Synthesis and biological evaluation of thiazolidine-2,4-dione-pyrazole conjugates as antidiabetic,anti-inflammatory and antioxidant agents

A series of fourteen novel thiazolidine-2,4-dione derivatives clubbed with pyrazole moiety were synthesized via four step reaction procedure. Reactions were monitored by thin layer chromatography and were characterized by physicochemical and spectrophotometric (IR, Mass, ¹HNMR and ¹³CNMR) analysis. The spectral data were in good agreement with their structures. The title compounds were docked against peroxisome proliferated activated receptors (PPAR-γ) and alpha-amylase and further evaluated for in vivo and in vitro antidiabetic, in vitro anti-inflammatory and antioxidant activities. Compound GB14 exhibited significant blood glucose lowering activity and was also found to be active inhibitor of alpha-amylase. Compound GB7 was found to be potent anti-inflammatory agent in terms of reducing inflammatory markers (TNF-α, IL-β, MDA) and also showed antioxidant activity to good extent. Therefore, these compounds may be considered as promising candidates for the development of new antidiabetic agents.     

Discovery of novel indole-based aroylhydrazones as anticonvulsants: Pharmacophore-based design

A number of novel melatonin derivatives, containing aroylhydrazone moieties, were synthesized and explored in vivo for anticonvulsant activity, neurotoxicity in ICR mice as well as in-vitro for cytoxicity and oxidative stress in rats. The structures and configurations were confirmed by NMR, FTIR, HRMS and crystal X-ray diffraction method. For selection of potent structures for synthesis a pharmacophore model was used. Two compounds 3e, with a 2-furyl moiety fragment and 3f with 2-thienyl fragment, showed a potency in maximal electroshock (MES) test (ED₅₀ = 50.98 mg kg⁻¹, PI > 5.88 and ED₅₀ = 108.7 mg kg⁻¹; PI > 2.76), respectively, higher than melatonin (ED₅₀ = 160.3 mg kg⁻¹, PI > 1.87). The compounds 3c, 3e, 3f and 3i suppressed psychomotor seizures in the 6 Hz test and 3c was the most potent with higher ED₅₀ = 13.98 mg kg⁻¹ and PI of > 21.46 compared to that of melatonin (ED₅₀ = 49.76 mg kg⁻¹ and PI of > 6.03) in mice. None of the compounds displayed neurotoxicity in the rota-rod test. The novel melatonin derivatives exerted weak cytotoxic effects while 3f showed the lowest hepatoxic effects comparable to that of the positive control melatonin in rats. The high affinities to the elucidated pharmacophore model of the novel melatonin compounds derived from the inclusion of aroylhydrazone moiety in the indole scaffold yielded suitable candidates with anticonvulsant activity in the MES and 6 Hz test of psychomotor seizures.     

Synthesis,antioxidant, and antimicrobial evaluation of some 2-arylbenzimidazole derivatives

A series of 2-arylbenzimidazole derivatives (3a–3p and 4a–4i) were synthesized and evaluated as potential antioxidant and antimicrobial agents. Their antioxidant properties were evaluated by various in vitro assays including hydroxyl radical (HO) scavenging, superoxide radical anion (O₂^?) scavenging, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging, and ferric reducing antioxidant power. Results demonstrated that compounds with hydroxyl group at the 5-position of benzimidazole ring had a comparable or better antioxidant activity in comparison to standard antioxidant tert-butylhydroquinone (TBHQ). Markedly, compound 4h that showed the highest HO scavenging activity (EC₅₀ = 46 μM) in vitro had a significant reduction of 2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH)-induced intracellular oxidative stress and H₂O₂-induced cell death. In addition, these compounds showed moderate to good inhibitory activity against Staphylococcus aureus selectively at noncytotoxic concentrations.     

Exploration of antimicrobial and antioxidant potential of newly synthesized 2,3-disubstituted quinazoline-4(3H)-ones

A series of 2-(chloromethyl)-3-(4-methyl-6-oxo-5-[(E)-phenyldiazenyl]-2-thioxo-5,6-dihydropyrimidine-1(2H)-yl)quinazoline-4(3H)-ones 9a-j was synthesized by treating 2-(chloroacetyl)amino benzoic acid with 3-amino-6-methyl-5-[(E)-phenyldiazenyl]-2-thioxo-2,5-dihydropyrimidine-4(3H)-one 8a-j and was screened for in vitro antibacterial activities against a representative panel of Gram-positive and Gram-negative bacteria. The compounds were synthesized in excellent yields and the structures were corroborated on the basis of IR, ¹H NMR, Mass and elemental analysis data. All the synthesized compounds elicited the potent inhibitory action against all the tested bacterial stains. Furthermore, in order to explore the antioxidant potential of newly synthesized compounds, the free radical scavenging activity measurement were performed by the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) assay method. It is revealed from the antioxidant screening results that the compounds 9c and f manifested profound antioxidant potential.     

In vivo anti-diabetic activity of derivatives of isoliquiritigenin and liquiritigenin

Isoliquiritigenin (ISL), a chalcone and liquiritigenin (LTG), a flavonoid found in licorice roots and several other plants. ISL displays antioxidant, anti-inflammatory, antitumor and hepatoprotective activities whereas LTG is an estrogenic compound, acts as an agonist selective for the β-subtype of the oestrogen receptor. Both the phenolics were isolated from the rhizomes of Glycyrrhiza glabra. Five derivatives from ISL and four derivatives from LTG were synthesized. All the compounds were established by extensive spectroscopic analyses and screened through oral glucose tolerance test to gain preliminary information regarding the antihyperglycemic effect in normal Swiss albino male mice. ISL (1), ISL derivatives 3, 4, 5, 7 and LTG derivatives 9 and 10 showed significant blood glucose lowering effect. The structure–activity relationship indicated that the presence of ether and ester groups in ISL and LTG analogues are important for exhibiting the activity. Compounds 1, 4 and 10 were selected for in vivo antidiabetic activity and found to be potential candidates for treatment of diabetes. It is the first report on antidiabetic activity of ISL derivative 4 and LTG derivative 10.     

Antioxidant and acetylcholinesterase inhibition properties of novel bromophenol derivatives

In this study, series of novel bromophenol derivatives were synthesized and investigated for their antioxidant and AChE inhibition properties. Novel brominated diarylmethanones were obtained from the acylation reactions of benzoic acids with substituted benzenes. One of the bromodiarylmethanone was synthesized from the bromination of diarylmethanone with molecular bromine. All diarylmethanones were converted into their bromophenol derivatives with BBr₃. The antioxidant activities of all synthesized compounds were elucidated by using various bioanalytical assays. Radical scavenging activities of compounds 10–24 were evaluated by means of DPPH and ABTS⁺ scavenging activities. In addition, reducing ability of 10–24 were determined by Fe³⁺, Cu²⁺, and [Fe³⁺-(TPTZ)₂]³ reducing activities. α-Tocopherol, trolox, BHA, and BHT were used as positive antioxidant and radical scavenger molecules. On the other hand, IC₅₀ values were calculated for DPPH, ABTS⁺ scavenging, and AChE inhibition effects of novel compounds. The results obtained from the current studies clearly show that novel bromophenol derivatives 20–24 have considerable antioxidant, antiradical, and AChE inhibition effects.     

Imidazolo and tryptophan-imidazolo hybrid derived ureas/thioureas as potent bioactive agents – SAR and molecular modelling studies

Herein, we used an imidazole derivative (IMD) which showed promising antibacterial, antifungal and antioxidant properties in our earlier investigation. Prompted by this, we converted IMD to hydrazide (IMH) by hydrazinolysis which was derivatized to various ureas (3–7) and thioureas (8–12). On the other hand, IMH was conjugated to Boc-Trp-OH as it has been shown in the past that hybridization of two molecules produced promising biologically active compounds. Boc of the conjugate was removed and further converted into several urea (14–18) and thiourea (19–23) derivatives. All the title compounds so also the starting materials and intermediates were assessed for potential biological applications. The results showed that compounds 3, 4, 8, 9, 14, 15, 19 and 20 were excellent antioxidants as revealed by DPPH, DMPD and ABTS assays. Further, certain analogues like 5–7, 10–12, 16–18 and 21–23 were found to be potent antimicrobials against pathogenic bacteria and fungi whereas good anti-inflammatory activity was obtained for molecules 5–7, 10–12, 16–18 and 21–23. All together, derivatives of the conjugates have shown superior activity over non-conjugated compounds and the former have exhibited potent activity against standard drugs in all the assays. In a quest to understand the binding interactions of the compounds with active site of tyrosine kinase (PDB ID: 2HCK), glucosamine-6-phosphate (GlcN-6-P) synthase (PDB ID: 2VF5) and cyclooxygenase-2 (PDB ID: 1CX2) enzymes, the correlation studies were conducted using molecular modelling which showed good receptor binding interactions with several amino acids of the enzymes. Overall, the current investigation may be considered for the discovery of lead compound(s) for treating multiple disorder conditions using singular molecular entity.     

Synthesis, biological evaluation and molecular docking studies of stellatin derivatives as cyclooxygenase (COX-1, COX-2) inhibitors and anti-inflammatory agents

Stellatin (4), isolated from Dysophylla stellata is a cyclooxygenase (COX) inhibitor. The present study reports the synthesis and biological evaluation of new stellatin derivatives for COX-1, COX-2 inhibitory and anti-inflammatory activities. Eight derivatives showed more pronounced COX-2 inhibition than stellatin and, 17 and 21 exhibited the highest COX-2 inhibition. They also exhibited the significant anti-inflammatory activity in TPA-induced mouse ear edema assay and their anti-inflammatory effects were more than that of stellatin and indomethacin at 0.5 mg/ear. The derivatives were further evaluated for antioxidant activity wherein 16 and 17 showed potent free radical scavenging activity against DPPH and ABTS radicals. Molecular docking study revealed the binding orientations of stellatin and its derivatives into the active sites of COX-1 and COX-2 and thereby helps to design the potent inhibitors.     

Synthesis,antimicrobial, antioxidant,cytotoxic, antiurease and molecular docking studies of N-(3-trifluoromethyl)benzoyl-N′-aryl thiourea derivatives

An irrefutable advancement has been noted for the infectious diseases caused due to ureolytic bacteria through the development of various drugs. Keeping in mind the extremely valuable synthetic utility and medicinal significance of thiourea derivatives, synthesis of new 3-trifluoromethyl benzoic acid thiourea derivatives (3a–j) were carried out. The biological potential of all compounds in terms of antimicrobial, antioxidant, cytotoxic and antiurease activities were studied. The compounds 3a, 3c and 3i with dichloro and methoxy groups substitution on the aryl group showed significant activity against all strain of bacteria while moderate to no activity was observed in remaining compounds. Whereas the antifungal evaluation showed that all compounds were active againts C. Albican and no activity was observed against C. Prapsilosis. The cytotoxic findings revealed the non-toxic nature of these compounds as IC₅₀ values of majority of the compounds are above 100 μm except for compounds 3f and 3g. In addition, these compounds exhibited better antioxidant potential as 100 μm concentration inhibited >50% reactive oxygen species (ROS) production except compounds 3e, 3f and 3j. The compound 3a proved to be the most potent urease inhibitor showing the highest enzyme % inhibition (93.1%) with IC₅₀ value of 8.17 ± 0.24 µM and found more active as compare to standard followed by compound 3e (92.6%), 3h (91.6%), 3d (90.8%), 3b (90.6%) and 3f (90.0%) with their respective IC₅₀ values. All the synthesized compounds were docked into the binding cavity of Urease (PDB ID: 4ubp). The most active compound 3a was also ranked as top on the docking score as it was found to show valuable interactions with the target protein along with good docking scores. Hence our results revealed that the synthesized compounds have potential to be used as potent urease inhibitors after further detailed mechanistic studies.     

Pyrazoles containing thiophene,thienopyrimidine and thienotriazolopyrimidine as COX-2 selective inhibitors: Design,synthesis, in vivo anti-inflammatory activity,docking and in silico chemo-informatic studies

New thiophene and annulated thiophene pyrazole hybrids were synthesized and screened for their in vitro COX-1/COX-2 enzymatic inhibition and in vivo anti-inflammatory activities. All compounds were more COX-2 selective inhibitors than COX-1 with compound 13 exhibiting the highest COX-2 selectivity index. Compounds 3, 6a, 9 and 11 were the most promising in the acute anti-inflammatory assay while compounds 3, 5, 6a, 6c, 9, 10, 11 and 13 exerted promising anti-inflammatory activity in the sub-acute anti-inflammatory assay. Compounds 3, 6a, 6c, 9, 10 and 11 were evaluated for their ED₅₀ values and were more potent than diclofenac sodium while compounds 6a, 6c and 9 were of greater potency than celecoxib with compound 6a being the most potent showing ED₅₀ = 0.033 mmol/kg. These compounds were non-toxic and proved to be gastrointestinal safe compared to indomethacin, diclofenac sodium and celecoxib. Docking studies into COX-2 active site (PDB code 3LN1) revealed that compounds 3, 6a, 6c, 9, 10, 11 and 13 had binding modes and energies comparable to that of celecoxib. Compounds 3, 9, 10 and 11 complied with Lipinski’s RO5 while compounds 6a and 6c showed one violation whereas compound 13 deviated by 2 violations. Compounds 6a, 6c and 13 showed 100% plasma protein binding (PPB) and showed no aqueous solubility while compounds 3, 10 and 11 demonstrated the best drug likeness model scores. Therefore, the thiophene analog 3 and the thienopyrimidine derivatives 10 and 11 are promising anti-inflammatory candidates that exert moderate selective COX-2 inhibition with acceptable physicochemical properties.     

Quiquelignan A–H,eight new lignoids from the rattan palm Calamus quiquesetinervius and their antiradical,anti-inflammatory and antiplatelet aggregation activities

Eight new lignin derivatives, termed quiquelignan A–H (1–8), comprising three tricin-type flavonolignans (1–3) and five 8-O-4′ neolignans (4–8), were isolated from the ethanol extract of Calamus quiquesetinervius stems. Structural elucidation of the new isolates was accomplished on the basis of spectroscopic data. Compounds 1–8 showed strong-to-moderate antioxidant activity against the hydroxy radical (OH). Among them, compound 5 showed significantly higher hydroxy radical scavenging activity (IC₅₀ 4.4 μg/mL). Compounds 2–4 and 6–8 dose-dependently suppressed the LPS-stimulated production of nitric oxide (NO) in RAW 264.7 cells. The anti-inflammatory potency of 4 and 6 was 2.7–4.5-fold higher compared with quercetin. Compounds 2–4, 6 and 8 also exhibited mild collagen-antagonistic activity, but were inactive with respect to thrombin-induced platelet aggregation.     

Synthesis,anti-inflammatory,analgesic, 5-lipoxygenase (5-LOX) inhibition activities,and molecular docking study of 7-substituted coumarin derivatives

In the present study, 7-subsituted coumarin derivatives were synthesized using various aromatic and heterocyclic amines, and evaluated in vivo for anti-inflammatory and analgesic activity, and for ulcerogenic risk. The most active compounds were evaluated in vitro for 5-lipoxygenase (5-LOX) inhibition. Docking study was performed to predict the binding affinity, and orientation at the active site of the enzyme. In vivo anti-inflammatory and analgesic activity, and in vitro 5-LOX enzyme inhibition study revealed that compound 33 and 35 are the most potent compounds in all the screening methods. In vitro kinetic study of 35 showed mixed or non-competitive type of inhibition with 5-LOX enzyme. Presence of OCH₃ group in 35 and Cl in 33 at C6-position of benzothiazole ring were found very important substitutions for potent activity.     

Design,synthesis and biological evaluation of some tetrazole acetamide derivatives as novel non-carboxylic PTP1B inhibitors

A series of ten N-(3-(1H-tetrazole-5-yl)phenyl)acetamide derivatives (NM-07 to NM-16) designed from a lead molecule identified previously in our laboratory were synthesized and evaluated for protein tyrosine phosphatase 1B (PTP1B) inhibitory activity. Among the synthesized molecules, NM-14, a 5-Cl substituted benzothiazole analogue elicited significant PTP1B inhibition with an IC₅₀ of 1.88 µM against reference standard suramin (IC₅₀ ≥ 10 µM). Furthermore, this molecule also showed good in vivo antidiabetic activity which was comparable to that of standard antidiabetic drugs metformin and glimepiride. Overall, the results of the study clearly reveal that the reported tetrazole derivatives especially NM-14 are valuable prototypes for the development of novel non-carboxylic inhibitors of PTP1B with antidiabetic potential.     

Synthesis,Antimicrobial and Antioxidant Activity of Pyrazole Based Sulfonamide Derivatives

A series of new sulfonamides have been synthesized from Ampyrone with different benzene sulfonyl chlorides to yield the N-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) benzenesulfonamides (4a–e). All synthesized compounds were characterized on the basis of FTIR, ¹H NMR, and ¹³C NMR, and also by the aid of mass spectral data. Further, all synthesized compounds have studied for their in vitro antimicrobial activities against selected bacterial as well as fungal strains by the agar well diffusion method. Free radical scavenging activity has been investigated by using DPPH method. Among all the synthesized compounds, 4b, 4d, and 4e exhibited significant antimicrobial and antioxidant activities.     

Imidazolylchromanone oxime ethers as potential anticonvulsant agents: Anticonvulsive evaluation in PTZ-kindling model of epilepsy and SAR study

As a continuation of our efforts to develop the azolylchromanone derivatives as potential anticonvulsant agents, we explored (Z)- and (E)-oxime ether derivatives of imidazolylchromanones bearing different lipophilic O-benzyl groups and tested their anticonvulsant activities in PTZ-kindling model of epilepsy. O-(2,4-Dichlorobenzyl) oximes 8a, 16a and 20a were significantly effective in delaying the onset of the PTZ-evoked seizures at the dose of 30 mg/kg in kindled animals. The most effective compounds in delaying seizures were 7-chlorochromanone-O-(2,4-dichlorobenzyl) oximes 8a and 20a. SAR studies showed that introduction of a chlorine atom to the 7-position and/or a methyl group to the 2-position of the chroman ring resulted in an improvement of anti-seizure efficacy in O-(2,4-dichlorobenzyl) oxime series.     

Synthesis and antioxidant activity of novel Mannich base of 1,3,4-oxadiazole derivatives possessing 1,4-benzodioxan

A new series of Mannich base of 1,3,4-oxadiazole derivatives possessing 1,4-benzodioxan (6a–6ae) were synthesized and characterized by ¹H NMR, ESI-MS and elemental analysis. The structure of 6b was further confirmed by single crystal X-ray diffraction. All these novel compounds were screened for their in vitro antioxidant activity employing 2,2′-diphenyl-1-picrylhydrazyl radical (DPPH), 2,2′-azinobis (3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS⁺) and ferric reducing antioxidant power (FRAP) scavenging assays. Due to the combination of 1,4-benzodioxan, 1,3,4-oxadiazoles and substituted phenyl ring, most of them exhibited nice antioxidant activities. In all of these three assays mentioned above, compounds 6f and 6e showed significant radical scavenging ability comparable to the commonly used antioxidants, BHT and Trolox. Seven compounds with representative substituents or activities were selected for further assays in chemical simulation biological systems—inhibition of microsomal lipid peroxidation (LPO) and protection against 2,2′-azobis (2-amidinopropane hydrochloride) (AAPH) induced DNA strand breakage, in which, 6f and 6e were demonstrated to be of the most potent antioxidant activities.     

New indole based hybrid oxadiazole scaffolds with N-substituted acetamides: As potent anti-diabetic agents

Current study is based on the sequential conversion of indolyl butanoic acid (1) into ethyl indolyl butanoate (2), indolyl butanohydrazide (3), and 1,3,4-oxadiazole-2-thiol analogs (4) by adopting chemical transformations. In a parallel series of reactions, 2-bromo-N-phenyl/arylacetamides (7a-l) were synthesized by reacting different amines derivatives (5a-l) with 2-bromoacetyl bromide (6) to serve as electrophile. Then, the synthesized electrophiles (7a-l) were treated with nucleophilic 1,3,4-oxadiazole-2-thiol analog (4) to afford a range of N-substituted derivatives (8a-l). The structural confirmation of all the synthetic compounds was carried out by IR, ¹H-, ¹³C NMR, EI-MS, and CHN analysis data. All synthesized molecules (8a-l) were tested for their antidiabetic potential via inhibition of the α-glucosidase enzyme followed by their in silico study. Their cytotoxicity profile was also ascertained via hemolytic activity and all of them possessed very low cytotoxicity. Compounds 8h and 8l were found most active having IC₅₀ values 9.46 ± 0.03 µM and 9.37 ± 0.03 µM, respectively. However, all other molecules also exhibited good to moderate inhibition potential with IC₅₀ values between 12.68 ± 0.04–37.82 ± 0.07, compared to standard acarbose (IC₅₀ = 37.38 ± 0.12 µM), hence can be used as lead molecules for further research in order to get better antidiabetic agents.     

A simple and efficient synthesis of benzimidazoles containing piperazine or morpholine skeleton at C-6 position as glucosidase inhibitors with antioxidant activity

A novel 2-(aryl)-6-morpholin-4-yl(or 4-methylpiperazin-1-yl)-1H-benzimidazole derivatives were designed and expeditiously synthesized starting from 5-morpholin-4-yl(or 4-methylpiperazin-1-yl)-2-nitroaniline with various aldehydes which were preliminarily screened for in vitro antioxidant activities and glucosidase inhibitors. The benzimidazoles were effectively synthesized by a rapid ‘onepot’ nitro reductive cyclization reaction using sodium hydrosulfite as a reagent. All reactions were conducted using both the microwave and conventional methods to compare yields and reaction times. Antioxidant activities of the synthesized compounds were clarified using various in vitro antioxidant assays including Cupric Reducing Antioxidant Capacity (CUPRAC, ranging from 5.511 to 19.703 mM Trolox/mg compound) and Ferric Reducing Antioxidant Power (FRAP) (1.141–12.943 mM FeSO₄·7H₂O/mg compound) assays. Also, the radical scavenging activities of these compounds were assayed using ABTS⁺ and DPPH methods. The results showed that all compounds exhibited very high scavenging activity. These synthesized compounds were then evaluated for their α-glucosidase inhibitory potential and seven compounds demonstrated an inhibitory potential much better than the standard acarbose. Herein, we will provide details of the structure activity relationship of the benzimidazole analog for the potency.     

Design,synthesis, biological evaluation,and molecular docking of chalcone derivatives as anti-inflammatory agents

In this study, two series of 35 new chalcone derivatives containing aryl-piperazine or aryl-sulfonyl-piperazine fragment were synthesized and their structures were characterized by ¹H, ¹³C and ESI-MS. The in vivo and in vitro anti-inflammatory activities of target compounds were evaluated by using classical para-xylene-induced mice ear-swelling model and ELISA assays. Furthermore, docking studies were performed in COX-2 (4PH9). The in vivo anti-inflammatory assays indicated that most of the target compounds showed significant anti-inflammatory activities. Docking results revealed that the anti-inflammatory activities of compounds correlated with their docking results. Especially, compound 6o exhibited the most potent anti-inflammatory activity in vivo with the lowest docking score of ?17.4 kcal/mol and could significantly inhibit the release of LPS-induced IL-6 and TNF-α in a dose-dependent manner in vitro.