Design,synthesis, and in vitro antituberculosis activity of benzo[6,7]cyclohepta[1,2‐b]pyridine‐1,3,4‐oxadiazole derivatives

A new antitubercular agents, benzo[6,7]cyclohepta[1,2‐b]pyridine‐1,3,4‐ oxadiazole hybrids ( 6a–o ), have been designed and synthesized involving oxidative cyclization of hydrazones by use of di(acetoxy)iodobenzene, characterized by IR,¹H NMR,¹³C NMR, and HRMS, and further confirmed by X‐ray analysis. All the newly synthesized compounds 4a–o evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294). Among the compounds tested, the compounds 4o (MIC: 1.56  μg/ml) and 4l, 4m (MIC: 3.125  μg/ml) are promising lead analogues and have shown lower cytotoxicity.     

Novel N‐(1‐thia‐4‐azaspiro[4.5]decan‐4‐yl)carboxamide derivatives as potent and selective influenza virus fusion inhibitors

Hemagglutinin is the surface protein of the influenza virus that mediates both binding and penetration of the virus into host cells. We here report on the synthesis and structure–activity relationship of some novel N‐(1‐thia‐4‐azaspiro[4.5]decan‐4‐yl)‐carboxamide compounds carrying the 5‐chloro‐2‐methoxybenzamide structure, designed as influenza virus fusion inhibitors. The carboxamides ( 1a–h, 2a–h ) have a similar backbone structure as the fusion inhibitors that we reported on previously. Compounds 2b and 2d displayed inhibitory activity against influenza A/H3N2 virus replication (average antiviral EC₅₀: 2.1 µM for 2b and 3.4 µM for 2d ). Data obtained in the hemolysis inhibition assay supported that these compounds act as inhibitors of the influenza virus hemagglutinin‐mediated fusion process.     

Design and syntheses of methyl 2‐methyl‐2‐[2‐(4‐benzoyl‐5‐phenyl‐7‐halo‐2‐azabicyclo[4.1.0]hept‐3‐ene)]acetates: novel inhibitors of cyclooxygenase‐2 (COX‐2) with analgesic‐antiinflammatory activity

A group of methyl 2‐methyl‐2‐[2‐(4‐benzoyl‐5‐phenyl‐7‐halo‐2‐azabicyclo[4.1.0]hept‐3‐ene)]acetates ( 10–15 ), and the related acetamide derivative ( 16 ), that possess a variety of C‐7 substituents (Br, Cl, F, H), were designed for evaluation as analgesic‐antiinflammatory agents. The effect of the C‐7 substituent(s) and the nature of the acetic acid ester (R¹ = Ome) or acetamide (R¹ = NH₂) moiety on analgesic activity was determined using a 4% NaCl‐induced abdominal constriction assay. Compounds 10–16 inhibited writhing by 36–82%, relative to the reference drugs aspirin (58% inhibition) and celecoxib (62% inhibition). The nature of the C‐7 substituents was a determinant of analgesic activity in the 7,7‐dihalo group of compounds where the relative activity profile was 7‐Cl₂ > 7‐Br₂ > 7‐F₂ > 7‐Cl,7‐F, and for 7‐monohalo compounds where the potency order was 7‐Br > 7‐Cl. Elaboration of the 7,7‐dibromo methyl acetate ester ( 10 ) to the corresponding acetamide derivative ( 16 ) enhanced analgesic activity. The nature of the 7‐halo substituent(s) in the 7,7‐dihalo group of compounds was a determinant of antiinflammatory activity, determined using the carrageenan‐induced rat paw edema assay, where the relative potency order was 7‐Br₂ > 7‐Cl₂ > 7‐F₂ > 7‐Cl,7‐F. The most potent 7,7‐dibromo compound ( 10 ) inhibited inflammation by 62%, relative to the reference drug ibuprofen (44%), and 10 inhibited COX‐2 (IC₅₀ = 26.4 μM) and COX‐1 (IC₅₀ = 227 μM) for a COX‐2 selectivity index of 8.6. Docking 10 in the active site of human COX‐2 showed it binds in the center of the COX‐2 binding site with the C‐5 phenyl ring oriented toward the acetylation site (Ser⁵³⁰), and the phenyl group of the C‐4 benzoyl moiety oriented in the vicinity of the COX‐2 secondary binding pocket near Val⁵²³. Drug Dev. Res. 49:75–84, 2000. © 2000 Wiley‐Liss, Inc.     

Synthesis and Antitubercular Activity of 2‐(substituted phenyl/benzyl‐amino)‐6‐(4‐chlorophenyl)‐5‐(methoxycarbonyl)‐4‐methyl‐3,6‐dihydropyrimidin‐1‐ium Chlorides

A series of 2‐(substituted phenyl/benzyl‐amino)‐6‐(4‐chlorophenyl)‐5‐(methoxycarbonyl)‐4‐methyl‐3,6‐dihydropyrimidin‐1‐ium chlorides 7–13 and 15 was synthesized in their hydrochloride salt form. The title compounds were characterized by FT‐IR, NMR (¹H and ¹³C) and elemental analysis. They were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv, multidrug resistance tuberculosis and extensively drug resistance tuberculosis by agar diffusion method and tested for the cytotoxic action on peripheral blood mononuclear cells by MTT assay. Among all the tested compounds in the series, compounds 7 and 11 emerged as promising antitubercular agents at 16 μg/mL against multidrug resistance tuberculosis and over 64 μg/mL against extensively drug resistance tuberculosis. The conformational features and supramolecular assembly of the promising compounds 7 and 11 were determined by single crystal X‐ray study.     

Synthesis and anti‐Helicobacter pylori properties of NO‐donor/metronidazole hybrids and related compounds

Two series (A, B) of 2‐(2‐methyl‐5‐nitro‐1H‐imidazolyl)ethyl derivatives ( 6–9, 18–23 ) conjugated through an oxygen or an aminomethyl bridge with either a furoxan NO‐donor moiety or a furazan substructure, devoid of NO‐donor properties, were synthesised. A third group (C) of 2‐(2‐methyl‐5‐nitro‐1H‐imidazolyl)ethyl derivatives conjugated with nitrooxy and dinitrooxy NO‐donor functions ( 35, 38 ) as well as the corresponding analogue without these functions ( 40 ) were prepared. All the compounds were evaluated in vitro for their activity against a number of Helicobacter pylori strains. Metronidazole ( 1 ) and its amino analogue ( 11 ) were taken as reference compounds. All the synthesised hybrids and their analogues exhibited good anti‐H. pylori activity with MIC₅₀ in the range less than 0.0039–1, resulting in compounds more active than metronidazole. Derivatives 6–9 displayed good potency also against metronidazole‐resistant strains. Compounds lacking the 5‐nitroimidazole moiety ( 24–29, 30–33 ) proved to be inactive against H. pylori with the exception of 33 . The lack of significant differences in the antibacterial potency between furoxan and furazan hybrids in both series (A, B) suggest that the role of the N‐oxide moiety of the furoxan system either as an inductor of oxidative stress or as a promoter of NO‐donor properties is marginal. The substitution of the furoxan substructures with nitrooxy moieties ( 35, 38 ) afforded active compounds. In view of their NO‐donor properties, NO‐metronidazole hybrids could represent potential therapeutic tools both in the treatment of gastric ulcer and in a number of extragastrointestinal disorders such as ischaemic heart diseases and atherosclerosis‐related to some H. pylori strains. Drug Dev. Res. 60:225–239, 2003. © 2003 Wiley‐Liss, Inc.     

Synthesis of Some N,N′‐Diacylhydrazine Derivatives with Radical‐Scavenging and Antifungal Activity

A series of N,N′‐diacylhydrazines were prepared and their structures were confirmed by ¹H NMR, MS and FTICR‐MS. They were tested radical‐scavenging activity in vitro. The preliminary bioassays of title compounds showed that two compounds had excellent radical‐scavenging activity comparable with vitamin C, while the activity is highly relative to the substituents. Surprisingly, several compounds also exhibit favorable fungicidal activities. To further explore the comprehensive structure–activity relationships about the fungicidal activity, a three‐dimensional quantitative structure–activity relationship analysis using the method of comparative molecular field analysis was performed.     

Identification of inhibitors of Tartrate‐resistant acid phosphatase (TRAP/ACP5) activity by small‐molecule screening

Tartrate‐resistant acid phosphatase (TRAP/ACP5) occurs as two isoforms—TRAP 5a with low enzymatic activity due to a loop interacting with the active site and the more active TRAP isoform 5b generated upon proteolytic cleavage of this loop. TRAP has been implicated in several diseases, including cancer. Thus, this study set out to identify small‐molecule inhibitors of TRAP activity. A microplate‐based enzymatic assay for TRAP 5b was applied in a screen of 30,315 compounds, resulting in the identification of 90 primary hits. After removal of promiscuous compounds, unwanted groups, and false positives by orthogonal assays and three‐concentration validation, the properties of 52 compounds were further investigated to better understand their mechanism of action. Full‐concentration–response curves for these compounds were established under different enzyme concentrations and (pre)incubation times to remove compounds with inconsistent results and low potencies. Full‐concentration–response curves were also performed for both isoforms, to examine isoform prevalence. Filtering led to six prioritized compounds, representing different clusters. One of these, CBK289001 or (6S)‐6‐[3‐(2H‐1,3‐benzodioxol‐5‐yl)‐1,2,4‐oxadiazol‐5‐yl]‐N‐(propan‐2‐yl)‐1H,4H,5H,6H,7H‐imidazo[4,5‐c]pyridine‐5‐carboxamide, demonstrated efficacy in a migration assay and IC₅₀ values from 4 to 125 μm . Molecular docking studies and analog testing were performed around CBK289001 to provide openings for further improvement toward more potent blockers of TRAP activity.     

Synthesis and biological evaluation of 1,2,4‐triazole‐3‐thione and 1,3,4‐oxadiazole‐2‐thione as antimycobacterial agents

Resistance among dormant mycobacteria leading to multidrug‐resistant and extremely drug‐resistant tuberculosis is one of the major threats. Hence, a series of 1,2,4‐triazole‐3‐thione and 1,3,4‐oxadiazole‐2‐thione derivatives ( 4a–5c ) have been synthesized and screened for their antitubercular activity against Mycobacterium tuberculosis H37Ra (H37Ra). The triazolethiones 4b and 4v showed high antitubercular activity (both MIC and IC₅₀) against the dormant H37Ra by in vitro and ex vivo. They were shown to have more specificity toward mycobacteria than other Gram‐negative and Gram‐positive pathogenic bacteria. The cytotoxicity was almost insignificant up to 100 μg/ml against THP‐1, A549, and PANC‐1 human cancer cell lines, and solubility was high in aqueous solution, indicating the potential of developing these compounds further as novel therapeutics against tuberculosis infection.     

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 .     

Synthesis and Biological Evaluation of a Series of 2‐((1‐substituted‐1H‐1,2,3‐triazol‐4‐yl)methylthio)‐6‐(naphthalen‐1‐ylmethyl)pyrimidin‐4(3H)‐one As Potential HIV‐1 Inhibitors

A series of novel S‐DABO derivatives with the substituted 1,2,3‐triazole moiety on the C‐2 side chain were synthesized using the simple and efficient CuAAC reaction, and biologically evaluated as inhibitors of HIV‐1. Among them, the most active HIV‐1 inhibitor was compound 4‐((4‐((4‐(2,6‐dichlorobenzyl)‐5‐methyl‐6‐oxo‐1,6‐dihydropyrimidin‐2‐ylthio)methyl)‐1H‐1,2,3‐triazol‐1‐yl)methyl)benzenesulfonamide ( B5b7) , which exhibited similar HIV‐1 inhibitory potency (EC₅₀ = 3.22 μm ) compared with 3TC (EC₅₀ = 2.24 μm ). None of these compounds demonstrated inhibition against HIV‐2 replication. The preliminary structure–activity relationship (SAR) of these new derivatives was discussed briefly.     

Synthesis of valproate,valerate, and 1‐methyl‐1, 4‐dihydropyridyl‐3‐carbonyloxy ester derivatives of Hantzsch 1,4‐dihydropyridines as potential prodrugs and their evaluation as calcium channel antagonist and anticonvulsant agents

A group of 3‐(hydroxyalkyl) 5‐alkyl 1,4‐dihydro‐2,6‐dimethyl‐4‐aryl‐3,5‐pyridinedicarboxylates ( 11–15 ) were prepared using a modified Hantzsch reaction, which were then elaborated to valproate ( 16–18 ), valerate ( 19, 20 ), and 1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyloxy ( 25, 26 ) derivatives. Alternatively, the valproate derivative 3‐(2‐n‐propylpentanoyloxymethyl) 5‐isopropyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(2,3‐dichlorophenyl)‐3,5‐pyridinedicarboxylate ( 34 ) was prepared by the reaction of isopropyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(2,3‐dichlorophenyl)‐3,5‐pyridinedicarboxylate ( 30 ) with chloromethyl valproate ( 33 ). This class of lipophilic compounds possess partition coefficients (Kp) in the 149–452 range, relative to the reference drug nimodipine (Kp = 187). All compounds exhibited potent calcium channel antagonist (CCA) activity (IC₅₀ = 10^–7 to 10^–10 M range), relative to the reference drug nimodipine (IC₅₀ = 1.49 × 10^–8 M). CCA structure–activity relationships showed the parent C‐3 2‐hydroxyethyl compounds were more potent than their valproate derivatives, but less active than their valerate derivatives. Compounds having a 1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyloxy chemical delivery system (CDS) were approximately equiactive to the parent C‐3 2‐hydroxyethyl compounds. Anticonvulsant activity was determined in the maximal electroshock (MES) and subcutaneous metrazol (scMet) screens. 3‐(2‐Hydroxyethyl) 5‐isopropyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(2,3‐dichlorophenyl)‐3,5‐pyridinedicarboxylate ( 12 ) provided modest protection in the MES and scMet screens. In the C‐3 valproate [CO₂(CH₂)nO₂CCH(n‐Pr)₂] group of compounds, those possessing an ethylene spacer (n = 2) provided protection in the MES screen, whereas those having a propylene spacer (n = 3) or methylene spacer (n = 1) were inactive. Related C‐3 valerate esters [CO₂(CH₂)₂O₂C‐n‐Bu] also provided protection in the MES screen, whereas those having a 1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyloxy CDS moiety were inactive. Drug Dev. Res. 48:26–37, 1999. © 1999 Wiley‐Liss, Inc.     

Design,Synthesis, and Antiviral Activity of Novel Ribonucleosides of 1,2,3‐Triazolylbenzyl‐aminophosphonates

A novel series of ribonucleosides of 1,2,3‐triazolylbenzyl‐aminophosphonates was synthesized through the Kabachnik–Fields reaction using I₂ as catalyst followed by copper‐catalyzed cycloaddition of the azide–alkyne reaction (CuAAC). All structures of the newly prepared compounds were characterized by ¹H NMR, ¹³C NMR, and HRMS spectra. The structures of 2e , 2f , 3d , and 3g were further confirmed by X‐ray diffraction analysis. These compounds were tested against various strains of DNA and RNA viruses; compounds 4b and 4c showed a modest inhibitory activity against respiratory syncytial virus (RSV) and compound 4h displayed modest inhibitory activity against Coxsackie virus B4.     

Synthesis and Anticonvulsant Activity of New N‐(Alkyl/Sub‐stituted aryl)‐N′‐[4‐(5‐cyclohexylamino)‐1,3,4‐thiadiazole‐2‐yl)phenyl]thioureas

A series of novel thiourea derivatives carrying the 5‐cylohexylamino‐1,3,4‐thiadiazole moiety was synthesized and their anticonvulsant activity was evaluated. Structures of the synthesized compounds have been confirmed by IR, ¹H‐NMR, and elemental analysis. All of the compounds were administered at a dose of 50 mg/kg. Some of the active compounds have different effects in pentylenetetrazole (PTZ) and maximal electroshock (MES) tests, indicating the therapeutical potential in petit mal seizures, but not in grand mal seizures. Compounds 10 , 11 , 13 , and 14 carrying 2‐methylphenyl, 4‐chlorophenyl, allyl, and 4‐methylphenyl on the thiourea pharmacophore, increased the survival rate in the PTZ model. The ED₅₀ values of the active compounds 10 , 11 , 13 , and 14 were found 68.42, 43.75, 18.75 and 25 mg/kg, respectively.     

N‐hydroxy‐substituted 2‐aryl acetamide analogs: A novel class of HIV‐1 integrase inhibitors

An in silico method has been used to discover N‐hydroxy‐substituted 2‐aryl acetamide analogs as a new class of HIV‐1 integrase inhibitors. Based on the molecular requirements of the binding pocket of catalytic active site, two molecules (compounds 2 and 4b ) were designed as fragments. These were further synthesized and biologically evaluated. In vitro potency along with docking studies highlighted compound 4b as an active fragment which was further used to synthesize new leads as HIV‐1 integrase inhibitors. Finally, six promising compounds (compounds 5b , 5c , 5e, 6–2c, 6–3b, and 6–5b ) were identified by integrase inhibition assay (>50% inhibition). Based on in vitro anti‐HIV‐1 activity in a reporter gene‐based cell assay system, compounds 5d , 6s , and 6k were found as novel HIV‐1 integrase inhibitors due to its better selectivity index. Additionally, docking study revealed the importance of H‐bond as well as hydrophobic interactions with Asn155, Lys156, and Lys159 which were required for their anti‐HIV‐1 activity.     

Synthesis and Evaluation of 3‐(furo[2,3‐b]pyridin‐3‐yl)‐4‐(1H‐indol‐3‐yl)‐maleimides as Novel GSK‐3β Inhibitors and Anti‐Ischemic Agents

A series of novel 3‐(furo[2,3‐b]pyridin‐3‐yl)‐4‐(1H‐indol‐3‐yl)‐maleimides were designed, synthesized, and biologically evaluated for their GSK‐3β inhibitory activities. Most compounds showed favorable inhibitory activities against GSK‐3β protein. Among them, compounds 5n , 5o , and 5p significantly reduced GSK‐3β substrate tau phosphorylation at Ser396 in primary neurons, indicating inhibition of cellular GSK‐3β activity. In the in vitro neuronal injury models, compounds 5n , 5o , and 5p prevented neuronal death against glutamate, oxygen–glucose deprivation, and nutrient serum deprivation which are closely associated with cerebral ischemic stroke. In the in vivo cerebral ischemia animal model, compound 5o reduced infarct size by 10% and improved the neurological deficit. The results may provide new insights into the development of novel GSK‐3β inhibitors with potential neuroprotective activity against brain ischemic stroke.     

Design,syntheses, and evaluation of novel 1,1‐dihalo‐2,3‐diphenylcyclopropanes as potential cyclooxygenase‐2 (COX‐2) inhibitors with analgesic‐antiinflammatory activity

A group of (Z)‐ and (E)‐1,1‐dihalo‐2‐(4‐substituted‐phenyl)‐3‐phenylcyclopropane [ (Z)‐10 , (E)‐11 ] stereoisomers having a variety of substituents (H, Br, Cl, F, NO₂, SO₂Me) at the para‐position of the C‐2 phenyl ring in conjunction with either two chloro or bromo substituents at C‐1 were synthesized for in vivo evaluation as analgesic and antiinflammatory (AI) agents, and as potential selective cyclooxygenase‐2 (COX‐2) inhibitors. This group of compounds ( 10‐11 ) exhibited significant analgesic activity since 4% NaCl‐induced abdominal constriction was reduced by 44–73% at 30 min, and 48–77% at 60 min, post‐drug administration relative to the reference drugs aspirin and celecoxib (58 and 32% inhibition at 30 min post‐drug administration) for a 50 mg/kg intraperitoneal dose. In the 1,1‐dichloro group of compounds, a Cl or MeSO₂ substituent at the para‐position of the C‐2 phenyl ring generally provided superior analgesic activity. The most active analgesic compound, (E)‐1,1‐dichloro‐2‐(4‐methanesufonylphenyl)‐3‐phenylcyclopropane ( 11h ) inhibited abdominal constriction by 72 and 77% at 30 and 60 min post‐drug administration, respectively. AI activities, determined using the carrageenan‐induced rat paw edema assay, showed that this class of ( Z)‐10 and ( E)‐11 compounds exhibited AI activities in the inactive‐to‐moderate activity range (1.5–45% inhibition) for a 50 mg/kg oral dose. The AI potency order, with respect to the para‐substitutent on the C‐2 phenyl ring, for the ( Z)‐10 compounds was NO₂ > MeSO₂ ≈ H ≥ Cl, and for the ( E)‐11 compounds was H ≥ MeSO₂ > Cl ≈ Br. (E)‐1,1‐dibromo‐2‐(4‐methanesufonylphenyl)‐3‐phenylcyclopropane ( 11l ), which was the most active AI compound, reduced inflammation by 45 and 37% at 3 and 5 h post‐drug administration, respectively. The ( E)‐11 stereoisomer was generally a more potent AI agent than the corresponding ( Z)‐10 stereoisomer. In vitro COX‐1 and COX‐2 inhibition studies showed that (E)‐1,1‐dichloro‐2‐(4‐nitrophenyl)‐3‐phenylcyclopropane ( 11c ) inhibited COX‐1 (IC₅₀ = 278.8 μM) and COX‐2 (IC₅₀ = 80.5 μM) for a COX‐2 selectivity index of 3.5, whereas (E)‐1,1‐dichloro‐2‐(4‐methanesulfonylphenyl)‐3‐phenylcyclopropane ( 11h ) was a more potent inhibitor of COX‐1 and COX‐2, but it was more selective for COX‐1 (COX‐1 IC₅₀ = 0.59 μM, COX‐2 IC₅₀ = 3.04 μM). A molecular modeling (docking) study for (E)‐1,1‐dichloro‐2‐(4‐methanesulfonylphenyl)‐3‐phenylcyclopropane ( 11h ) on the active site of the human COX‐2 isozyme shows it binds in the center of the active site with the 1,1‐dichloro substituents oriented in the direction of the mouth of the channel towards Arg¹²⁰, and the C‐2 MeSO₂ moiety oriented towards the apex of the active site with the S‐atom of the MeSO₂ substituent positioned about 6.56 Å inside the entrance to the secondary pocket (Val⁵²³) of COX‐2. In contrast, the corresponding (Z)‐10h stereoisomer assumes a different position in the COX‐2 binding site where the S‐atom of the MeSO₂ moiety is near (4.02 Å) the Ser⁵³⁰ OH, but a much greater distance from the COX‐2 secondary pocket (Val⁵²³). The results from these docking studies are consistent with the observation that (E)‐11h is an inhibitor of both COX isozymes, whereas the (Z)‐10h stereoisomer is an inactive COX inhibitor (COX‐1 IC₅₀ > 100 μM, COX‐2 IC₅₀ > 200 μM). Drug Dev. Res. 55:79–90, 2002. © 2002 Wiley‐Liss, Inc.     

4‐Substituted‐1‐phenyl‐1H‐pyrazolo[3,4‐d]pyrimidine Derivatives: Design,Synthesis, Antitumor and EGFR Tyrosine Kinase Inhibitory Activity

Four series of some 4‐substituted‐1‐phenyl‐1H‐pyrazolo[3,4‐d]pyrimidine derivatives 5a – f , 6a – f , 8a – f , and 9a – f were designed to be screened for their antitumor activity. All compounds were evaluated against breast (MCF‐7) and lung (A‐549) cell lines. Six compounds 5a , 5b , 6b , 6e , 9e , and 9f displaying activity against both cell lines were further estimated for their EGFR‐TK inhibitory activity where they revealed 41–91% inhibition and compound 6b elicited the highest activity (91%). A docking study of these compounds into the ATP‐binding site of EGFR‐TK demonstrated their binding mode where H‐bonding interaction with Met793 through N¹ of pyrimidine or N² of pyrazole was observed.     

One pot multi‐component synthesis of functionalized spiropyridine and pyrido[2,3‐d]pyrimidine scaffolds and their potent in‐vitro anti‐inflammatory and anti‐oxidant investigations

A new series of functionalized fused pyridines 4(a–i) and fused pyrido[2,3‐d]pyrimidines 8(a–c) were designed and synthesized through a multi‐component reaction where in pyridine ring formation step plays a key role. All the newly formed compounds were well characterized by spectral techniques such as FTIR, ¹HNMR, ¹³CNMR, HRMS and XRD. The potential therapeutic activities such as anti‐inflammatory activity by protein denaturation and RBC membrane stabilization methods, and anti‐oxidant activity by DPPH scavenging method of the newly synthesized compounds were studied. Interestingly, in‐vitro testing of these compounds reveals that the compounds 4d , 4g , 4i , 8a and 8b showed comparable anti‐inflammatory activity with respect to the standard drug, diclofenac. Similarly, fused pyridine 4f showed excellent anti‐oxidant activity when compared with the standard, ascorbic acid.     

Synthesis,in‐vitro Antimicrobial and Cytotoxic Studies of Novel Azetidinone Derivatives

Developing novel antimicrobial drugs is increasingly important in the modern pharmaceutical industry. A series of novel 3‐chloro‐4‐[4‐(2‐oxo‐2H‐chromen‐4‐ylmethoxy)phenyl]‐1‐phenylazetidin‐2‐ones 5a–o have been synthesized from 4‐bromomethylcoumarins 1a–e and 4‐aryliminomethyl‐phenols 3a–c . These compounds were screened for their in‐vitro antibacterial activity against two Gram‐positive (Staphylococcus aureus and Vancomycin resistant enteroccoccus) and two Gram‐negative (Escherichia coli and Shigella dysentery) bacterial strains and antifungal activity against Aspergillus fumigatus, Candida albicans, and Penicillium. Results revealed that compounds 5c , 5f , 5h , 5j , and 5m showed excellent activity against a panel of microorganisms. The brine‐shrimp bioassay was also carried out to study their in‐vitro cytotoxic properties and two compounds, 5h and 5m , possessing LD₅₀ = 7.154×10^–4 M and 5.782×10^–4 M, respectively, displayed potent cytotoxic activity against Artemia salina. The presence of a chlorine group in the coumarin moiety, its effect on their antibacterial, antifungal, and cytotoxic activities is discussed. All newly synthesized compounds were characterized by elemental analysis, IR, ¹H‐NMR, ¹³C‐NMR, and MS.     

Synthesis,Evaluation of Pharmacological Activities and Quantitative Structure–Activity Relationship Studies of a Novel Group of bis(4‐Nitroaryl‐1,4‐dihyropyridine)

Voltage‐dependent calcium channels are crucial targets for a wide range of clinically active pharmacological agents. From these agents, 1,4‐dihydropyridines constitute a group of small organic compounds are based on a core pyridine structure which can both block and enhance calcium currents. They are considered specific for L‐Type calcium channels; however, other channel types, and in particular certain T‐Type channels, may show sensitivity to dihydropyridine compounds. In this study, we synthesized a novel group of bis‐1,4‐dihydropyridines using the procedure reported by Dagnino that involved the condensation of n‐alkyl diacetoacetate (n = 2–7) with methyl‐3‐aminocrotonate and nitrophenylaldehyde. The synthesis was run under two conditions: (i) reflux and (ii) microwave. Calcium channels antagonist activity were determined in vitro using guinea‐pig ileum longitudinal smooth muscle assay. Synthesis of these compounds was confirmed with 1H‐NMR, IR and mass spectrometry. Then IC₅₀ of them are calculated and compared with Nifedipine. Finally, the result of this pharmacological assay was used in quantitative structure–activity relationship studies utilizing multiple linear regression analysis. Most of these compounds are less active compared with Nifedipine. Decrease in activity is the result of increase in steric hindrance. The quantitative structure–activity relationship study indicates that the activity is related to the electrostatic and topological parameters and the distance between two C5‐esteric groups of 1,4‐dihydropyridine rings.