PEG mediated synthesis and pharmacological evaluation of some fluoro substituted pyrazoline derivatives as antiinflammatory and analgesic agents

A new series of fluoro substituted pyrazoline derivatives 5a–g and 6a–g were synthesized in good to excellent yield from the corresponding pyrazole chalcones, 4a–g, by using polyethylene glycol-400 (PEG-400) as an alternative reaction medium. The newly synthesized compounds were characterized and screened for their in vivo antiinflammatory and analgesic activity. Compounds 5g and 6g were found to be more potent than standard drug Diclofenac and six other compounds 5b, 5c, 5f, 6b, 6c and 6f showed significant antiinflammatory activity as compared to standard drug. Compounds 5c, 5d, 5e, 5f, 6c, 6d, 6e and 6f showed significant analgesic activity as compared to standard drug Aspirin.     

Synthesis of novel hetero ring fused pyridine derivatives; Their anticancer activity,CoMFA and CoMSIA studies

A series of novel furo[2,3-b]pyridine-2-carboxamide 4a–h/pyrido[3′,2′:4,5]furo[3,2-d] pyrimidin-4(3H)-one derivatives 5a–p were prepared from pyridin 2(1H) one 1 via selective O-alkylation with α-bromoethylester followed by cyclization, then reaction with different aliphatic primary amines to obtain 4 and further reaction with triethyl orthoacetate/triethyl orthoformate. Also prepared novel furo[2,3-b]pyridine-2-carbohydrazide Schiff’s bases 7a–h and pyrido [3′,2′:4,5]furo[3,2-d]pyrimidin-4(3H)-one derivatives 8a–h starting from furo[2,3-b]pyridine carboxylate derivatives 3 by reaction with hydrazine hydrate to form 6 and reaction with diverse substituted aldehydes and cyclization. Products 4a–h, 5a–p, 7a–h and 8a–h were screened against four human cancer cell lines (HeLa, COLO205, Hep G2 and MCF 7) and one normal cell line (HEK 293). Compounds 4e, 4f, 4g, 5h, 7c, 7d, 7e and 7f showed significant anticancer activity against all the cell lines at micro molar concentration and found to be non-toxic to normal cell line. Studies for HeLa, COLO205 and MCF-7 using CoMFA and CoMSIA. Models from 3D-QSAR provided a strong basis for future rational design of more active and selective HeLa, COLO205 and MCF-7 cell line inhibitors.     

Pyranocoumarins: A new class of anti-hyperglycemic and anti-dyslipidemic agents

A series of pyranocoumarin derivatives were synthesized and evaluated in vivo for their anti-hyperglycemic as well as anti-dyslipidemic activities. Compounds 7a, 7c, 8a, 8b, 8c, 8e and 8f have shown promising anti-hyperglycemic activities in sucrose loaded model (SLM) as well as sucrose challenged streptozotocin induced diabetic rat model (STZ). Compounds 8a and 8b were showing 38.0% and 42.0% blood glucose lowering activity in db/db mice model. In vitro anti-hyperglycemic activity evaluation exhibited that compounds 8a (IC₅₀ = 24.5 μM) and 8b (IC₅₀ = 36.2 μM) are potential PTP-1B inhibitors thereby revealing their possible mechanism of anti-diabetic action. Compounds 7a, 7b, 8a, 8b, 8d, 8e and 8f have shown significant anti-dyslipidemic activity in triton induced dyslipidemia in rats.     

Synthesis and evaluations of selective COX-2 inhibitory effects: Benzo[d]thiazol analogs

A series of benzo[d]thiazole analogs were synthesized and evaluated for their anti-inflammatory and analgesic effects. Using an ear edema model, except for compounds 2k, 2m-2q and 3a, other compounds showed the anti-inflammatory effects. Among them, compounds 2c, 2d, and 2g showed the best anti-inflammatory activity (inhibition rate: 86.8%, 90.7% and 82.9%, respectively). By the acetic acid-induced abdominal writhing test, except for compounds 2e, 2l, 2m, 2o, 2p and 3a, other compounds showed the analgesic effects with inhibition rate values of 51.9–100% (2a-2r) and 68.6–100% (3a-3g). Next, compounds 2c, 2d, 2g, 3d, 3f, 3g that displayed the excellent anti-inflammatory and analgesic activities were evaluated for their inhibitory effect against ovine COX-1 and COX-2. Compounds 2c, 2d, 2g, 3d, 3f, 3g were weak inhibitors of the COX-1 isozyme but exhibited the moderate COX-2 isozyme inhibitory effects IC₅₀ from 0.28 to 0.77 μM and COX-2 selectivity indexes (SI: 18.6 to 7.2). This benzo[d]thiazole moiety will be proved to be of great significance for developing more potent COX-2 inhibitors.     

Natural products as sources of new fungicides (V): Design and synthesis of acetophenone derivatives against phytopathogenic fungi in vitro and in vivo

A series of acetophenone derivatives (10a–10i, 11, 12a–12g, 13a–13g, 14a–14d and 15a–15l) were designed, synthesized and evaluated for antifungal activities in vitro and in vivo. The antifungal activities of 53 compounds were tested against several plant pathogens, and their structure–activity relationship was summarized. Compounds 10a–10f displayed better antifungal effects than two reference fungicides. Interestingly, the most potent compound 10d exhibited antifungal properties against Cytospora sp., Botrytis cinerea, Magnaporthe grisea, with IC₅₀ values of 6.0–22.6?µg/mL, especially Cytospora sp. (IC₅₀?=?6.0?µg/mL). In the in vivo antifungal assays, 10d displayed the significant protective efficacy of 55.3% to Botrytis cinerea and 73.1% to Cytospora sp. The findings indicated that 10d may act as a potential pesticide lead compound that merits further investigation.     

Natural products as sources of new fungicides (IV): Synthesis and biological evaluation of isobutyrophenone analogs as potential inhibitors of class-II fructose-1,6-bisphosphate aldolase

Several recently identified antifungal compounds share the backbone structure of acetophenones. The aim of the present study was to develop new isobutyrophenone analogs as new antifungal agents. A series of new 2,4-dihydroxy-5-methyl isobutyrophenone derivatives were prepared and characterized by ¹H, ¹³C NMR and MS spectroscopic data. These products were evaluated for in vitro antifungal activities against seven plant fungal pathogens by the mycelial growth inhibitory rate assay. Compounds 3, 4a, 5a, 5b, 5e, 5f and 5g showed a broad-spectrum high antifungal activity. On the other hand, for the first time, these compounds were also assayed as potential inhibitors against Class II fructose-1,6-bisphosphate aldolase (Fba) from the rice blast fungus, Magnaporthe grisea. Compounds 5e and 5g were found to exhibit the inhibition constants (Ki) for 15.12 and 14.27?μM, respectively, as the strongest competitive inhibitors against Fba activity. The possible binding-modes of compounds 5e and 5g were further analyzed by molecular docking algorithms. The results strongly suggested that compound 5g could be a promising lead for the discovery of new fungicides via targeting Class II Fba.     

Synthesis and antiviral properties of novel indole-based thiosemicarbazides and 4-thiazolidinones

A novel series of indolylthiosemicarbazides (6a–6g) and their cyclization products, 4-thiazolidinones (7a–7g), have been designed, synthesized and evaluated, in vitro, for their antiviral activity against a wide range of DNA and RNA viruses. Compounds 6a, 6b, 6c and 6d exhibited notable antiviral activity against Coxsackie B4 virus, at EC₅₀ values ranging from 0.4 to 2.1 μg/mL. The selectivity index (ratio of cytotoxic to antivirally effective concentration) values of these compounds were between 9 and 56. Besides, 6b, 6c and 6d also inhibited the replication of two other RNA viruses, Sindbis virus and respiratory syncytial virus, although these EC₅₀ values were higher compared to those noted for Coxsackie B4 virus. The SAR analysis indicated that keeping the free thiosemicarbazide moiety is crucial to obtain this antiviral activity, since the cyclization products (7a–7g) did not produce any antiviral effect.     

Synthesis,characterization, and in vitro antimicrobial activities of 5-alkenyl/hydroxyalkenyl-2-phenylamine-1,3,4-oxadiazoles and thiadiazoles

The long-chain alkenoic acid hydrazides (1a–d) on reaction with phenylisocyanate and phenylthiocyanate gave their corresponding semicarbazides (2a–d) and thiosemicarbazides (4a–d), which on further refluxing with POCl₃ and Ac₂O yielded corresponding 1,3,4-oxadiazoles (3a–d) and thiadiazoles (5a–d), respectively.The structure elucidation of synthesized compounds is based on the elemental analysis and spectral data (IR, ¹H NMR, ¹³C NMR and MS). The synthesized oxadiazoles and thiadiazoles have been screened for antibacterial and antifungal activities. The investigation of antimicrobial screening revealed that compounds 3c, 3d, 5c, 5d and compounds 3b, 5b, showed good antibacterial and antifungal activities, respectively.     

COX-1/COX-2 inhibition assays and histopathological study of the new designed anti-inflammatory agent with a pyrazolopyrimidine core

Four pyrazolopyrimidine series were prepared with a substitution at position- 4 by Schiff base, triazole, oxadiazole and pyrazole moieties (7a-f, 8a,b, 9a-f, 10a,b and 13a,b), respectively. All the synthesized compounds were evaluated in vitro against COX-2 and in vivo against carrageenan-induced rat paw edema as anti-inflammatory agents. Regarding the anti-inflammatory activity (AI) compounds 7c, 7f, 8a, and 9a showed higher activity with respect to celecoxib. Compounds 9a, 7d, and 7f were closely selective to celecoxib. Also, 7c and 7d were safer than indomethacin and similar to celecoxib as resulted from the histopathological study. In addition, the docking study that showed the binding mode of prominent pyrazolopyrimidine compounds inside the COX-2 receptor. Formation of unexpected pyrazole 13a and 13b was briefly discussed using 2D NMR.     

4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole and -pyrazole derivatives as potent and selective inhibitors of transforming growth factor-β type I receptor kinase

A series of 4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazoles and -pyrazoles 14a–c, 15a–c, 16a, 16b, 19a–d, 21a, and 21b has been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. Among them, the pyrazole derivative 21b inhibited ALK5 phosphorylation with an IC₅₀ value of 0.018 μM and showed 95% inhibition at 0.03 μM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct. The 21b showed a high selectivity index of 284 against p38α MAP kinase. The binding pose of 21b generated by docking analysis reveals that it fits well into the ATP binding cavity of ALK5 by forming several hydrogen bond interactions.     

Design,synthesis, molecular docking of new lipophilic acetamide derivatives affording potential anticancer and antimicrobial agents

Fifteen new substituted N-2-(2-oxo-3-phenylquinoxalin-1(2H)-yl) acetamides 5a-f, 6a-f, and 8a-c were synthesized by reacting ethyl 2-(2-oxo-3-phenylquinoxalin-1(2H)-yl)acetate with various primary amines including benzylamines, sulfonamides, and amino acids. The in vitro antimicrobial screening of the target compounds was screened to assess their antibacterial and antifungal activity. As a result, seven compounds namely; 5a, 5c, 5d, 6a, 6c, 8b and 8c showed a promising broad spectrum antibacterial activity against both Gram-positive and Gram-negative strains. Among these, the analogs 5c and 6d were nearly as equiactive as ciprofloxacin drug. Meanwhile, four compounds namely; 5c, 6a, 6f and 8c exhibited appreciable antifungal activity with MIC values range 33–40 mg/mL comparable with clotrimazole (MIC 25 mg/mL). In addition, the anticancer effects of the synthesized compounds were evaluated against three cancer lines. The data obtained revealed the benzylamines and sulpha derivatives were the most active compounds especially 5f and 6f ones. Further EGFR enzymatic investigation was carried out for these most active compounds 5f and 6f resulting in inhibitory activity by 1.89 and 2.05 µM respectively. Docking simulation was performed as a trial to study the mechanisms and binding modes of these compounds toward the enzyme target, EGFR protein kinase enzyme. The results revealed good compounds placement in the active sites and stable interactions similar to the co-crystallized reference ligand. Collectively, the analogs 5f and 6f could be further utilized and optimized as good cytotoxic agents.     

Synthesis,antioxidant, antifungal,molecular docking and ADMET studies of some thiazolyl hydrazones

Some thiazolyl hydrazones were synthesized by one pot reaction of thiophene-2-carbaldehyde or 2, 4-dichlorobenzaldehyde, thiosemicarbazide and various phenacyl bromides which were preliminarily screened for in vitro antioxidant and antifungal activities. Excellent DPPH and H₂O₂ radical scavenged antioxidant activities were observed with almost all the tested compounds. Compounds 4a, 4b, 4c, 4e, 4f and 4i showed comparable DPPH scavenged antioxidant potential (90.26–96.56%) whereas H₂O₂ scavenged antioxidant activity (90.98–92.08%) was noticeable in case of 4a and 4f; showing significant antioxidant potential comparable with the standard ascorbic acid (95.3%). In vitro antifungal activity of synthesized compounds against fungal species Candida albicance, Aspergillus niger and Aspergillus flavus was found to be moderate to good as compared with the standard fluconazole and MIC values were found in the range of 3.12–25 μg/mL. Molecular docking studies revealed that the compounds 4a, 4b and 4c have a potential to become lead molecules in drug discovery process. In silico ADMET study was also performed for predicting pharmacokinetic and toxicity profile of the synthesized antioxidants which expressed good oral drug like behaviour and non-toxic nature.     

New imidazo[1,2-a]pyridines carrying active pharmacophores: Synthesis and anticonvulsant studies

Five new series of imidazo[1,2-a]pyridines carrying biologically active pyrazoline (4a–e), cyanopyridone (5a, b), cyanopyridine (6a–f), 2-aminopyrimidine (7a–f) and pyrimidine-2-thione (8a–d) systems were designed and synthesized as prominent anticonvulsant agents. The target compounds were screened for their in vivo anticonvulsant activity following maximal electroshock (MES) and subcutaneous pentylene tetrazole (scPTZ) methods at a small test dose of 10 mg/kg. Further, Rotarod toxicity method was used to study the toxicity profile of selected compounds. Compounds 4b, 5a, 5b, 6a, 7e and 8d possessing 4-fluorophenyl substituent at 2nd position of imidazo[1,2-a]pyridine ring displayed potent anticonvulsant activity without displaying any toxicity. Enhanced activity profile was observed for new compounds in PTZ method over MES method.     

Novel aryl carboximidamide and 3-aryl-1,2,4-oxadiazole analogues of naproxen as dual selective COX-2/15-LOX inhibitors: Design,synthesis and docking studies

A series of novel naproxen analogues containing 3-aryl-1,2,4-oxadiazoles moiety (4b-g) and their reaction intermediates aryl carboximidamides moiety (3b-g) was synthesized and evaluated in vitro as dual COXs/15-LOX inhibitors. Compounds 3b-g exhibited superior inhibitory activity than celecoxib as COX-2 inhibitors. Compounds 3b-d and 3g were the most potent COX-2 inhibitors with IC₅₀ range of 6.4 – 8.13 nM and higher selectivity indexes (3b, SI = 26.19; 3c, SI = 13.73; 3d, SI = 29.27; 3g, SI = 18.00) comparing to celecoxib (IC₅₀ = 42.60 nM, SI = 8.05). Regarding 15-LOX inhibitory activity, compounds belonging to aryl carboximidamide backbone 3b-e and 3g were the most potent with IC₅₀ range of 1.77–4.91 nM comparing to meclofenamate sodium (IC₅₀ = 5.64 µM). Data revealed that The levels of NO released by aryl carboximidamides 3b-g were more higher than 3-aryl-1,2,4-oxadiazole derivatives 4b-g, which correlated well with their COX-2 inhibitory activities.     

Synthesis of novel celecoxib analogues by bioisosteric replacement of sulfonamide as potent anti-inflammatory agents and cyclooxygenase inhibitors

Two series of celecoxib analogues having 1,5-diaryl relationship were synthesized. The key strategy of the molecular design was oriented towards exploring bioisosteric modifications of the sulfonamide moiety of celecoxib. First series (2a–2i) of celecoxib analogues bearing cyano functionality in place of sulfonamide moiety was synthesized by the reaction of appropriate trifluoromethyl-β-diketones (5a–5i) with 4-hydrazinylbenzonitrile hydrochloride (4) in ethanol. Cyano moiety of pyrazoles 2 was then converted into corresponding carbothioamides 3 by bubbling H₂S gas in the presence of triethylamine. All the synthesized compounds (2a–2i and 3a–3i) were screened for their in vivo anti-inflammatory (AI) activity using carrageenan-induced rat paw edema assay. COX-1 and COX-2 inhibitory potency was evaluated through in vitro cyclooxygenase (COX) assays. Compounds 2a, 2b, 2c, 2e and 3c showed promising AI activity at 3–4 h after the carrageenan injection that was comparable to that of the standard drug indomethacin. Although compounds 3d, 3e and 3f exhibited more pronounced COX-2 inhibition but they also inhibit COX-1 effectively thus being less selective against COX-2. Three compounds 2a, 2f and 3a were found to have a COX profile comparable to the reference drug indomethacin. However 2e, 3b, 3c and 3i compounds were the most potent selective COX-2 inhibitors of this study with 3b showing the best COX-2 profile. In order to better rationalize the action and the binding mode of these compounds, docking studies were carried out. These studies were in agreement with the biological data.     

1-Malonyl-1,4-dihydropyridine as a novel carrier for specific delivery of drugs to the brain

A group of 1-malonyl-1,4-dihydropyridine derivatives were synthesized as novel carrier systems for site-specific and sustained drug delivery to the brain. Such carriers are expected to be stable against air oxidation due to the presence of the carbonyl group close to nitrogen of the dihydropyridine. These carrier systems were attached to a group of different aldehydes to afford novel quaternary pyridinium derivatives 9a–e, 11a–d, 13 and 18a–b. Reduction of the prepared quaternary pyridinium derivatives with sodium dithionite afforded a novel group of 1-malonyl-1,4-dihydropyridine chemical delivery systems (CDSs) 10a–e, 12a–d, 14 and 19a–b. The synthesized 1-malonyl-1,4-dihydropyridine CDSs were subjected to various chemical and biological investigations to evaluate their ability to cross the blood–brain barrier, and to be oxidized biologically into their corresponding quaternary derivatives. The in vitro oxidation studies showed that most of the 1-malonyl-1,4-dihydropyridine CDSs could be oxidized into their corresponding quaternary derivatives at an adequate rate. The in vivo studies showed that compounds 10c and 14 were able to cross the blood–brain barrier at detectable concentrations. Moreover, the pyridinium quaternary intermediates 9a, 9c, 13, 18a and their corresponding dihydro derivatives 10a, 10c, 14 and 19a were screened for their antidepressant activity using tail suspension behavioral despair test compared to imipramine as a reference at a dose level of 10 mg/kg. The results indicated that compounds 13, 14 and 19a induced remarkable antidepressant activity comparable to imipramine. Compounds 10a, 10c and 18a exhibited good antidepressant activity, their activities nearly equal to 92.8%, 86.7% and 90.20% of the activity of imipramine, respectively. The other derivatives 9a and 9c exhibited moderate antidepressant activity compared with imipramine.     

Role of the side chain stereochemistry in the α-glucosidase inhibitory activity of kotalanol,a potent natural α-glucosidase inhibitor. Part 2

To examine the role of the side chain of kotalanol (2), a potent natural α-glucosidase inhibitor isolated from Salacia reticulata, on inhibitory activity, four diastereomers (11a–11d) with reversed configuration (S) at the C-4′ position in the side chain were synthesized and evaluated. Two of the four (11b and 11d) significantly lost their inhibitory activity against both maltase and sucrase, while the other two (11a and 11c) sustained the inhibitory activity to a considerable extent, showing distinct activity in response to the change of stereochemistry of the hydroxyls at the 5′and 6′ positions. Different activities were rationalized with reference to in silico docking studies on these inhibitors with hNtMGAM. Against isomaltase, all four analogs showed potent inhibitory activity as well as 2, and 11b and 11d exhibited enzyme selectivity.     

Synthesis of new triazole fused imidazo[2,1-b]thiazole hybrids with emphasis on Staphylococcus aureus virulence factors

A series of new triazole fused imidazo[2,1-b]thiazole hybrids (9a–u) were designed, synthesized and evaluated as antimicrobial agents. Compounds 9c, 9d, 9e, 9j and 9l showed promising broad spectrum antimicrobial activity. Further, compound 9c exhibited significant anti-biofilm activity with single and mixed biofilm disruption demonstrated by Field Emission Scanning Electron Microscope (FE-SEM). Furthermore, molecular docking studies revealed that they interact with the virulence factor, Staphylococcus aureus dehydrosqualene synthase (CrtM) (PDB ID: 2ZCS). Overall, the findings suggest compound 9c as potential lead for further development of novel antibacterial and anti-biofilm agents.     

Synthesis of 3-aroyl-4-aryl-1-isopropylamino-4-piperidinols and evaluation of the cytotoxicities of the compounds against human hepatoma and breast cancer cell lines

Abstract

Some 4-piperidinol derivatives were synthesized and their cytotoxicity was tested against human hepatoma (Huh7) and breast cancer (T47D) cells. Aryl part was changed as phenyl in 2a, 4-methylphenyl in 2b, 4-methoxyphenyl in 2c, 4-chlorophenyl in 2d, 4-fluorophenyl in 2e, 4-bromophenyl in 2f, 4-nitrophenyl in 2g and 2-thienyl in 3. Compounds were synthesized and reported for the first time by this study except 2a and 2d. Chemical structures were confirmed by ¹H NMR, ¹³C NMR, IR, MS and elemental analyses. Compounds 2a (3.1 times), 2c (3.8 times), 2f (4.6 times), 2g (1.3 times) and 3 (3.2 times) had 1.3–4.6 times higher cytotoxic potency than the reference compound 5-FU against Huh7 cell line while all the compounds synthesized had shown lower activities against T47D cell line than 5-FU. In the light of these results, compounds 2a, 2c, 2f, 2g and 3 may serve as model compounds for further studies.     

Synthesis and bio-evaluation of alkylaminoaryl phenyl cyclopropyl methanones as antitubercular and antimalarial agents

A series of 4-alkylaminoaryl phenyl cyclopropyl methanones (6a–6u and 8a–8c) were synthesized from 4-fluorochalcones (3a and 3b) by cyclopropanation of double bond followed by nucleophilic substitution of F with different amines. The compounds were screened for their antitubercular and antimalarial activities against Mycobacterium tuberculosis H37Rv and Plasmodium falciparum 3D7 strains in vitro respectively. Several compounds (6a, 6d–6h, 6p, 6q and 8a–8c) exhibited good in vitro antitubercular activities with MIC values 3.12–12.5 μg/mL and preferentially inhibited the growth of P. falciparum in vitro (4a, 4c, 6a–6d, 6f, 6s, 8a and 8c) with IC₅₀ as low as 0.080 and 0.035 μg/mL and SI values 4975 and 6948, respectively. Molecular docking studies and in vitro evaluation against FAS-II enzymes using reporter gene assays were carried out to elucidate the mode of action of these molecules. Two compounds 4a and 6g showed significant inhibition at 25 μM concentration of the compound.