Synthesis,In Vitro Protoporphyrinogen Oxidase Inhibition,and Herbicidal Activity of N‐(Benzothiazol‐5‐yl)hexahydro‐1H‐isoindole‐1,3‐diones and N‐(Benzothiazol‐5‐yl)hexahydro‐1H‐isoindol‐1‐ones

Protoporphyrinogen oxidase ( EC 1.3.3.4 ) is one of the most significant targets for a large family of herbicides. As part of our continuous efforts to search for novel protoporphyrinogen oxidase‐inhibiting herbicides, N‐(benzothiazol‐5‐yl)tetrahydroisoindole‐1,3‐dione was selected as a lead compound for structural optimization, leading to the syntheses of a series of novel N‐(benzothiazol‐5‐yl)hexahydro‐1H‐isoindole‐1,3‐diones ( 1a – o ) and N‐(benzothiazol‐5‐yl)hexahydro‐1H‐isoindol‐1‐ones ( 2a – i ). These newly prepared compounds were characterized by elemental analyses, ¹H NMR, and ESI‐MS, and the structures of 1h and 2h were further confirmed by X‐ray diffraction analyses. The bioassays indicated that some compounds displayed comparable or higher protoporphyrinogen oxidase inhibition activities in comparison with the commercial control. Very promising, compound 2a , ethyl 2‐((6‐fluoro‐5‐(4,5,6,7‐tetrahydro‐1‐oxo‐1H‐isoindol‐2(3H)‐yl)benzo[d]thiazol‐2‐yl)‐sulfanyl)acetate, was recognized as the most potent candidate with K_i value of 0.0091 μm . Further greenhouse screening results demonstrated that some compounds exhibited good herbicidal activity against Chenopodium album at the dosage of 150 g/ha.     

Preparation and antiplasmodial activity of 3',4'‐dihydro‐1'H‐spiro(indoline‐3,2'‐quinolin)‐2‐ones

A series of 3',4'‐dihydro‐1'H‐spiro(indoline‐3,2'‐quinolin)‐2‐ones were prepared by the inverse‐electron‐demand aza‐Diels–Alder reaction (Povarov reaction) of imines derived from isatin and substituted anilines, and the electron‐rich alkenes trans‐isoeugenol and 3,4‐dihydro‐2H‐pyran. These compounds were assessed for in vitro antiplasmodial activity against drug‐sensitive and drug‐resistant forms of the P. falciparum parasite. Three compounds derived from 3,4‐dihydro‐2H‐pyran and four compounds derived from trans‐isoeugenol showed antiplasmodial activity in the low micromolar range against the drug‐resistant FCR‐3 strain (1.52–4.20 µM). Only compounds derived from trans‐isoeugenol showed antiplasmodial activity against the drug‐sensitive 3D7 strain (1.31–1.80 µM).     

An Interactive Human Carbonic Anhydrase‐II (hCA‐II) Receptor – Pharmacophore Molecular Model & Anti‐Convulsant Activity of the Designed and Synthesized 5‐Amino‐1,3,4‐Thiadiazole‐2‐Thiol Conjugated Imine Derivatives

New imines, derived from aromatic aldehyde, chalcones and 5‐amino‐1,3,4‐thiadiazole‐2‐thiol exhibited promising anti‐convulsant activity which is explained through chemo‐biological interactions at receptor site producing the inhibition of human Carbonic Anhydrase‐II enzyme (hCA‐II) through the proposed pharmacophore model at molecular levels as basis for pharmacological activity. The compounds 5‐{1‐(4‐Chlorophenyl)‐3‐[4‐(methoxy‐phenyl)‐prop‐2‐en‐1‐ylidene]amino}‐1,3,4‐thiadiazole‐2‐thiol ( 2b ), 5‐{[1‐(4‐chloro‐phenyl)]‐3‐[4‐(dimethyl‐amino‐phenyl)‐prop‐2‐en‐1‐ylidene]amino}‐1,3,4‐thiadiazole‐2‐thiol ( 2c ) and 5‐{[1‐(4‐chloro‐phenyl)]‐3‐[(4‐amino‐phenyl)‐prop‐2‐en‐1‐ylidene]amino}‐1,3,4‐thiadiazole‐2‐thiol ( 2f ) showed 100% activity in comparison with standard Acetazolamide, a known anti‐convulsant drug. The compounds 2c , 2f also passed the Rotarod and Ethanol Potentiation tests which further confirmed them to be safe in motor coordination activity and safe from generating neurological toxicity.     

Synthesis,molecular docking,and pharmacological evaluation of N‐(2‐(3,5‐dimethoxyphenyl)benzoxazole‐5‐yl)benzamide derivatives as selective COX‐2 inhibitors and anti‐inflammatory agents

A series of N‐(2‐(3,5‐dimethoxyphenyl)benzoxazole‐5‐yl)benzamide derivatives ( 3am ) was synthesized and evaluated for their in vitro inhibitory activity against COX‐1 and COX‐2. The compounds with considerable in vitro activity (IC₅₀ < 1 μM) were evaluated in vivo for their anti‐inflammatory potential by the carrageenan‐induced rat paw edema method. Out of 13 newly synthesized compounds, 3a , 3b , 3d , 3g , 3j , and 3k were found to be the most potent COX‐2 inhibitors in the in vitro enzymatic assay, with IC₅₀ values in the range of 0.06–0.71 μM. The in vivo anti‐inflammatory activity of these six compounds ( 3a , 3b , 3d , 3g , 3j , and 3k ) was assessed by the carrageenan‐induced rat paw edema method. Compounds 3d (84.09%), 3g (79.54%), and 3a (70.45%) demonstrated significant anti‐inflammatory activity compared to the standard drug ibuprofen (65.90%) and were also found to be safer than ibuprofen, by ulcerogenic studies. A docking study was done using the crystal structure of human COX‐2, to understand the binding mechanism of these inhibitors to the active site of COX‐2.

     

Synthesis,Hypoglycaemic, Hypolipidemic and PPARγ Agonist Activities of 5‐(2‐Alkyl/aryl‐6‐Arylimidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene‐1,3‐Thiazolidinediones

A novel series of 5‐(2‐alkyl/aryl‐6‐arylimidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene‐1,3‐thiazolidinediones were synthesized as possible PPARγ agonists. The structures of these target molecules were established by spectral and analytical data. All the newly synthesized compounds were screened for their in vivo hypoglycaemic and hypolipidemic activity in male Wistar rats. Further, compounds with good activity were screened for PPARγ agonist activity. Among the screened compounds, 5‐{[2‐Cyclohexyl‐6‐(4‐methoxyphenyl)imidazo[2,1‐b] [1,3,4]thiadiazol‐5‐yl]methylene}‐1,3‐thiazolidine‐2,4‐dione (3i) exhibits promising hypoglycaemic and hypolipidemic activity via potential PPARγ agonist activity.     

Synthesis and kinetics studies of N′‐(2‐(3,5‐disubstituted‐4H‐1,2,4‐triazol‐4‐yl)acetyl)‐6/7/8‐substituted‐2‐oxo‐2H‐chromen‐3‐carbohydrazide derivatives as potent antidiabetic agents

A novel series of N′‐(2‐(3,5‐disubstituted‐4H‐1,2,4‐triazol‐4‐yl)acetyl)‐6/7/8‐substituted‐2‐oxo‐2H‐chromen‐3‐carbohydrazides were synthesized and studied for their α‐glucosidase inhibition activity. Most of the synthesized compounds exhibited potential α‐glucosidase inhibition activity with IC₅₀ values ranging from 0.96 ± 0.02 to 32.86 ± 0.73 µg/ml. Among them, compounds 3e and 4e , having a methoxy group on the coumarin ring, proved to be the most potent ones, showing an enzyme inhibition activity with IC₅₀ = 0.96 ± 0.02 and 1.44 ± 0.06 µg/ml, respectively. The kinetic study through Lineweaver–Burk plots revealed that the inhibition mechanism of the most active compounds 3d, 3e, 4d , and 4e , on the α‐glucosidase activity, was found to be in the competitive mode.     

Synthesis and Antimicrobial Evaluation of 6‐Alkylamino‐N‐phenylpyrazine‐2‐carboxamides

This work presents synthesis and antimicrobial evaluation of nineteen 6‐alkylamino‐N–phenylpyrazine‐2‐carboxamides. Antimycobacterial activity was determined against Mycobacterium tuberculosis H37Rv, M. kansasii and two strains of M. avium. Generally, the antimycobacterial activity increased with prolongation of simple alkyl chain and culminated in compounds with heptylamino substitution ( 3e , 4e ) with MIC = 5–10 μm against M. tuberculosis H37Rv. On the contrary, derivatives with modified alkyl chain (containing e.g. terminal methoxy or hydroxy group) as well as phenylalkylamino derivatives were mainly inactive. The most active compounds (with hexyl to octylamino substitution) were evaluated for their in vitro activity against drug‐resistant strains of M. tuberculosis and possessed activity comparable to that of the reference drug isoniazid. None of the tested compounds were active against M. avium. Some derivatives exhibited activity against Gram‐positive bacteria including methicillin‐resistant Staphylococcus aureus (best MIC = 7.8 μm ), while Gram‐negative strains as well as tested fungal strains were completely unsusceptible. Active compounds were tested for in vitro toxicity on various cell lines and in most cases were non‐toxic up to 100 μm .     

Design,Synthesis, Antioxidant,and Anti‐Breast Cancer Activities of Novel Diethyl(alkyl/aryl/heteroarylamino)(4‐(pyridin‐2‐yl)phenyl)methylphosphonates

A series of new diethyl(alkyl/aryl/heteroarylamino)(4‐(pyridine‐2‐yl)phenyl)methylphosphonates ( 4a–t ) were synthesized via three‐component Kabachnik–Field's reaction of 4‐(pyridin‐2‐yl)benzaldehyde, diethylphosphite and various primary amines, catalyzed by cupric acetate monohydrate [Cu(OAc)₂ · H₂O] under solvent‐free and microwave irradiation conditions. Their computational docking analysis supported them as good therapeutic agents to the breast cancer aromatase enzyme and ascertained 4a , 4h , 4m , 4n , and 4t as potential molecules with good binding affinities varying from ?9.0 to ?9.6 kcal/mol and containing the 4‐(pyridine‐2‐yl)phenyl moiety as a pharmacophore. Their in vitro screening performed for the anti‐cell proliferation activity against MBC‐MCF7 cells by MTT and Trypan blue assays confirmed 4m , 4n , and 4q as promising compounds to sustain a low percentage of cell viability at 20 µg/mL concentration. These compounds were also evaluated for their antioxidant activity by the DPPH method and the results established that compounds 4m , 4n , and 4q show around 10% higher activity than the standard antioxidant ascorbic acid.     

Synthesis and Positive Inotropic Evaluation of (E)‐2‐(4‐Cinnamylpiperazin‐1‐yl)‐N‐(1‐substituted‐4,5‐dihydro‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamides

A series of (E)‐2‐(4‐cinnamylpiperazin‐1‐yl)‐N‐(1‐substituted‐4,5‐dihydro‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamides were synthesized and evaluated for their positive inotropic activity by measuring the left atrium stroke volume on isolated rabbit heart preparations. This class of compounds presented favorable in vitro activity compared with the standard drug, milrinone, among which N‐(1‐(3‐chlorophenyl)‐4,5‐dihydro‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)‐2‐(4‐cinnamylpiperazin‐1‐yl)acetamide 5e was found to be the most potent with 16.58 ± 0.11% increased stroke volume (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10^?5 M. The chronotropic effects of the compounds having inotropic effects were also evaluated.     

Design,Synthesis and Bioevaluation of Novel N‐Substituted‐3,5‐Bis(Arylidene)‐4‐piperidone Derivatives as Cytotoxic and Antitumor Agents with Fluorescent Properties

Ten new N‐substituted‐3,5‐bis(arylidene)‐4‐piperidone derivatives (series 1 and 2 ) were synthesized and subsequently evaluated against human carcinoma cell lines SW1990, MIA PaCa‐2, PG‐BE1, NCI‐H460, and SK‐BR‐3 for cytotoxic activity by the CCK‐8 method, and their fluorescent properties were investigated as well. The compounds were confirmed to display greater cytotoxic activity to the neoplastic cells, and approximately 50% of the IC₅₀ values were lower than 5 μm . In particular, compounds 1a , 1c , 1d, and 1e bearing 3‐bromophenyl groups were revealed as the most active antitumor drug candidates and had the average IC₅₀ values of 1.94, 1.11, 1.16, and 0.817 μm , respectively. Furthermore, their fluorescent properties were interesting and might contribute to the visualization of their distribution in tumor cells. Some possible reasons for the disparity between cytotoxic activity and fluorescent properties in the two series of compounds were explored. This study revealed high potential of these molecules for further development as fluorescent cytotoxic and antitumor agents.     

Synthesis of N,N‐diethyl‐4‐[phenyl‐(piperidin‐4‐ylidene)methyl]‐[carboxy‐14C]benzamide,a potent δ opioid receptor agonist

The synthesis of carbon‐14 labelled N,N‐diethyl‐4‐[phenyl‐(piperidin‐4‐ylidene)methyl]‐benzamide is described. The radioisotope is introduced via an aryllithium reaction with ¹⁴CO₂ to form the labelled acid, which is subsequently transformed into the amide. Copyright © 2002 John Wiley & Sons, Ltd.     

Scalable synthesis and antibacterial evaluation of 2‐(3‐(N‐(substituted phenyl)sulfamoyl)ureido)benzothiazoles

A new series of 2‐(3‐(N‐(substituted phenyl)sulfamoyl)ureido)benzothiazoles was synthesized via a one‐pot efficient and scalable method, involving the condensation of 2‐aminobenzothiazoles derivatives, substituted anilines, and chlorosulfonyl isocyanate. The products were obtained in good yield with a simple workup, and their structures were confirmed from their spectral analyses. The synthesized compounds were further screened for their antibacterial activity against Gram‐positive and Gram‐negative pathogenic strains. The molecules show promising activity in the MIC value range of 2–0.25 µg/ml against selected bacterial strains, especially against nonfermentative carbapenem‐resistant bacteria (Pseudo VIM‐2 and Acinetobacter baumanni).     

Synthesis and antimicrobial activity of new 2‐piperazin‐1‐yl‐N‐1,3‐thiazol‐2‐ylacetamides of cyclopenta[c]pyridines and pyrano[3,4‐c]pyridines

In this study, we report the synthesis and antimicrobial activity of some new disubstituted piperazines. Thus, 3‐chlorocyclopenta[c]pyridines and 6‐chloropyrano[3,4‐c]pyridine 1 under mild reaction conditions with piperazine gave the 3(6)‐piperazine‐substituted cyclopenta[c]pyridines and pyrano[3,4‐c]pyridine 2 . Furthermore, the latter, by alkylation with 2‐chloro‐N‐1,3‐thiazol‐2‐ylacetamide, led to the formation of the target compounds. The evaluation of the antibacterial activity revealed that 3k was the most potent compound. The most sensitive bacterium was found to be Listeria monocytogenes, whereas Staphylococcus aureus was the most resistant one. Three compounds, 3d , 3g , and 3k , were tested also against the following resistant strains: methicillin‐resistant S. aureus (MRSA), Escherichia coli, and Pseudomonas aeruginosa. All three compounds appeared to be more potent than ampicillin against MRSA. Moreover, compound 3d showed a better activity than the reference drug ampicillin against P. aeruginosa, whereas 3g was more efficient against E. coli. The best antifungal activity was observed again for compound 3k . The most resistant fungi appeared to be Aspergillus fumigatus, whereas Trichoderma viride seemed the most sensitive one toward the compounds tested. Molecular docking studies on E. coli MurB, as well as on Candida albicans CYP51 and dihydrofolate reductase, were used for the prediction of the mechanisms of the antibacterial and antifungal activities, confirming the experimental results.     

Pre‐clinical evidence of safety and protective effect of isatin and oxime derivatives against malathion‐induced toxicity

The inhibition of acetylcholinesterase (AChE) is a common outcome caused by organophosphorus (OPs) intoxication. Although inconsistent, the standard treatment consists of a muscarinic receptor antagonist (atropine) and AChE‐reactivating molecules such as oximes. This study proposes to test unpublished compounds which contain the moieties of isatin and/or oxime have protective effects against the toxicity induced by malathion in two animal models: Artemia salina and Rattus norvegicus (Wistar rats). The lethality was assessed in A salina, and the calculated LD₅₀ to (3Z)‐5‐chloro‐3‐(hydroxyimino) indolin‐2‐one oxime (C?‐HIN) and 2‐(5‐chloro‐2‐oxoindolin‐3‐ylidene)‐hydrazinecarbothioamide (C?‐OXHS) was higher than 1000 µM while to 3‐(phenylhydrazono) butan‐2‐one oxime (PHBO) was 38 µM. Our screening showed that C?‐HIN seems to be the most promising molecule, with low toxicity to A salina, protection against mortality (with or without atropine) and AChE inhibition induced by malathion. Similarly, the oral administration of 300 mg/kg of C?‐HIN induced low or no toxicity in rats. The plasma butyrylcholinesterase (BChE) and cortical AChE activities were reactivated by C?‐HIN (50 mg/kg, p.o.) in rats exposed to malathion (250 mg/kg, i.p). No difference was observed in paraoxonase‐1 (PON‐1) activity among groups treated. In conclusion, C?‐HIN restored the cholinesterase activities inhibited by malathion in A salina and rats with low toxicity in both. Thus, the data provide evidence that C?‐HIN, a compound that combines isatin and oxime functional groups, is safe and has important properties to reactivate the cholinesterases inhibited by malathion. In addition, we demonstrate the importance of a preliminary assessment in an alternative model in order to reduce the use of mammalians in drug discovery.     

Design,Synthesis, and Antitumor Activity of (E,Z)‐1‐(dihydrobenzofuran‐5‐yl)‐3‐phenyl‐2‐(1,2,4‐triazol‐1‐yl)‐2‐propen‐1‐ones

A series of (E,Z)‐1‐(dihydrobenzofuran‐5‐yl)‐3‐phenyl‐2‐(1,2,4‐triazol‐1‐yl)‐2‐propen‐1‐ones ( C1 – C35 ) were designed and synthesized, and the structures of compounds (Z)‐ C27 and (Z)‐ C29 were confirmed by single‐crystal X‐ray diffraction. The antitumor activities of these novel compounds against cervical cancer (HeLa), lung cancer (A549), and breast cancer (MCF‐7) cell lines were evaluated in vitro. Majority of the title compounds exhibited strong antitumor activities and were much more promising than the positive control Taxol, which were also accompanied by lower cytotoxicity to normal cells. In particular, compounds (E,Z)‐ C24 exhibited the most consistent potent activities against three neoplastic cells with IC₅₀ values ranging from 3.2 to 7.1 μm . Further researches demonstrated that compounds (E,Z)‐ C24 could induce cell apoptosis and arrest cell cycle at the G2/M and S phases. Meanwhile, the structure–activity relationship between the configurations and cytotoxicity of the compounds was also investigated.     

3‐(3‐Ethylphenyl)‐2‐substituted hydrazino‐3H‐quinazolin‐4‐one Derivatives: New Class of Analgesic and Anti‐Inflammatory Agents

A new series of 3‐(3‐ethylphenyl)‐2‐substituted hydrazino‐3H‐quinazolin‐4‐ones were synthesized by reacting the amino group of 2‐hydrazino‐3‐(3‐ethylphenyl)‐3H‐quinazolin‐4‐one with a variety of aldehydes and ketones. The title compounds were investigated for analgesic, anti‐inflammatory and ulcerogenic index behavior. The compound 2‐(N′‐3‐pentylidene‐hydrazino)‐3‐(3‐ethylphenyl)‐3H‐quinazolin‐4‐one ( AS2 ) emerged as the most active compound in exhibiting analgesic activity and the compound 2‐(N′‐2‐pentylidene‐hydrazino)‐3‐(3‐ethylphenyl)‐3H‐quinazolin‐4‐one ( AS3 ) emerged as the most active compound in exhibiting anti‐inflammatory activity; and these compounds are moderately potent when compared with the reference standard diclofenac sodium. Interestingly, the test compounds showed only mild ulcerogenic potential when compared with aspirin.     

Synthesis,analgesic, anti‐inflammatory and ulcerogenic index activities of novel 2‐methylthio‐3‐substituted‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐ones

A variety of novel 2‐methylthio‐3‐substituted amino‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐ones were synthesized by reacting 3‐amino‐2‐methylthio‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐one with different aldehydes and ketones. The starting material 3‐amino‐2‐methylthio‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐one was synthesized from 2‐amino‐3‐carbethoxy‐4,5‐dimethyl thiophene. The compounds were investigated for their analgesic activity in albino mice, and for their anti‐inflammatory and ulcerogenic index activities in Wistar rats. The compound 2‐(1‐ethylpropylideneamino)‐2‐methylthio‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐one (AS2) showed the most potent analgesic activity of the series. It also showed more potent anti‐inflammatory activity when compared to the reference standard, diclofenac sodium. The test compounds showed only mild ulcerogenic potential when compared to aspirin. Drug Dev Res 68:134–142, 2007. © 2007 Wiley‐Liss, Inc.     

Synthesis and Positive Inotropic Evaluation of 2‐(4‐(4‐Substituted benzyloxy)‐3‐methoxybenzyl)‐1,4‐diazepan‐1‐yl)‐N‐(4,5‐dihydro‐1‐methyl[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)‐acetamides

In an attempt to search for more potent positive inotropic agents, a series of 2‐(4‐(4‐substituted benzyloxy)‐3‐methoxybenzyl)‐1,4‐diazepan‐1‐yl)‐N‐(4,5‐dihydro‐1‐methyl[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamides was synthesized and their positive inotropic activities were evaluated by measuring left atrium stroke volume on isolated rabbit‐heart preparations. Several compounds showed favorable activity compared with the standard drug Milrinone among which 2‐(4‐(4‐(2‐chlorobenzyloxy)‐3‐methoxybenzyl)‐1,4‐diazepan‐1‐yl)‐N‐(4,5‐dihydro‐1‐methyl‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamide 6e was found to have the most desirable potency with the 6.79 ± 0.18% increased stroke volume (Milrinone: 1.67 ± 0.64%) at a concentration of 1×10^–5 M in our in‐vitro study. The chronotropic effects of those compounds having inotropic effects were also evaluated in this work.     

Synthesis of New N‐Substituted 5‐Arylidene‐2,4‐thiazolidinediones as Anti‐Inflammatory and Antimicrobial Agents

A novel series of 5‐arylidene ‐ 2,4‐thiazolidinediones (TZDs) 2a – p was synthesized from the condensation of 3‐((2‐phenylthiazol‐4‐yl)methyl)thiazolidine‐2,4‐dione with different benzaldehyde derivatives. All the structures were confirmed by their spectral (IR, ¹H NMR, ¹³C NMR and mass) and elemental analytical data. The new molecules were evaluated in vivo as anti‐inflammatory agents in an acute experimental inflammation, evaluating the acute phase bone marrow response and phagocyte activity. All compounds, excepting one, reduced the absolute leukocytes count due to the lower neutrophil percentage. Phagocytary index was decreased by the same molecules, while only half of them reduced the phagocytary activity. The effect was superior to meloxicam, the reference anti‐inflammatory drug, for the majority of the TZD derivatives. The new molecules were also investigated for their antimicrobial properties on Gram‐positive and Gram‐negative bacteria and one fungal strain. Two compounds ( 2e and 2n ) manifested growth inhibition capacity on all the tested strains.