Chalcone-based Turn-Off Chemosensor for Selective and Susceptible Detection of Fe2+ Ions: Spectroscopic and DFT Investigations.

Herein, in this report we are introducing newly synthesized chalcone derivative, "(E)-1-phenyl-3-(4-((5-(((Z)-thiophen-2-ylmethylene)amino)-1,3,4-thiadiazol-2-yl)thio)phenyl)prop-2-en-1-one" (5), as a chemosensor to detect Fe2+ metal ions in HEPES buffer solution of pH 7.5. Spectroscopic techniques were used to confirm the synthesized sensor. To determine the chemical reactivity and molecular stability of the probe, a frontier molecular orbitals investigation was carried out. A molecular electrostatic potential map was investigated to know the binding site of 5 for metal ion coordination. The theoretical absorption and fluorescence emission properties were estimated and correlated with the experimental observations. The sensor showed excellent selectivity for Fe2+ compared to all other studied metal ions. The fluorescence binding studies were carried out by adding different amounts of Fe2+ ions for a fixed concentration of probe 5. The inclusion of Fe2+ ions resulted in a decrease in fluorescence intensity with a bathochromic shift of emission wavelength of 5 due to the 5-Fe2+ complexation. The binding affinity value for the probe was found to be 576.2 M-1 with the help of the Stern-Volmer plot. The Job's plot and mass spectra supported the 2:1 (5: Fe2+) stoichiometry of complex formation. The detection limit and limit of quantification of 5 for Fe2+ were calculated to be 4.79 × 10-5 M and 14.54 × 10-5 M. Further, in addition to this, the photophysical parameters such as fluorescence lifetime of 5 and 5-Fe2+ complex measured to be 0.1439 and 0.1574 ns. The quantum yield of 5 and 5-Fe2+ was found to be 0.0398 and 0.0376. All these experimental findings revealed that probe 5 has excellent selectivity and sensitivity for Fe2+ ions.

In vitro α-amylase and α-glucosidase inhibition study of dihydropyrimidinones synthesized via one-pot Biginelli reaction in the presence of a green catalyst.

A green catalyst WELPSA-catalyzed three-component condensation (Biginelli) process involving an aldehyde, barbituric/thiobarbituric/1,3-dimethylbarbituric acid, and urea/thiourea/guanidine hydrochloride in a single pot in presence of a green solvent for the production of DHPM have been presented. The catalyst is reusable and this methodology is scalable. By using the in vitro experiments, the antidiabetic potentiality of synthesized compounds that inhibit α-amylase along with α-glucosidase efficiencies was assessed. All the synthesized compounds except for 4a and 4e, showed the most significant inhibition for α-amylase and α-glucosidase activities. Among the synthesized DHPM compounds, 4c and 4b exhibited significant inhibition profiles compared to the standard antidiabetic drug acarbose. Furthermore, synthesized substances' energy-minimized structures, 3D structures, and DFT calculations were performed using Gaussian 09 software, hybrid models, and MM2 force approaches. Strong hydrogen bonds with amino acid residues Arg-672, Arg-600, Trp-613, Asp-404, Asp-282, and Asp-616 indicate that an α-glucosidase-inhibitory peptide may have hypoglycemic efficacy confirmed by the molecular docking study of the synthesized DHPM.

Synthesis, antimycobacterial, cytotoxicity, anti-inflammatory, in silico studies and molecular dynamics of pyrazole-embedded thiazolidin-4-one hybrids.

In the present investigation, we devolved and synthesized a new series of pyrazole-embedded thiazolidin-4-one derivatives (9a-p) with the goal to produce promising antitubercular leads. The in vitro antimycobacterial activity of the synthesized compounds was tested against replicating and nonreplicating Mtb H37Rv strains. With MIC ranging from 3.03 to 22.55 µg/ml, five compounds (9a, 9c, 9d, 9e, and 9f) emerged as promising antitubercular agents. The active molecules were nontoxic to normal Vero cells. All the synthesized compounds were evaluated for in vitro anti-inflammatory studies. Compounds 9a, 9b, 9c, 9h, and 9i exhibited excellent anti-inflammatory efficacy. Docking study was performed to understand the binding pattern of the significantly active compound 9a with 1P44.

Design and synthesis of amino acid derivatives of substituted benzimidazoles and pyrazoles as Sirt1 inhibitors.

Owing to its presence in several biological processes, Sirt1 acts as a potential therapeutic target for many diseases. Here, we report the structure-based designing and synthesis of two distinct series of novel Sirt1 inhibitors, benzimidazole mono-peptides and amino-acid derived 5-pyrazolyl methylidene rhodanine carboxylic acid. The compounds were evaluated for in vitro enzyme-based and cell-based Sirt1 inhibition assay, and cytotoxic-activity in both liver and breast cancer cells. The tryptophan conjugates i.e.13h (IC50 = 0.66 µM, ΔG bind = -1.1 kcal mol-1) and 7d (IC50 = 0.77 µM, ΔG bind = -4.4 kcal mol-1) demonstrated the maximum efficacy to inhibit Sirt1. The MD simulation unveiled that electrostatic complementarity at the substrate-binding-site through a novel motif "SLxVxP(V/F)A" could be a cause of increased Sirt1 inhibition by 13h and 13l over Sirt2 in cell-based assay, as compared to the control Ex527 and 7d. Finally, this study highlights novel molecules 7d and 13h, along with a new key hot-spot in Sirt1, which could be used as a starting lead to design more potent and selective sirtuin inhibitors as a potential anticancer molecule.

Potential Fluorinated Anti-MRSA Thiazolidinone Derivatives with Antibacterial, Antitubercular Activity and Molecular Docking Studies.

MRSA infection is one of the alarming diseases in the current scenario. Identifying newer molecules to treat MRSA infection is of urgent need. In the present study, we have designed fluorinated thiazolidinone derivatives with various aryl/heteroaryl units at 5th position of the thiazolidinone core as promising anti-MRSA agents. All the compounds were screened for antibacterial activity against four bacterial strains. Among the tested compounds, the halogenated compounds with simple arylidene ring, (5Z)-5-[(3-chloro-2-fluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4b), (5Z)-5-[(4-chloro-2-fluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4c), (5Z)-5-[(3-fluoro-4-methylphenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4f) and (5Z)-5-[(3,5-difluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4g) showed excellent activity with MIC 3.125-6.25 µg/mL against S. aureus and P. aeruginosa organism. Furthermore, these potent compounds were screened against MRSA strains, ESKAPE panel organism, and H37Rv mycobacterium strain. Compounds 4c (MIC 0.39 µg/mL), and 4f (MIC 0.39 and 0.79 µg/mL) displayed promising activity against MRSA strains (ATCC and clinical isolates, respectively). The most potent compounds, 4c and 4f eradicated the growth of bacterial colonies in a time-kill assay indicated that these are bactericidal in nature. The preliminary toxicity study of the potent molecules revealed that these compounds are non-hemolytic in nature as they did not induce lysis in human RBCs. In addition, the molecular docking and dynamics studies of compounds 4b, 4c, 4f and 4g were carried out on MurB protein of S. aureus (PDB code: 1HSK). Docking results demonstrated remarkable hydrogen bonding interaction with key amino acids ARG310, ASN83, GLY79 and π-π interactions with TYR149 which confirm the mode of action of the molecules.

In vitro and in silico studies of fluorinated 2,3-disubstituted thiazolidinone-pyrazoles as potential α-amylase inhibitors and antioxidant agents.

As part of our effort to identify potent α-amylase inhibitors, in the present study, a novel series of fluorinated thiazolidinone-pyrazole hybrid molecules were prepared by the condensation of 3-(aryl/benzyloxyaryl)-pyrazole-4-carbaldehydes with fluorinated 2,3-disubstituted thiazolidin-4-ones. The structures of the newly synthesized compounds were confirmed by infrared, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and liquid chromatography-mass spectrometry data. All the compounds were screened for their α-amylase inhibitory and free radical scavenging activities by DPPH (1,1-diphenyl-2-picrylhydrazyl) and ABTS methods. Among the tested compounds, compound 8g emerged as a promising α-amylase inhibitor with IC50 = 0.76 ± 1.23 µM, and it was found to be more potent than the standard drug acarbose (IC50 = 0.86 ± 0.81 µM). Compounds 8b and 8g showed strong free radical scavenging activity compared to the standard butylated hydroxyl anisole. The kinetic study of compound 8g revealed the reversible, classical competitive inhibition mode on the α-amylase enzyme. Molecular docking and dynamic simulations studies were performed for the most potent compound 8g, which displayed remarkable hydrogen bonding with the α-amylase protein (PDB ID: 1DHK).

Pyridine- and Thiazole-Based Hydrazides with Promising Anti-inflammatory and Antimicrobial Activities along with Their In Silico Studies.

A new class of compounds formed by the linkage of -C(O)-NH- with pyridine and thiazole moieties was designed, synthesized, and characterized by various spectral approaches. The newly characterized compounds were evaluated for their antimicrobial as well as anti-inflammatory properties. The in vitro anti-inflammatory activity of these compounds was evaluated by denaturation of the bovine serum albumin method and showed inhibition in the range of IC50 values-46.29-100.60 µg/mL. Among all the tested compounds, compound 5l has the highest IC50 value and compound 5g has the least IC50 value. On the other hand, antimicrobial results revealed that compound 5j showed the lowest MIC values and compound 5a has the highest MIC values. Furthermore, molecular docking of the active compounds demonstrated a better docking score and interacted well with the target protein. Physicochemical parameters of the titled compounds were found suitable in the reference range only. The in silico molecular docking study revealed their COX-inhibitory action. Compound 5j emerged as a significant bioactive molecule among the synthesized analogues.

Novel pyrazole-clubbed thiophene derivatives via Gewald synthesis as antibacterial and anti-inflammatory agents.

The aim of this study was to synthesize newer potent Schiff bases by condensing 2-amino-5-(2,4-dichlorophenyl)thiophene-3-carbonitrile and 1,3-disubstituted-1H-pyrazole-4-carbaldehydes, and to investigate their biological activity. The compounds were synthesized via Gewald synthesis and characterized by spectral data and elemental analyses. They were screened for their in vitro antibacterial and anti-inflammatory activities. The synthesized compounds were also evaluated for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv using the microplate Alamar Blue assay. Compounds 8b, 8c, 8f, 8g, 8k, 8n, and 8o showed promising antibacterial activity. The interactions between the substituted pyrazoles and bovine protein showed promising anti-inflammatory activity. The experimental results revealed compound 8a as a promising antitubercular agent. Hemolytic assays confirmed that the compounds are nontoxic, with percentage hemolysis ranging from 3.6 to 20.1, at a concentration of 1 mg/ml. The results suggest that the pyrazole ring and the substitution pattern on the heterocyclic moiety have an effect on the bioactivity.

Synthesis of novel Schiff bases using 2-Amino-5-(3-fluoro-4-methoxyphenyl)thiophene-3-carbonitrile and 1,3-Disubstituted pyrazole-4-carboxaldehydes derivatives and their antimicrobial activity.

2-Amino-5-(3-fluoro-4-methoxyphenyl)thiophene-3-carbonitrile have been synthesized from 1-(3-fluoro-4-methoxyphenyl)ethanone, malononitrile, a mild base and sulfur powder using Gewald synthesis technique and the intermediate was treated with 1,3-disubstituted pyrazole-4-carboxaldehyde to obtain the novel Schiff bases. 1,3-disubstituted pyrazole-4-carboxaldehyde derivatives have been synthesized by Vilsmeier-Haack reaction in the course of a multi-step reaction. The structure of novel compounds were established on the basis of their elemental analyses IR, 1H NMR, 13C NMR, and mass spectral data and then screened for their in vitro antimicrobial activity. Among them 5a, 5c, 5f and 5h showed excellent activity when compared to other derivatives. Remaining derivatives showed moderate activity.

Synthesis of novel Schiff bases containing arylpyrimidines as promising antibacterial agents.

Pursuing our recent interest regarding the antimicrobial activity of Schiff bases derivatives, we have synthesized a series of 6-(substitutedphenyl)-N'-((E)-(substitutedphenyl)methylidene)-2-methylpyridine-3-carbohydrazides (5a-n) and evaluated their antibacterial activity. Structures of these compounds were confirmed by standard studies of FTIR, 1H NMR, 13C NMR, MS and elemental analysis. Antibacterial activity of synthesized molecules was tested against Gram-positive (S. aureus and E. faecalis) and Gram-negative (E. coli and P. aeruginosa) bacterial strains. Synthesized compounds showed good antibacterial activity at a lower concentration than standard. Most of the compounds (5a, 5c, 5i, 5j and 5n) are potent against all the tested bacterial strains with MIC values ranging from 1.56-12.5 µg/mL.

A preliminary study on quinazolinylaminobenzoyl monopeptide esters as effective Gram-positive bacteriostatic agents.

AIM: To investigate a novel series of quinazoline monopeptide esters for the in vitro antibacterial activity. METHODOLOGY/RESULTS: The compounds were synthesized via one-pot Dimroth rearrangement of suitable formamidine intermediates with 3-aminobenzoic acid, followed by coupling the resulting acids with amino acid esters and screening for their antibacterial activity by broth dilution method. The compounds 5a, 5b, 5c, 5g, 5i and 5j showed promising activity against the Gram-positive bacteria, 5c and 5g being the most potent against Enterococcus faecalis and Staphylococcus aureus, respectively, with a minimal inhibitory concentration of 0.51 µM. The percentage hemolysis of the compounds ranged from 2.79 to 12.92 at a concentration of 100 µg/ml. The molecular docking studies revealed their GlmU inhibitory action. CONCLUSION: The compounds 5a and 5g emerged as antibacterial hits.

Efficient Synthesis and in Silico Studies of the Benzimidazole Hybrid Scaffold with the Quinolinyloxadiazole Skeleton with Potential α-Glucosidase Inhibitory, Anticoagulant, and Antiplatelet Activities for Type-II Diabetes Mellitus Management and Treating Thrombotic Disorders.

The current study evaluates antidiabetic, anticoagulant, and antiplatelet activity of novel benzimidazole-containing quinolinyl oxadiazoles. These derivatives are synthesized and characterized using spectroscopy (FT-IR, 1H NMR, and mass spectroscopy) and single-crystal X-ray diffraction methods. The inhibitory effects of these compounds were evaluated by the α-glucosidase inhibitory assay and shows the activity in the range of IC50 = 0.66 ± 0.05 to 3.79 ± 0.46 µg/mL. In addition, molecular docking studies revealed that benzimidazole-containing quinolinyl oxadiazoles can correctly dock into the target receptor protein of the human intestinal α-glucosidase, while their bioavailability/drug-likeness was predicted to be acceptable but requires further optimization. On the other hand, compound 8a and 8d showed anticoagulant activity as they enhanced the clotting time from control 180-410 and 180-390 s, respectively, in platelet rich plasma and 230-460 and 230-545 s in platelet poor plasma. Furthermore, only 8a showed antiplatelet activity by inhibiting epinephrine-induced platelet aggregation, and the observed aggregation inhibition was found to be 93.4%. Compounds 8a-f show nontoxic properties because of the non-hydrolyzing properties in the RBC cells. In addition, 8a and 8d show anti-edema and anti-hemorrhagic properties in the experimental mice. These findings reveal that benzimidazole-containing quinolinyl oxadiazoles act as α-glucosidase inhibitors to develop novel therapeutics for treating type-II diabetes mellitus and can act as lead molecules in drug discovery as potential antidiabetic and antithrombotic agents.

Synthesis and evaluation of thiazolidinone-pyrazole conjugates as anticancer and antimicrobial agents.

AIM: To synthesize a series of new thiazolidinone-pyrazole hybrids (5a-o) and assess their anticancer (in vitro and in vivo) and antimicrobial activities. RESULTS: The compounds 5h (against Ehrlich ascites carcinoma cells), 5e and 5i (against the human breast cancer [MDA-MB231] cell line) exhibited potent anticancer activity. All the compounds except 5g and 5e found to be less toxic for the human dermal fibroblast cells. The effective interactions of the compounds in silico with MDM2 exemplified their inhibitory potency. The derivatives also showed moderate antimicrobial activity. CONCLUSION: The halogen atoms on various positions of the N-arylamino ring played an advantageous role in elevating the potency of the molecules. Thus, these conjugates could be used as a lead for further optimization to achieve promising therapeutics.

Fluorinated pyrrole incorporated 2-thiazolyl hydrazone motifs: a new class of antimicrobial and anti tuberculosis agents.

In aim of obtaining novel bio-active compounds, a new series of fluorinated 1-(4-(aryl)thiazol-2-yl)-2-((1-(aryl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)hydrazines (5a-t) and 1-(4-(4-aryl)thiazol-2-yl)-2-((3-(2,4-dichlorophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazines (8a-d) were synthesized and screened for their antibacterial and antifungal activities. The potent compounds were further screened in vitro for anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain. Compounds 5a, 5c-5h and 5m were found to be good inhibitors of B. subtilis with MIC ranging from 0.2 to 0.8 µg mL-1, which are nearly three to ten times more potent than the standard drug Ciprofloxacin. Compounds 5a, 5h-5k and 5o exhibited potent antifungal activity against C. albicans strain with MIC ranging from 0.4 to 1.6 µg mL-1. Compounds 8a-8c were found to be excellent inhibitors of A. niger. Compounds 5a and 5k showed significant anti tubercular activity with MIC 3.12 and 6.25 µg mL-1 respectively. Furthermore, highly active compounds were tested for their preliminary toxicity profile by hemolytic assay and were found to be non hemolytic at higher concentration with good selectivity index. Cytotoxicity of the potent compounds 5a, 5d, 5g, 5i and 5k was checked by MTT assay using normal embryonic kidney cell line HEK 293 and found to be non-toxic up to 50-200 times the MIC for antibacterial activity.

SYNTHESIS AND BIOLOGICAL EVALUATION OF N-(SUBSTITUTED PHENYL)-2-(5H-[1,2,4]TRIAZINO[5,6-b]INDOL-3-YLSULFANYL)ACETAMIDES AS ANTIMICROBIAL, ANTIDEPRESSANT AND ANTICONVULSANT AGENTS.

A new series of N-Aryl-2-(5H-[1,2,4]triazino[5,6-b]indol-3-ylsulfanyl)acetamides were synthesized by condensation of tricyclic compound 2,5-dihydro-3H-[1,2,4]triazino[5,6-b]indole-3-thione with chloro N-phenylacetamides. The tricyclic compound was obtained by condensation of Isatin with thiosemicarbazide. Chloro N-phenylacetamides were obtained from different substituted anilines. Their structures were characterized by IR, 1H NMR, LC-MS and elemental analyses. Newly synthesized compounds were screened for antimicrobial, antidepressant and anticonvulsant activities. Preliminary results indicated that most of the compounds showed lesser MIC value than the standard drug used when tested for antimicrobial activity. Some of the compounds were endowed with very good antidepressant and anticonvulsant activity.

Preparation of substituted quaternized arylfuran chitosan derivatives and their antimicrobial activity.

Heterocyclic modification of chitosan has been achieved through the formation of a Schiff base intermediate by the reaction of chitosan with substituted arylfurfural. The Schiff bases were further reacted with 10% sodium borohydride followed by reaction with methyl iodide to get the quaternized products. The formation of the Schiff bases and quaternized derivatives has been confirmed by elemental analysis, FTIR, (1)H NMR and UV-vis spectroscopy. The compounds are also characterized by thermo-gravimetric analysis. The parent compound and quaternized derivatives were compared for their antibacterial and antifungal activity. The results indicated that quaternized derivatives possess better inhibitory property than chitosan. Further this study confirms that heterocyclic aromatic substituent containing 'Cl' and 'NO2' are effective in enhancing the antimicrobial activity of Chitosan.

Synthesis, spectral characterization and biological evaluation of a novel series of 6-arylsubstituted-3-[2-(4-substitutedphenyl)propan-2-yl]-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines.

On account of the reported anticancer activity of triazolothiadiazines, we have synthesized a novel series of 6-arylsubstituted-3-[2-(4-substitutedphenyl)propan-2-yl]-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and tested for in-vitro cytotoxicity by trypan blue exclusion and MTT assay. These compounds were also evaluated for their in-vivo anthelmintic activity, as well as in-vitro antimicrobial studies. Amongst the tested compounds, the compound 7j was the most promising cytotoxic agent with IC(50) value of 10.54µM in MCF-7 cells. The compounds 7l and 7q exhibited excellent anthelmintic activity. The compounds 7d, 7f, 7j, 7l, 7o, 7p and 7r showed good antibacterial activity, whereas compounds 7e and 7k exhibited excellent antifungal activity. The structures of newly synthesized compounds were characterized by IR, (1)H NMR, (13)C NMR and LCMS analysis.

Facile synthesis, cytotoxic and antimicrobial activity studies of a new group of 6-aryl-3-[4-(methylsulfonyl)benzyl]-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines.

The reaction of 4-(methylsulfonyl)phenylacetohydrazide (3) with carbon disulfide and potassium hydroxide followed by hydrazine hydrate gave 4-amino-5-[4-(methylsulfonyl)benzyl]-4H-[1,2,4]triazole-3-thione (4). The resulting triazole was subjected to cyclocondensation reaction with different phenacyl bromides to afford 6-substituted-3-[4-(methylsulfonyl)benzyl]-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines (5a-i). All structures of the newly synthesized compounds were confirmed by IR, NMR, mass spectral studies and elemental analyses. The newly synthesized compounds were screened for their cytotoxic, antibacterial and antifungal activity. Some of the derivatives have exhibited promising biological activity.

Design, synthesis and biological evaluation of a novel series of 1,3,4-oxadiazole bearing N-methyl-4-(trifluoromethyl)phenyl pyrazole moiety as cytotoxic agents.

On account of the reported anticancer activity of pyrazoles and oxadiazoles, we have designed and synthesized a novel combinatorial library of S-substituted-1,3,4-oxadiazole bearing N-methyl-4-(trifluoromethyl)phenyl pyrazole moiety and tested for in-vitro cytotoxic activity by MTT assay. Amongst the tested compounds, the compound 5e was the most promising anticancer agent with IC(50) value of 15.54 µM in MCF-7 cells, compared to Doxorubicin as standard drug. The newly synthesized compounds were characterized by NOE, IR, (1)H NMR, (13)C NMR and LC-MS analysis.

Facile synthesis, characterization and pharmacological activities of 3,6-disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles and 5,6-dihydro-3,6-disubstituted-1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles.

Two new series of compounds namely, 3,6-disubstituted-1,2,4-triazolo[3,4-b][1,3,4]thiadizoles (5a-j) and 5,6-dihydro-3,6-disubstituted-1,2,4-triazolo[3,4-b][1,3,4]thiadizoles (7a-j) were prepared. In continuation of a previously reported study, the first series (5a-j) were synthesized by the cyclocondensation of 4-amino-5-(2-bromo-5-methoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (4) with various substituted aromatic carboxylic acids in phosphorus oxychloride and the second series (7a-j) by the reaction of (4) with various substituted aromatic aldehydes in the presence of p-Toluene sulfonic acid. Reaction of (4) with the aldehyde (9) afforded the Schiff's base (10) and not the cyclised product (11) on treatment with p-Toluene sulfonic acid. Synthesized compounds were structurally confirmed by spectral analysis and studied for their anti-inflammatory, analgesic, anti-oxidant and antimicrobial activities. Some of the tested compounds showed significant pharmacological activities.