for the treatment of Parkinson’s disease (PD). The binding affinity of the compounds (15–26) with A_2AR was evaluated using radioligand binding assay on isolated membranes from stably transfected HEK293 cells. Selectivity of the compounds towards A_2AR was assessed by comparing their binding affinities with A₁ receptors (A₁R). cAMP concentrations were measured from HEK293 cells treated with compounds (15–26) as compared to NECA (A_2AR agonist). The compound (16) possessed strongest A_2AR binding affinity (K_i value = 0.0038 nM) and selectivity (737-fold) versus A₁R. Decrease in A_2AR-coupled release of endogenous cAMP from HEK293 cells treated with compounds (15–26) is evocative of their potential as A_2AR antagonist.     

Optimization of the electrophile of chloronitrobenzamide leads active against Trypanosoma brucei

We previously reported the phenylchloronitrobenzamides (PCNBs), a novel class of compounds active against the species of trypanosomes that cause Human African Trypanosomiasis (HAT). Herein, we explored the potential to adjust the reactivity of the electrophilic chloronitrobenzamide core. These studies identified compound 7d that potently inhibited the growth of trypanosomes (EC₅₀ = 120 nM for Trypanosoma b. brucei, 18 nM for Trypanosoma b. rhodesiense, and 38 nM for Trypanosoma b. gambiense) without significant cytotoxicity against mammalian cell lines (EC₅₀ > 25 μM for HepG2, HEK293, Raji, and BJ cell lines) and also had good stability in microsomal models (t_1/2 > 4 h in both human and mouse). Overall these properties indicate the compound 7d and its analogs are worth further exploration as potential leads for HAT.     

Synthesis,antimycobacterial activity and docking study of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives and related hydrazide-hydrazones

A new convenient method for preparation of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b–g and coumarin containing hydrazide-hydrazone analogues 4a–e was presented. The antimycobacterial activity against reference strain Mycobacterium tuberculosis H37Rv and cytotoxicity against the human embryonic kidney cell line HEK-293 were tested in vitro. All compounds demonstrated significant minimum inhibitory concentrations (MIC) ranging 0.28–1.69 μM, which were comparable to those of isoniazid. The cytotoxicity (IC₅₀ > 200 µM) to the “normal cell” model HEK-293T exhibited by 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b–e, was noticeably milder compared to that of their hydrazone analogues 4a–e (IC₅₀ 33–403 µM). Molecular docking studies on compounds 4a–e and 5b–g were also carried out to investigate their binding to the 2-trans-enoyl-ACP reductase (InhA) enzyme involved in M. tuberculosis cell wall biogenesis. The binding model suggested one or more hydrogen bonding and/or arene-H or arene-arene interactions between hydrazones or pyrazole-fused coumarin derivatives and InhA enzyme for all synthesized compounds.     

Cytotoxic,antimicrobial activities,AChE and BChE inhibitory effects of compounds from Tanacetum chiliophyllum (Fisch. & Mey.) Schultz Bip. var. oligocephalum (D.C.) Sosn. and T. chiliophyllum (Fisch. & Mey.) Schultz Bip. var. monocephalum Grierson

Tanacetum L. species traditionally used for insecticidal purposes as well as in folk medicine for their antitumor, antimicrobial, antifungal activities. In our previous study a novel sesquiterpene lactone and triterpene lactone together with 12 known flavonoids, coumarin and a triterpene were isolated from T. chiliophyllum var. oligocephalum and T. chiliophyllum var. monocephalum extracts which have insecticidal and antimicrobial activity. In this study, cytotoxic, antimicrobial activities and acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory effects of pure compounds isolated from these plants were investigated. The tested compounds showed AChE and BChE inhibition which ranged between 7.20–80.37% and 9.19%–76.99% respectively. The highest AChE and BChE inhibition was observed for ulubelenolide which afforded 80.37% and 76.99% inhibition respectively. The cytotoxic effect of the compounds ranged between 22.34–49.77 μg/mL IC₅₀ values. Highest cytotoxic activity was observed against MCF-7 and HEK 293 cell line by 5–hydroxy-3′,4′,7-trimethoxy flavone and 5-hydroxy-3′,4′,6,7-tetramethoxyflavone that produced 25.80 ± 0.17 and 22.34 ± 0.70 IC₅₀ values respectively. Compounds eupatilin, cirsilineol, 5–hydroxy-3′,4′,7-trimethoxy flavone and ulubelenolide showed significant antimicrobial effect on C. albicans with 7.8 μg/mL MIC. The new compound ulubelenolide afforded high AChE and BChE inhibition as well as high antifungal activity. In our opinion activity of this substance should be evaluated further against other fungal species.     

Bis-phosphonium salts of pyridoxine: The relationship between structure and antibacterial activity

A series of 23 novel bis-phosphonium salts based on pyridoxine were synthesized and their antibacterial activities were evaluated in vitro. All compounds were inactive against gram-negative bacteria and exhibited the structure-dependent activity against gram-positive bacteria. The antibacterial activity enhanced with the increase in chain length at acetal carbon atom in the order n-Pr > Et > Me. Further increasing of length and branching of alkyl chain leads to the reduction of antibacterial activity. Replacement of the phenyl substituents at the phosphorus atoms in 5,6-bis(triphenylphosphonio(methyl))-2,2,8-trimethyl-4H-[1,3]-dioxino[4,5-c]pyridine dichloride (compound 1) with n-butyl, m-tolyl or p-tolyl as well as chloride anions in the compound 1 with bromides (compound 14a) increased the activity against Staphylococcus aureus and Staphylococcus epidermidis up to 5 times (MICs = 1–1.25 μg/ml). But in practically all cases chemical modifications of compound 1 led to the increase of its toxicity for HEK-293 cells. The only exception is compound 5,6-bis[tributylphosphonio(methyl)]-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine dichloride (10a) which demonstrated lower MIC values against S. aureus and S. epidermidis (1 μg/ml) and lower cytotoxicity on HEK-293 cells (CC₅₀ = 200 μg/ml). Compound 10a had no significant mutagenic and genotoxic effects and was selected for further evaluation. It should be noted that all bis-phosphonium salt based on pyridoxine were much more toxic than vancomycin.     

Design,synthesis, cytotoxicity,HuTopoIIα inhibitory activity and molecular docking studies of pyrazole derivatives as potential anticancer agents

In an attempt to find potential anticancer agents, a series of novel ethyl 4-(3-(aryl)-1-phenyl-1H-pyrazol-4-yl)-2-oxo-6-(pyridin-3-yl)cyclohex-3-enecarboxylates 5a-i and 5-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-dihydropyrazole-1-carbothioamides 6a-i were designed, synthesized and evaluated for their topoisomerase IIα inhibitory activity and in vitro cytotoxicity against a panel of cancerous cell lines (MCF-7, NCI-H460, HeLa) and a normal cell line (HEK-293T). Molecular docking studies of all the synthesized compounds into the binding site of topoisomerase IIα protein (PDB ID: 1ZXM) were performed to gain a comprehensive understanding into plausible binding modes. These compounds were also screened for in silico drug-likeliness properties on the basis of the absorption, distribution, metabolism and excretion (ADME) prediction. Among all the synthesized compounds, analogue 5d showed superior cytotoxicity with an IC₅₀ value of 7.01 ± 0.60 μM for HeLa, 8.55 ± 0.35 μM for NCI-H460 and 14.31 ± 0.90 for MCF-7 cancer cell lines. Further, compound 5d showed 70.82% inhibition of topoisomerase IIα at a concentration of 100 μM with maximum docking score of −8.24. Results of ADME prediction revealed that most of these compounds showed in silico drug-likeliness properties within the ideal range.     

Design,synthesis, and bioactivities of novel oxadiazole-substituted pyrazole oximes

A series of novel pyrazole oxime derivatives containing a substituted oxadiazole group were designed and synthesized. The bioassay results indicated that some title compounds displayed good acaricidal and insecticidal activities against Tetranychus cinnabarinus, Aphis medicaginis, Oriental armyworm, and Nilaparvata lugens. Especially, compounds 7a, 7b, and 7c had 80%, 90%, and 90% insecticidal activities against A. medicaginis at 20 μg/mL, respectively. Interestingly, some of the designed compounds displayed wonderful fungicidal activities in vivo against cucumber Pseudoperonospora cubensis. Furthermore, compounds 7a (EC₅₀ = 4.97 μg/mL) and 7h (EC₅₀ = 0.51 μg/mL) showed excellent fungicidal activity against P. cubensis comparable or better than that of the control Pyraclostrobin (EC₅₀ = 4.59 μg/mL).     

1,2,3-Triazole-nimesulide hybrid: Their design,synthesis and evaluation as potential anticancer agents

A new hybrid template has been designed by integrating the structural features of nimesulide and the 1,2,3-triazole moiety in a single molecular entity at the same time eliminating the problematic nitro group of nimesulide. The template has been used for the generation of a library of molecules as potential anticancer agents. A mild and greener CuAAC approach has been used to synthesize these compounds via the reaction of 4-azido derivative of nimesulide and terminal alkynes in water. Three of these compounds showed promising growth inhibition (IC₅₀ ～6–10 μM) of A549, HepG2, HeLa and DU145 cancer cell lines but no significant effects on HEK293 cell line. They also inhibited PDE4B in vitro (60–70% at 10 μM) that was supported by the docking studies (PLP score 87–94) in silico.     

Development of smart cell-free and cell-based assay systems for investigation of leukotriene C4 synthase activity and evaluation of inhibitors

Cysteinyl leukotrienes (cys-LTs) cause bronchoconstriction in anaphylaxis and asthma. They are formed by 5-lipoxygenase (5-LOX) from arachidonic acid (AA) yielding the unstable leukotriene A₄ (LTA₄) that is subsequently conjugated with glutathione (GSH) by LTC₄ synthase (LTC₄S). Cys-LT receptor antagonists and LTC₄S inhibitors have been developed, but only the former have reached the market. High structural homology to related enzymes and lack of convenient test systems due to instability of added LTA₄ have hampered the development of LTC₄S inhibitors. We present smart cell-free and cell-based assay systems based on in situ-generated LTA₄ that allow studying LTC₄S activity and investigating LTC₄S inhibitors. Co-incubations of microsomes from HEK293 cells expressing LTC₄S with isolated 5-LOX efficiently converted exogenous AA to LTC₄ (~ 1.3 μg/200 μg protein). Stimulation of HEK293 cells co-expressing 5-LOX and LTC₄S with Ca^2 +-ionophore A23187 and 20 μM AA resulted in strong LTC₄ formation (~ 250 ng/10⁶ cells). MK-886, a well-known 5-LOX activating protein (FLAP) inhibitor that also acts on LTC₄S, consistently inhibited LTC₄ formation in all assay types (IC₅₀ = 3.1–3.5 μM) and we successfully confirmed TK04a as potent LTC₄S inhibitor in these assay systems (IC₅₀ = 17 and 300 nM, respectively). We demonstrated transcellular LTC₄ biosynthesis between neutrophils or 5-LOX-expressing HEK293 cells that produce LTA₄ from AA and HEK293 cells expressing LTC₄S that transform LTA₄ to LTC₄. In conclusion, our assay approaches are advantageous as the substrate LTA₄ is generated in situ and are suitable for studying enzymatic functionality of LTC₄S including site-directed mutations and evaluation of LTC₄S inhibitors.     

In vitro and in vivo pharmacological characterization of the novel neuropeptide S receptor ligands QA1 and PI1

The pharmacological activity of the novel neuropeptide S (NPS) receptor (NPSR) ligands QA1 and PI1 was investigated. In vitro QA1 and PI1 were tested in calcium mobilization studies performed in HEK293 cells expressing the recombinant mouse (HEK293_mNPSR) and human (HEK293_hNPSRIle107 and HEK293_hNPSRAsn107) NPSR receptors. In vivo the compounds were studied in mouse righting reflex (RR) and locomotor activity (LA) tests. NPS caused a concentration dependent mobilization of intracellular calcium in the three cell lines with high potency (pEC₅₀ 8.73–9.14). In inhibition response curve and Schild protocol experiments the effects of NPS were antagonized by QA1 and PI1. QA1 displayed high potency (pK_B 9.60–9.82) behaving as a insurmountable antagonist. However in coinjection experiments QA1 produced a rightward swift of the concentration response curve to NPS without modifying its maximal effects; this suggests that QA1 is actually a slow dissociating competitive antagonist. PI1 displayed a competitive type of antagonism and lower values of potencies (pA₂ 7.74–8.45). In vivo in mice NPS (0.1 nmol, i.c.v.) elicited arousal promoting action in the RR assay and stimulant effects in the LA test. QA1 (30 mg kg⁻¹) was able to partially counteract the arousal promoting NPS effects, while PI1 was inactive in the RR test. In the LA test QA1 and PI1 only poorly blocked the NPS stimulant action. The present data demonstrated that QA1 and PI1 act as potent NPSR antagonists in vitro, however their usefulness for in vivo investigations in mice seems limited probably by pharmacokinetic reasons.     

New antiprotozoal agents: Synthesis and biological evaluation of different 4-(7-chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives

In an endeavor to develop efficacious antiprotozoal agents 4-(7-chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives (5–14) were synthesized, characterized and biologically evaluated for antiprotozoal activity. The compounds were screened in vitro against the HM1: IMSS strain of Entamoeba histolytica and NF54 chloroquine-sensitive strain of Plasmodium falciparum. Among the synthesized compounds six exhibited promising antiamoebic activity with IC₅₀ values (0.14–1.26 μM) lower than the standard drug metronidazole (IC₅₀ 1.80 μM). All nine compounds exhibited antimalarial activity (IC₅₀ range: 1.42–19.62 μM), while maintaining a favorable safety profile to host red blood cells. All the compounds were less effective as an antimalarial and more toxic (IC₅₀ range: 14.67–81.24 μM) than quinine (IC₅₀: 275.6 ± 16.46 μM) against the human kidney epithelial cells. None of the compounds exhibited any inhibitory effect on the viability of Anopheles arabiensis mosquito larvae.     

Comparative molecular field analysis of fenoterol derivatives: A platform towards highly selective and effective β2-adrenergic receptor agonists

Purpose: To use a previously developed CoMFA model to design a series of new structures of high selectivity and efficacy towards the β₂-adrenergic receptor. Results: Out of 21 computationally designed structures 6 compounds were synthesized and characterized for β₂-AR binding affinities, subtype selectivities and functional activities. Conclusion: the best compound is (R,R)-4-methoxy-1-naphthylfelnoterol with K_iβ₂-AR = 0.28 μm, K_iβ₁-AR/K_iβ₂-AR = 573, EC_50cAMP = 3.9 nm, EC_50cardio = 16 nm. The CoMFA model appears to be an effective predictor of the cardiomocyte contractility of the studied compounds which are targeted for use in congestive heart failure.     

Rubiyunnanins C-H, cytotoxic cyclic hexapeptides from Rubia yunnanensis inhibiting nitric oxide production and NF-κB activation

Six new (rubiyunnanins C–H, 1–6) and five known (7–11) cyclic hexapeptides were isolated from the roots of Rubia yunnanensis (Franch.) Diels. The structures and stereochemistry of 1–6 were established by extensive spectroscopic analyses and chemical methods. All compounds (1–11) not only exhibited cytotoxic activities against a panel of eleven cancer cell lines with IC₅₀ values ranging from 0.001 to 56.24 μM, but also exerted inhibitory activities against nitric oxide (NO) production in LPS and IFN-γ-induced RAW 264.7 murine macrophages with IC₅₀ values ranging from 0.05 to 12.68 μM. Furthermore, this is the first time it is being reported that compounds 2 and 7–10 significantly inhibited TNF-α-induced NF-κB activation in HEK-293-NF-κB luciferase stable cells with IC₅₀ values of 35.07, 0.03, 1.69, 12.64 and 1.18 μM, respectively.     

Does conjugation of antioxidants improve their antioxidative/anti-inflammatory potential?

A series of symmetric and asymmetric spermine (SPM) conjugates with all-trans-retinoic acid (ATRA), acitretin (ACI), (E)-3-(trioxsalen-4′-yl)acrylic acid (TRAA) and l-DOPA, amides of ACI, l-DOPA and TRAA with 1-aminobutane, benzylamine, dopamine and 1,12-diaminobutane as well as hybrid conjugates of O,O′-dimethylcaffeic acid (DMCA) with TRAA or N-fumaroyl-indole-3-carboxanilide (FICA) and 2-(2-aminoethoxy)ethanol were synthesized and their antioxidant properties were studied. The reducing activity (RA)% of the compounds were evaluated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical-scavenging assay and found to be in the range 0–92(20 min)%/96(60 min)% at 100 μM, the most powerful being the conjugates l-DOPA-SPM-l-DOPA (8, RA = 89%/96%) and l-DOPA-dopamine (13, RA = 92%/92%). Conjugate DMCA-NH(CH₂CH₂O)₂-FICA (14) was the most powerful LOX inhibitor with IC₅₀ 33.5 μM, followed by the conjugates ACI-NHCH₂Ph (10, IC₅₀ 40.5 μM), ACI-SPM-TRAA (7, IC₅₀ 41.5 μM), DMCA-NH(CH₂CH₂O)₂-TRAA (15, IC₅₀ 65 μM), 13 (IC₅₀ 81.5 μM) and ACI-dopamine (11, IC₅₀ 87 μM). The most potent inhibitors of lipid peroxidation at 100 μM were the conjugates 15 (98%) and ACI-SPM-ACI (4, 97%) whereas all other compounds showed activities comparable or lower than trolox. The most interesting compounds, namely ATRA-SPM-ATRA (3), 4, 10, 11 and 15, as well as unconjugated compounds such as ATRA and dopamine, were studied for their anti-inflammatory activity in vivo on rat paw oedema induced by Carrageenan and found to exhibit, for doses of 0.01 mmol/mL of conjugates per Kg of rat body weight, weaker anti-inflammatory activities (3.6–40%) than indomethacin (47%) with conjugate 3 being the most potent (40%) in this series of compounds. The cytocompatibility of selected compounds was evaluated by the viability of RAMEC cells in the presence of different concentrations (0.5–50 μM) of the compounds. Conjugates 3 (IC₅₀ 2.6 μM) and 4 (IC₅₀ 4.7 μM) were more cytotoxic than the corresponding unconjugated retinoids ATRA (IC₅₀ 18.3 μM) and ACI (IC₅₀ 14.6 μM), whereas conjugate 15 (IC₅₀ 12.9 μM) was less cytotoxic than either DCSP (IC₅₀ 11.3 μM) or the tert-butyl ester of TRAA (IC₅₀ 2.9 μM).     

Antimycobacterial activity of novel hydrazide-hydrazone derivatives with 2H-chromene and coumarin scaffold

This study reports the synthesis of new 2H-chromene or coumarin based acylhydrazones, which were evaluated for their in vitro antimycobacterial activity against reference strain Mycobacterium tuberculosis H37Rv and compared to the first-line antituberculosis drugs, isoniazid (INH) and ethambutol (EMB). The most active compounds 7m (MIC 0.13 μM), 7o (MIC 0.15 μM) and 7k (MIC 0.17 μM) demonstrated antimycobacterial activity at submicromolar concentration level and remarkably minimal associated cytotoxicity in the human embryonic kidney cell line HEK-293T. Structure-activity relationship for this class of compounds has been established.     

Synthesis and QSAR study of novel α-methylene-γ-butyrolactone derivatives as antifungal agents

Thirty-six new α-benzylidene-γ-lactone compounds based α-methylene-γ-butyrolactone substructure were prepared and characterized by spectroscopic analysis. All compounds were evaluated for antifungal activities in vitro against six plant pathogenic fungi and the half maximal inhibitory concentration (IC₅₀) against Botrytis cinerea and Colletotrichum lagenarium were investigated. Compounds 5c-3 and 5c-5 with the halogen atom exhibited excellent fungicidal activity against B. cinerea (IC₅₀ = 22.91, 18.89 μM). The structure-activity relationships (SARs) analysis indicated that the derivatives with electron-withdrawing substituents at the meta- or para-positions improves the activity. Via the heuristic method, the generated quantitative structure-activity relationship (QSAR) model (R² = 0.961) revealed a strong correlation of antifungal activity against B. cinerea with molecular structures of these compounds. Meanwhile, the cytotoxicity of 20 representative derivatives was tested in the human tumor cells line (HepG2) and the hepatic L02 cells line, the result indicated that the synthesized compounds showed significant inhibitory activity and limited selectivity. Compound 5c-5 has the highest fungicidal activity with IC₅₀ = 18.89 μM (against B. cinerea.) but low cytotoxicity with IC₅₀ = 35.4 μM (against HepG2 cell line) and IC₅₀ = 68.8 μM (against Hepatic L02 cell line). These encouraging results can be providing an alternative, promising use of α-benzylidene-γ-lactone through the design and exploration of eco-friendly fungicides with low toxicity and high efficiency.     

Synthesis of thiobarbituric acid derivatives: In vitro α-glucosidase inhibition and molecular docking studies

Synthesis, structure, and evaluation of in vitro α-glucosidase enzyme inhibition of a new class of diethylammonium salts of aryl substituted thiobarbituric acid is described. This protocol is straight, environmentally benign and efficient, involving Aldol-Michael addition reaction in one pot fashion. The 3D chemical structures of the synthesized compounds were assigned based on spectroscopic methods and X-ray single crystal diffraction analyses. All synthesized compounds 3a-3n were evaluated for their in vitro α-glucosidase enzyme inhibitory activity, whereas acarbose was used as the standard drug (IC₅₀ = 840 ± 1.73 µM). All tested compounds were found to possess varying degree of α-glucosidase enzyme inhibition activity with (IC₅₀ = 19.46 ± 1.84–415.8 ± 4.0 µM). Compound 3i (IC₅₀ = 19.4 ± 1.84 µM) exhibited the highest activity. To the best of knowledge this is the first report of the in vitro α-glucosidase enzyme inhibition by the diethylamonium salts of aryl substituted thiobarbituric acid. Furthermore, molecular docking studies of selected compounds were also performed to see interactions between active compounds and binding sites.