Structure-activity relationship of Hydrazinylthiazole-5-carbaldehydes as potential anti-diabetic agents.

Diabetes is an emerging threat to the world due to large number of deaths reported within the last decade. To overcome its spread and complications, herein, we reported synthesis and anti-diabetic potential of twelve novel 2-[(arylidene)methylidene]hydrazinyl-1,3-thiazole-5-carbaldehydes (3a-l). All compounds have shown good to excellent α-amylase inhibition activity, among them ortho substituted analogues, the compound 3a (IC50= 14.6 mM) and 3l (IC50= 17.9 mM) showed excellent inhibition potential due to their strong electron donating nature of the substituents attached at the aryl ring. The compounds 3a to 3h (IC50= 6.70-10.80 ppm) exhibited excellent anti-glycation potential as compared to standard amino-guanidine (IC50= 11.92 ppm). Almost all the tested compounds are found biocompatible and very safe to the human erythrocyte cells at all tested concentrations. The molecular docking results have found that the binding energy score of all the tested compounds against human serum albumin protein (pdb: 1AO6) is between -5.1827 to -6.8661 kcal/mol far better than standard amino-guanidine (-4.234 kcal/mol).

Synthesis of Arylidenehydrazinyl-4-methoxyphenylthiazole Derivatives: Docking Studies, Probing Type II Diabetes Complication Management Agents.

Thiazole has been a key scaffold in antidiabetic drugs. In quest of new and more effective drugs a simple, efficient, high yielding (67-79 %) and convenient synthesis of arylidenehydrazinyl-4-methoxyphenyl)thiazoles is accomplished over two steps. The synthesis involved the condensation of aryl substituted thiosemicarbazones and 2-bromo-4-methoxyacetophenone in absolute ethanol. The structures of the resulting thiazoles are in accord with their UV/VIS, FT-IR, 1 H-, 13 C-NMR and HRMS data. All compounds were evaluated for alpha(α)-amylase inhibition potential, antiglycation, antioxidant abilities and biocompatibility. The compounds library identified 2-(2-(3,4-dichlorobenzylidene)hydrazinyl)-4-(4-methoxyphenyl)thiazole as a lead molecule against α-amylase inhibition with an IC50 of 5.75±0.02 µM. α-Amylase inhibition is also supported by molecular docking studies against α-amylase. All the obtained thiazoles also showed promising antiglycation activity with 4-(4-methoxyphenyl)-2-{2-[2-(trifluoromethyl)benzylidene]hydrazinyl}thiazole exhibiting the best inhibition (IC50 = 0.383±0.001 mg/mL) compared to control. The tested compounds are also biocompatible at the concentration used i. e., 10 µM.

Synthesis, anti-diabetic profiling and molecular docking studies of 2-(2-arylidenehydrazinyl)thiazol-4(5H)-ones.

Aim: To synthesize novel more potent anti-diabetic agents. Methodology: A simple cost effective Hantzsch's synthetic strategy was used to synthesize 2-(2-arylidenehydrazinyl)thiazol-4(5H)-ones. Results: Fifteen new 2-(2-arylidenehydrazinyl)thiazol-4(5H)-ones were established to check their anti-diabetic potential. From alpha(α)-amylase inhibition, anti-glycation and anti-oxidant activities it is revealed that most of the compounds possess good anti-diabetic potential. All tested compounds were found to be more potent anti-diabetic agents via anti-glycation mode. The results of α-amylase and anti-oxidant inhibition revealed that compounds are less active against α-amylase and anti-oxidant assays. Conclusion: This study concludes that introduction of various electron withdrawing groups at the aryl ring and substitution of different functionalities around thiazolone nucleus could help to find out better anti-diabetic drug.

Diabetes is a most spreading chronicle disease effecting millions of peoples across the globe every year and this number increases day by day. To cure the human population from this dilemma, we had synthesized, characterized and evaluated the anti-diabetic behavior of our synthesized compounds. α-Amylase, in vitro anti-glycation and anti-oxidant assays were performed to find out good lead for Diabetes Mellitus. All tested compounds were found to be excellent anti-glycating agents with IC₅₀ values far better than standard amino-guanidine (IC₅₀ = 3.582 ± 0.002 µM). Compound 4m was most efficient glycation inhibitor (IC₅₀ = 1.095 ± 0.002 µM). Cytotoxicity of all compounds was determined with in vitro hemolytic assay and found all compounds safe and bio-compatible to humans at all tested concentrations. The inhibition potential was also examined with theoretical docking studies to support our experimental results against human pancreatic alpha-amylase (HPA) and human serum albumin (HSA) proteins. All compounds showed excellent binding affinity with HSA active pockets however, only compound 4h and 4k binding affinity was good with HPA.

Synthesis of hydrazinyl-thiazole ester derivatives, in vitro trypanocidal and leishmanicidal activities.

Aim: To synthesize novel more potent trypanocidal and leishmanicidal agents. Methods: Hantzsch's synthetic strategy was used to synthesize 1,3-thiazole-4-carboxylates and their N-benzylated derivatives. Results: 28 new thiazole-carboxylates and their N-benzylated derivatives were established to test their trypanocidal and leishmanicidal activities. From both series, compounds 3b, 4f, 4g, 4j and 4n exhibited a better or comparable trypanocidal profile to benznidazole. Among all tested compounds, 4n was found to be the most potent and was better than benznidazole. Conclusion: Further variation of substituents around 1,3-thiazole-4-carboxylates and or hydrazinyl moiety may assist in establishing better and more potent trypanocidal and leishmanicidal agents.

Chagas disease and leishmaniasis are neglected tropical diseases. Herein, 28 1,3-thiazoles have been synthesized from thiosemicarbazones in a rapid, efficient and cost-effective manner. In vitro assays were performed against intracellular amastigotes of Trypanosoma cruzi (T. cruzi) and promastigotes and intracellular amastigote forms of Leishmania infantum (L. infantum) and Leishmania amazonensis (L. amazonensis). Some of the 1,3-thiazole-4-carboxylates inhibited the amastigote form of T. cruzi without affecting macrophage viability, compound 4n being the most potent and better than benznidazole. Our synthesized compounds exhibited promising activity against T. cruzi, thus broadening options for scaffold and lead compound optimization. Concerning the leishmanicidal activity, compound 4g was the best prototype in terms of potency and selectivity. Compounds 4g and 3m showed moderate selectivity and potency against intracellular amastigotes of L. amazonensis and L. infantum, respectively.

Synthesis of hydrazinylthiazole carboxylates: a mechanistic approach for treatment of diabetes and its complications.

Aim: The deaths of thousands of people and millions affected by diabetes mellitus triggered us to look for alternative possible solutions to cure diabetes and its complications. Materials & methods: A series of hydrazinylthiazole carboxylates (3a-n) was prepared by cyclocondensation reaction of thiosemicarbazones with ethyl 2-chloroacetoacetate. These compounds were screened for antidiabetic potential through α-amylase inhibition, antiglycation and antioxidant assays. Results & conclusion: Most of the compounds exhibited a promising antidiabetic property. Compounds 3e and 3h showed excellent α-amylase and glycation inhibition properties. The hemolytic assay indicated that all compounds are biocompatible. Docking studies carried out on α-amylase target showed correlation between in vitro inhibition and binding energy.

4-Adamantyl-(2-(arylidene)hydrazinyl)thiazoles as potential antidiabetic agents: experimental and docking studies.

Aim: To develop an efficient and cost-effective antidiabetic agent. Methods: A simple and convenient Hantzsch synthetic strategy was used to prepare 4-adamantyl-(2-(arylidene)hydrazinyl)thiazoles. Results: Fifteen newly established structures of 4-adamantyl-(2-(arylidene)hydrazinyl)thiazoles were tested for their α-amylase, antiglycation and antioxidant activities. Almost all tested compounds showed excellent α-amylase inhibition. Compounds 3a and 3j exhibited the highest potency, with IC50 values of 16.34 ± 2.67 and 16.64 ± 1.12 µM, respectively. Compounds 3c and 3i exhibited comparable antiglycation potential with the standard, aminoguanidine. The antioxidant potential of compound 3g was found to be excellent, with an IC50 value of 28.19 ± 0.2563 µM. The binding interactions of compound 3a (binding energy = -8.833 kcal/mol) with human pancreatic α-amylase identified 3a as a potent α-amylase inhibitor. Conclusion: Enrichment of established structures with more electron-donating functionalities may assist/lead to the development of more potent antidiabetic drugs.

Diabetes is one of the major causes of death in the present era. To combat damaging processes associated with diabetes, called glycation and oxidation, we prepared a series of compounds called 4-adamantyl-(2-(arylidene)hydrazinyl)thiazoles. The established structures were tested for their antidiabetic potential. The compounds 4-adamantyl-(2-(4-chlorobenzylidene)hydrazinyl)thiazole and 4-adamantyl-(2-(2-chlorobenzylidene)hydrazinyl)thiazole showed the highest potency. The compounds 4-adamantyl-(2-(4-bromobenzylidene)hydrazinyl)thiazole and 4-adamantyl-(2-(2-hydroxybenzylidene)hydrazinyl)thiazole exhibited comparable antiglycation potential. The antioxidant potential of compound 4-adamantyl-(2-(3-nitrobenzylidene)hydrazinyl)thiazole was found to be excellent. A further test was used to check toxicity and all compounds were found to be biocompatible. We also investigated, through docking studies, the way in which these compounds interact with the human proteins albumin and pancreatic α-amylase.

Synthesis, characterization and exploration of photovoltaic behavior of hydrazide based scaffolds: a concise experimental and DFT study.

Solar energy being a non-depleting energy resource, has attracted scientists' attention to develop efficient solar cells to meet energy demands. Herein, a series of hydrazinylthiazole-4-carbohydrazide organic photovoltaic compounds (BDTC1-BDTC7) with an A1-D1-A2-D2 framework was synthesized with 48-62% yields, and their spectroscopic characterization was accomplished using FT-IR, HRMS, 1H and 13C-NMR techniques. Density functional theory (DFT) and time dependent DFT analyses were performed utilizing the M06/6-31G(d,p) functional to calculate the photovoltaic and optoelectronic properties of BDTC1-BDTC7via numerous simulations of the frontier molecular orbitals (FMOs), transition density matrix (TDM), open circuit voltage (V oc) and density of states (DOS). Moreover, the conducted analysis on the FMOs revealed efficient transference of charge from the highest occupied to the lowest unoccupied molecular orbitals (HOMO → LUMO), further supported by TDM and DOS analyses. Furthermore, the values of binding energy (E b = 0.295 to 1.150 eV), as well as reorganization energy of the holes (-0.038-0.025 eV) and electrons (-0.023-0.00 eV), were found to be smaller for all the studied compounds, which suggests a higher exciton dissociation rate with greater hole mobility in BDTC1-BDTC7. V oc analysis was accomplished with respect to HOMOPBDB-T-LUMOACCEPTOR. Among all the synthesized molecules, BDTC7 was found to have a reduced band gap (3.583 eV), with a bathochromic shift and absorption maximum at 448.990 nm, and a promising V oc (1.97 V), thus it is regarded as a potential candidate for high performance photovoltaic applications.

Synthesis of Fluorinated Hydrazinylthiazole Derivatives: A Virtual and Experimental Approach to Diabetes Management.

A novel series of fluorophenyl-based thiazoles was synthesized following the Hanztsch method. All of the compounds were initially verified with physical parameters (color, melting point, retardation factor (R f)), which were further confirmed by several spectroscopic methods, including ultraviolet-visible (UV-visible), Fourier-transform infrared (FTIR), 1H, 13C, 19F NMR, and high-resolution mass spectrometry (HRMS). The binding interactions of all compounds were studied using a molecular docking simulation approach. Furthermore, each compound was evaluated for its alpha(α)-amylase, antiglycation, and antioxidant potentials. The biocompatibility of all compounds was checked with an in vitro hemolytic assay. All synthesized scaffolds were found biocompatible with minimal lysis of human erythrocytes as compared to the standard Triton X-100. Among the tested compounds, the analogue 3h (IC50 = 5.14 ± 0.03 µM) was found to be a highly potent candidate against α-amylase as compared to the standard (acarbose, IC50 = 5.55 ± 0.06 µM). The compounds 3d, 3f, 3i, and 3k exhibited excellent antiglycation inhibition potential with their IC50 values far less than the standard amino guanidine (IC50 = 0.403 ± 0.001 mg/mL). The antidiabetic potential was further supported by docking studies. Docking studies revealed that all synthesized compounds exhibited various interactions along enzyme active sites (pi-pi, H-bonding, van der Waals) with varied binding energies.

Facile Synthesis and DFT Analysis of Novel Thiazole-Based Hydrazones: An Experimental and Theoretical Perspective.

Hydrazone compounds with remarkable nonlinear optical (NLO) properties were found with vast applications due to their cost-effective synthesis and greater stability. Therefore, we synthesized hydrazone scaffolds (TCAH1-TCAH8) by condensation reaction, and their structural confirmation was accomplished with spectroscopic methods (1H-, 13C-NMR, and HRMS). Quantum chemical calculations were also performed at B3PW91/6-311G(d,p) functional of DFT to explore electronic, structural, and chemical properties. To understand the NLO responses of afore-said chromophores, various kinds of analyses such as natural bonding orbitals (NBOs), frontier molecular orbitals (FMOs), UV-vis analysis, and density of states (DOS) were performed. Findings showed that the HOMO-LUMO energy gap in TCAH8 (3.595 eV) was found to be lower than the TCAH1-TCAH7 (4.123-3.932 eV) with a large red shift which leads to a substantial NLO response. Furthermore, strong intramolecular interactions showed the highest stabilization energy (24.1 kcal mol-1) for TCAH8 in the NBO transitions, combined with the least binding energy. The significant NLO response of TCAH4 was explored with ⟨α⟩, ßtot, and ⟨γ⟩ values as 5.157 × 10-23, and 2.185 × 10-29, and 2.753 × 10-34 esu, respectively, among the entitled compounds. The recent findings may inspire scientists to develop extremely effective NLO materials for forthcoming hi-tech applications.

Design, and synthesis of selectively anticancer 4-cyanophenyl substituted thiazol-2-ylhydrazones.

Cyclization of substituted thiosemicarbazones with α-bromo-4-cyanoacetophenone allows rapid single-step sustainable syntheses of 4-cyanophenyl-2-hydrazinylthiazoles libraries (30 examples, 66-79%). All show anticancer efficacy against HCT-116 and MCF-7 carcinoma cell lines with the majority being more active than cisplatin positive controls. The compounds 2-(2-(2-hydroxy-3-methylbenzylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3f) and 2-(2-((pentafluorophenyl)methylene)-hydrazinyl)-4-(4-cyanophenyl)thiazole (3a') show optimal GI50 values (1.0 ± 0.1 µM and 1.7 ± 0.3 µM) against MCF-7 breast cancer cells. Against colorectal carcinoma HCT-116 cells, (2-(2-(3-bromothiophen-2-yl)methylene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3b'), 2-(2-(2-hydroxy-3-methylbenzylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3f), 2-(2-(2,6-dichlorobenzylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3n) and 2-(2-(1-(4-fluorophenyl)ethylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3w) are the most active (GI50 values: 1.6 ± 0.2, 1.6 ± 0.1, 1.1 ± 0.5 and 1.5 ± 0.8 µM respectively). Control studies with MRC-5 cells indicate appreciable selectivity towards the cancer cells targeted. Significant (p < 0.005) growth inhibition and cytotoxicity effects for the thiazoles 3 were corroborated by cell count and clonogenic assays using the same cancer cell lines at 5 and 10 µM agent concentrations. Cell cycle, caspase activation and Western blot assays demonstrated that compounds 3b' and 3f induce cancer cell death via caspase-dependent apoptosis. The combination of straight forward synthesis and high activity makes the thiazoles 3 an interesting lead for further development.