Non‐peptide‐based new class of platelet aggregation inhibitors: Design,synthesis, bioevaluation,SAR, and in silico studies

A series of 2‐oxo‐2‐phenylethylidene linked 2‐oxo‐benzo[1,4]oxazine analogues 17a–x and 18a–o , incorporated with a variety of electron‐withdrawing as well as electron‐donating groups at ring A and ring C, were synthesized under greener conditions in excellent yields (up to 98%). These analogues 17a–x and 18a–o were evaluated for their arachidonic acid (AA)‐induced platelet aggregation inhibitory activities in comparison with the standard reference aspirin (IC₅₀ = 21.34 ± 1.09 µg/mL). Among all the screened compounds, eight analogues, 17i , 17x , 18f , 18g , 18h , 18i , 18l , and 18o , were identified as promising platelet aggregation inhibitors as compared to aspirin. In addition, cytotoxic studies in 3T₃ fibroblast cell lines by MTT assay of the promising compounds ( 17i , 17x , 18f–18i , 18l , and 18o ) were also performed and the compounds were found to be non‐toxic in nature. Furthermore, the results on the AA‐induced platelet aggregation inhibitory activities of these compounds ( 17i , 17x , 18f–18i , 18l , and 18o ) were validated via in silico molecular docking simulation studies. To the best of our knowledge, this is the first report of the identification of non‐peptide‐based functionalized 2‐oxo‐benzo[1,4]oxazines as platelet aggregation inhibitors.

     

Synthesis,enzyme inhibitory kinetics,and computational studies of novel 1‐(2‐(4‐isobutylphenyl) propanoyl)‐3‐arylthioureas as Jack bean urease inhibitors

In this article, synthesis of a novel 1‐(2‐(4‐isobutylphenyl)propanoyl)‐3‐arylthioureas ( 4a–j) as jack bean urease inhibitors has been described. Freshly prepared 2‐(4‐isobutylphenyl) propanoyl isothiocyanate was treated with substituted aromatic anilines in one pot using anhydrous acetone. The compounds 4e, 4h, and 4j showed IC₅₀ values 0.0086 nm , 0.0081 nm , and 0.0094 nm , respectively. The enzyme inhibitory kinetics results showed that compound 4h inhibit the enzyme competitively while derivatives 4e and 4j are the mixed type inhibitors. The compound 4h reversibly binds the urease enzyme showing Ki value 0.0012 nm . The Ki values for 4e and 4j are 0.0025 nm and 0.003 nm , respectively. The antioxidant activity results reflected that compounds 4b, 4i, and 4j showed excellent radical scavenging activity. Moreover, the cytotoxic activity of the target compounds was evaluated using brine shrimp assay and it was found that all of the synthesized compounds exhibited no cytotoxic effects to brine shrimps. The computational molecular docking and molecular dynamic simulation of title compounds were also performed, and results showed that the wet laboratory findings are in good agreement to the dry laboratory results. Based upon our results, it is proposed that compound 4h may act as a lead candidate to design the clinically useful urease inhibitors.     

A Facile One‐Pot Synthesis of 2‐Arylamino‐5‐Aryloxylalkyl‐1,3,4‐Oxadiazoles and Their Urease Inhibition Studies

A one‐pot method for the synthesis of structural type urease inhibitors, 2‐amino‐1,3,4‐oxadiazoles, was developed. The structures of the compounds were established using spectroanalytical techniques and unambiguously confirmed by single‐crystal X‐ray analysis of compound 3o . The synthesized compounds were tested against jack beans urease, and most of the compounds ( 3c , 3g , 3j , 3k , 3n , 3r – 3v ) were found more active than the standard. The most potent compound ( 3u ) had an IC₅₀ value of 6.03 ± 0.02 μm as compared to the IC₅₀ value of the standard (thiourea; 22.0 ± 1.2 μm ). The prominent urease inhibition activity of these compounds may serve as an important finding in the development of less toxic and more potent antiulcer drugs. The compounds were also investigated against four bacterial strains, and some of the compounds ( 3g and 3r ) were found more potent than the standard drug (ciprofloxacin) against all the tested strains. The MIC value for compound 3g was 0.156 μmol/mL against the tested bacterial strains.     

An expedient synthesis of N‐(1‐(5‐mercapto‐4‐((substituted benzylidene)amino)‐4H‐1,2,4‐triazol‐3‐yl)‐2‐phenylethyl)benzamides as jack bean urease inhibitors and free radical scavengers: Kinetic mechanism and molecular docking studies

In this study, some new azomethine‐triazole hybrids 5a–5l derived from N‐benzoyl‐L‐phenylalanine were synthesized and characterized. The synthesized compounds showed first‐rate, urease inhibition, and compounds 5c and 5e were found to be most effective inhibitors with 0.0137 ± 0.00082 μm and 0.0183 ± 0.00068 μm , respectively (thiourea 15.151 ± 1.27 μm ). The kinetic mechanism of urease inhibition revealed the compounds 5c and 5e to be non‐competitive inhibitors, whereas compounds 5d and 5j were found to be of mixed‐type inhibitors. Docking studies also indicated better interaction patterns with urease enzyme. The results of enzyme inhibition, kinetic mechanism and molecular docking suggest that these compounds can serve as lead compounds in the design of more effective urease inhibitors.     

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 of labeled BCX‐4208, a potent inhibitor of purine nucleoside phosphorylase

BCX‐4208, a novel inhibitor of the enzyme purine nucleoside phosphorylase, mimics the charged ribosyl oxocarbenium ion formed during the transition state of the enzyme‐catalyzed C‐N bond cleavage of nucleosides. A slow‐onset, tight‐binding inhibitor with a of 16 ± 1.4 pM, BCX‐4208 is one of the most potent inhibitors known for the enzyme. In support of our BCX‐4208 clinical program, a mass spectrometric assay has been developed that required labeled BCX‐4208 as an internal standard. The synthesis of [²H]₂‐BCX‐4208 and [¹³C]‐BCX‐4208 is described in this report. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis and biological evaluation of a lipophilic,fluorine‐18‐labeled 5‐ethynyl‐2′‐deoxyuridine derivative

The synthesis and preliminary biological evaluation of a lipophilic, fluorine‐18‐labeled 5‐ethynyl‐2′‐deoxyuridine derivative [¹⁸F]‐ 3 is described. Initially, 5‐ethynyl‐2′‐deoxyuridine 5 was synthesized by coupling trimethylsilyl protected acetylene to 5‐iodo‐2′‐deoxyuridine 4 , followed by deprotection in alkaline conditions. Compound 5 was then reacted with 4‐(4′‐iodophenyl)phenol to give 5‐[4(4′‐hydroxyphenyl)phenyl]ethynyl‐2′‐deoxyuridine 6 . Compound 6 was reacted with BrCH₂CHF as alkylating agent to give stable or radiolabeled 3 . The crude products were purified using reversed phase‐high performance liquid chromatography to obtain compound 3 and [¹⁸F]‐ 3 in 33 and 7.4% yield (decay corrected), respectively. The synthesis time to obtain pure [¹⁸F]‐ 3 was about 60 min (starting from BrCH₂CHF). The specific radioactivity of the tracer was between 74 and 222 GBq/µmol. The log P_7.4 of [¹⁸F]‐ 3 was found to be 2.4. However, biodistribution study in normal mice showed low uptake of the tracer in the brain. The affinity of compounds 6 and 3 for varicella‐zoster virus thymidine kinase enzyme (VZV‐TK) was examined in vitro and the results revealed that the fluorinated analog 3 has a poor affinity for the enzyme in contrast to the phenol precursor 6 . Copyright © 2007 John Wiley & Sons, Ltd.     

Design,synthesis, and molecular docking study of 3H‐imidazole[4,5‐c]pyridine derivatives as CDK2 inhibitors

A novel series of imidazo[4,5‐c]pyridine‐based CDK2 inhibitors were designed from the structure of CYC202 via scaffold hopping strategy. These compounds were synthesized and biologically evaluated for their CDK2 inhibitory and in vitro anti‐proliferation potential against cancer cell lines. Several compounds exhibited potent CDK2 inhibition with IC₅₀ values of less than 1 µM. The most potent compound 5b showed excellent CDK2 inhibitory (IC₅₀ = 21 nM) and in vitro anti‐proliferation activity against three different cell lines (HL60, A549, and HCT116). The molecular docking and dynamic studies portrayed the potential binding mechanism between 5b and CDK2, and several key interactions between them were observed, which would be the reason for its potent CDK2 inhibitory and anti‐proliferation activities. Therefore, the pyridin‐3‐ylmethyl moiety would serve as an excellent pharmacophore for the development of novel CDK2 inhibitors for targeted anti‐cancer therapy.

     

Selectivity of antagonists for the Cys‐loop native receptors for ACh, 5‐HT and GABA in guinea‐pig myenteric neurons

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Synthesis,p38α MAP kinase inhibition,anti‐inflammatory activity,and molecular docking studies of 1,2,4‐triazole‐based benzothiazole‐2‐amines

Recent studies have demonstrated that inhibition of p38α MAP kinase could effectively inhibit pro‐inflammatory cytokines including TNF‐α and interleukins. Thus, inhibition of this enzyme can prove greatly beneficial in the therapy of chronic inflammatory diseases. A new series of N‐[3‐(substituted‐4H‐1,2,4‐triazol‐4‐yl)]‐benzo[d]thiazol‐2‐amines ( 4a–n ) were synthesized and subjected to in vitro evaluation for anti‐inflammatory activity (BSA anti‐denaturation assay) and p38α MAPK inhibition. Among the compounds selected for in vivo screening of anti‐inflammatory activity ( 4b , 4c , 4f , 4g , 4j , 4m , and 4n ), compound 4f was found to be the most active with an in vivo anti‐inflammatory efficacy of 85.31% when compared to diclofenac sodium (83.68%). It was also found to have a low ulcerogenic risk and a protective effect on lipid peroxidation. The p38α MAP kinase inhibition of this compound (IC₅₀ = 0.036 ± 0.12 μM) was also found to be superior to the standard SB203580 (IC₅₀ = 0.043 ± 0.27 μM). Furthermore, the in silico binding mode of the compound on docking against p38α MAP kinase exemplified stronger interactions than those of SB203580.

     

Iminothiazoline‐Sulfonamide Hybrids as Jack Bean Urease Inhibitors; Synthesis,Kinetic Mechanism and Computational Molecular Modeling

The present work reports the synthesis of several 2‐iminothiazoline derivatives of sulfanilamide ( 3a – j ) as inhibitors of jack bean ureases. The title compounds were synthesized by the heterocyclization of sulfanilamide thioureas with propragyl bromide in dry ethanol in the presence of 1,8‐Diazabicyclo[5.4.0]undec‐7‐ene as a base. All of the compounds showed higher urease inhibitory activity than the standard thiourea. The compounds ( 3h ) and ( 3i ) exhibited excellent enzyme inhibitory activity with IC₅₀ 0.064 and 0.058 μ m , respectively, while IC₅₀ of thiourea is 20.9 μ m . The kinetic mechanism analyzed by Dixon plot showed that compound ( 3h ) is a mixed‐type inhibitor while ( 3i ) is a competitive one. Docking studies suggested that Asp633, Ala636, His492, Ala440, Lue523, Asp494 and Arg439 are the major interacting residues in the binding site of the protein and may have an instrumental role in the inhibition of enzyme's function. 2‐iminothiazoline analogues ( 3a – j ) showed good docking score (?10.6466 to ?8.7215 Kcal/mol) and binding energy (London dG ranging from ?14.4825 to ?10.4087 Kcal/mol) which is far better than the standard thiourea (binding score in S field ?4.5790 Kcal/mol London dG ?4.7726 Kcal/mol). Our results inferred compound ( 3i ) may serve as a structural model for the design of most potent urease inhibitors.     

Design,synthesis, and biological evaluation of 5‐(4‐(pyridin‐4‐yl)‐1H‐1,2,3‐triazol‐1‐yl)benzonitrile derivatives as xanthine oxidase inhibitors

A series of 5‐(4‐(pyridin‐4‐yl)‐1H‐1,2,3‐triazol‐1‐yl)benzonitrile derivatives ( 1a–p ) was designed, synthesized, and identified as xanthine oxidase inhibitors with micromolar level potencies. Among them, the most promising compounds 1j and 1k were obtained with IC₅₀ values of 8.1 and 6.7 μm , respectively. The Lineweaver–Burk plot revealed that compound 1k acted as a mixed‐type xanthine oxidase inhibitor. SAR analysis revealed that a carbon atom occupying the X³ position is not as effective as a nitrogen atom, and an iso‐pentyloxy or a cyclopentyloxy at the 2‐position of benzonitrile moiety will benefit the inhibitory potency. The basis of xanthine oxidase inhibition by 1k was rationalized by molecular modeling studies.     

Synthesis and in vitro activities of new non‐peptidic APA Inhibitors

Abstract: Aminopeptidase A (APA) is involved in the maturation of angiotensin III, a peptide which seems to be implicated in blood pressure regulation at the brain level. Therefore APA inhibitors are potential new antihypertensive agents with possible novel applications. With the aim of enhancing the bioavailability and potency of EC 33, the APA inhibitor (Ki = 300 nm ) initially used in the earlier studies, we have synthesized new non‐peptidic inhibitors able to interact with the S₁ and S subsites of the targeted enzyme. Compound 10a , (3S,4S)‐3‐amino‐4‐mercapto‐6‐phenyl‐hexane‐1‐sulfonic acid was obtained using an asymmetric synthesis. Inhibitor 10a exhibits a Ki value of 30 nm .     

Design,synthesis, and biological evaluation of novel 1,2‐diaryl‐4‐substituted‐benzylidene‐5(4H)‐imidazolone derivatives as cytotoxic agents and COX‐2/LOX inhibitors

A new series of 1,2‐diaryl‐4‐substituted‐benzylidene‐5(4H)‐imidazolone derivatives 4a–l was synthesized. Their structures were confirmed by different spectroscopic techniques (IR, ¹H NMR, DEPT‐Q NMR, and mass spectroscopy) and elemental analyses. Their cytotoxic activities in vitro were evaluated against breast, ovarian, and liver cancer cell lines and also normal human skin fibroblasts. Cyclooxygenase (COX)‐1, COX‐2 and lipoxygenase (LOX) inhibitory activities were measured. The synthesized compounds showed selectivity toward COX‐2 rather than COX‐1, and the IC₅₀ values (0.25–1.7 µM) were lower than that of indomethacin (IC₅₀ = 9.47 µM) and somewhat higher than that of celecoxib (IC₅₀ = 0.071 µM). The selectivity index for COX‐2 of the oxazole derivative 4e (SI = 3.67) was nearly equal to that of celecoxib (SI = 3.66). For the LOX inhibitory activity, the new compounds showed IC₅₀ values of 0.02–74.03 µM, while the IC₅₀ of the reference zileuton was 0.83 µM. The most active compound 4c (4‐chlorobenzoxazole derivative) was found to have dual COX‐2/LOX activity. All the synthesized compounds were docked inside the active site of the COX‐2 and LOX enzymes. They linked to COX‐2 through the N atom of the azole scaffold, while C?O of the oxazolone moiety was responsible for the binding to amino acids inside the LOX active site.

     

Design,synthesis, and evaluation of new α‐aminonitrile‐based benzimidazole biomolecules as potent antimicrobial and antitubercular agents

The study explores the one‐pot synthesis of novel α‐aminonitriles by reacting 4‐[(1H‐benzimidazol‐2‐yl)methoxy]benzaldehyde, substituted anilines and sodium cyanide using a catalytic amount of copper dipyridine dichloride (CuPy₂Cl₂) and employing the Strecker reaction under mild conditions. All the synthesized compounds were screened for antimicrobial and antitubercular activity. The promising lead compounds 4d and 4e were identified, with MIC values ranging between 3.9 and 7.8 µg/mL against different bacterial strains. Compounds 4c–e and 4g also showed good antifungal activities against the tested fungal strain. Among those tested, compound 4e exhibited excellent antitubercular activity (MIC 0.05 μg/mL) with a low level of cytotoxicity, suggesting that compound 4e is a promising lead for subsequent investigations in search for new antitubercular agents.

     

Channel‐forming,self‐assembling,bishelical amphiphilic peptides: design,synthesis and crystal structure of Py(Aibn)2, n = 2, 3, 4

Abstract: The design, synthesis, characterization and self‐assembling properties of a new class of amphiphilic peptides, constructed from a bifunctional polar core attached to totally hydrophobic arms, are presented. The first series of this class, represented by the general structure Py(Aib_n)₂ (Py = 2,6‐pyridine dicarbonyl unit; Aib = α, α′‐dimethyl glycine; n = 1–4), is prepared in a single step by the condensation of commercially available 2,6‐pyridine dicarbonyl dichloride with the methyl ester of homo oligoAib peptide (Aib_n‐OMe) in the presence of triethyl amine. ¹H NMR VT and ROESY studies indicated the presence of a common structural feature of 2‐fold symmetry and an NH…N hydrogen bond for all the members. Whereas the Aib3 segment in Py(Aib3)₂ showed only the onset of a 3₁₀‐helical structure, the presence of a well‐formed 3₁₀‐helix in both Aib4 arms of Py(Aib4)₂ was evident in the ¹H NMR of the bispeptide. X‐ray crystallographic studies have shown that in the solid state, whereas Py(Aib2)₂ molecules organize into a sheet‐like structure and Py(Aib3)₂ molecules form a double‐stranded string assembly, the tetra Aib bispeptide, Py(Aib4)₂, is organized to form a tetrameric assembly which in turn extends into a continuous channel‐like structure. The channel is totally hydrophobic in the interior and can selectively encapsulate lipophilic ester (CH₃COOR, R = C₂H₅, C₅H₁₁) molecules, as shown by the crystal structures of the encapsulating channel. The crystal structure parameters are: 1b , Py(Aib2)₂, C₂₅H₃₇N₅O₈, sp. gr. P2₁2₁2₁, a = 9.170(1) Å, b = 16.215(2) Å, c = 20.091(3) Å, R = 4.80; 1c , Py(Aib3)₂, C₃₃H₅₁N₇O₁₀·H₂O, sp. gr. P, a = 11.040(1) Å, b = 12.367(1) Å, c = 16.959(1) Å, α = 102.41°, β = 97.29°, γ = 110.83°, R₁ = 6.94; 1 da, Py(Aib4)₂?et ac, C₄₁H₆₅N₉O₁₂?1.5H₂O·C₄H₈O₂, sp. gr. P, a = 16.064(4) Å, b = 16.156 Å, c = 21.655(5) Å, α = 90.14(1)°, β = 101.38(2)°, γ = 97.07(1)°, Z = 4, R₁ = 9.03; 1db, Py(Aib4)₂?amylac,C₄₁H₆₅N₉O₁₂?H₂O ·C₇H₁₄O₂, P2₁/c, a = 16.890(1) Å, b = 17.523(1) Å, c = 20.411(1) Å, β = 98.18 °, Z = 4, R = 11.1 (with disorder).     

Cis/trans conformational equilibrium across the N‐methylphenylalanine2‐ N‐methylphenylalanine3 peptide bond of arginine vasopressin analogs

Abstract: Two cyclic analogs of vasopressin, ‐Pro‐Arg‐Gly‐NH₂ ( 1 ) and ‐Pro‐Arg‐Gly‐NH₂ ( 2 ) were synthesized by the solid phase method. Their structure was determined in aqueous solution by two‐dimensional NMR techniques and simulated annealing algorithm from an extended template in X‐PLOR. The total chemical shift correlation spectroscopy and rotating‐frame Overhauser enhancement spectroscopy of the peptides displayed four distinct sets of residual proton resonances. This suggests that both analogs adopt four families of conformations in H₂O/D₂O (9 : 1) (one major and three minor species). In further analysis only signals of major species (M) and of one minor species (m₁) were considered. The major species of both peptides include a trans peptide bond between the first and second residue, and a cis form between the second and third residue. In the minor species, all peptide bonds were found to exist in trans geometry.