Synthesis and anti‐coronavirus activity of a series of 1‐thia‐4‐azaspiro[4.5]decan‐3‐one derivatives

A series of 1‐thia‐4‐azaspiro[4.5]decan‐3‐ones bearing an amide group at C‐4 and various substitutions at C‐2 and C‐8 were synthesized and evaluated against human coronavirus and influenza virus. Compounds 7m , 7n , 8k , 8l , 8m , 8n , and 8p were found to inhibit human coronavirus 229E replication. The most active compound was N‐(2‐methyl‐8‐tert‐butyl‐3‐oxo‐1‐thia‐4‐azaspiro[4.5]decan‐4‐yl)‐3‐phenylpropanamide ( 8n ), with an EC₅₀ value of 5.5 µM, comparable to the known coronavirus inhibitor, (Z)‐N‐[3‐[4‐(4‐bromophenyl)‐4‐hydroxypiperidin‐1‐yl]‐3‐oxo‐1‐phenylprop‐1‐en‐2‐yl]benzamide ( K22 ). Compound 8n and structural analogs were devoid of anti‐influenza virus activity, although their scaffold is shared with a previously discovered class of H3 hemagglutinin‐specific influenza virus fusion inhibitors. These findings point to the 1‐thia‐4‐azaspiro[4.5]decan‐3‐one scaffold as a versatile chemical structure with high relevance for antiviral drug development.     

Design,Synthesis, and Biological Evaluation of 1,5‐Diaryl‐1,2,4‐triazole Derivatives as Selective Cyclooxygenase‐2 Inhibitors

A series of 1,5‐diaryl‐1,2,4‐triazole derivatives were synthesized and evaluated as cyclooxygenase‐2 (COX‐2) inhibitors. The results of the preliminary biological assays in vivo showed that eight compounds 5b , 6b , 6c , 7c , 8b , 8d , 9c , and 9d have potent anti‐inflammatory activity (P < 0.01), while compounds 6b , 6c , and 9c exhibit marked potency. Compound 6c was then selected for further investigation. In the COX inhibition assay in vitro, compound 6c was identified as a potent and selective inhibitor of COX‐2 (COX‐2 IC₅₀ = 0.37 µM; SI = 0.018), being equipotent to celecoxib (COX‐2 IC₅₀ = 0.26 µM; SI = 0.015). In a rat carrageenan‐induced paw edema assay, 6c exhibited moderate anti‐inflammatory activity (35% inhibition of inflammation) at 2 h after administration of 15 mg/kg as an oral dose. A docking study also revealed that compound 6c binds in the active site of COX‐2 in a similar mode to that of the known selective COX‐2 inhibitor SC‐558.     

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.     

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.

     

Synthesis and Antitubercular Activity Evaluation of Novel Unsymmetrical Cyclohexane‐1,2‐diamine Derivatives

A library of unsymmetrical cyclohexane‐1,2‐diamine derivatives were synthesized and evaluated for their activity against Mycobacterium tuberculosis H37Rv in vitro. Out of the 46 compounds synthesized, eight compounds ( 11h , 13a , 13e , 13f , 14a , 14c , 14d , and 15d ) were found to be active at or below 6.25 µM concentration, with negligible toxicity to human red blood cells at a concentration much higher than the MIC₉₉. Compound 13a was the best active compound showing inhibition at 3.125–6.25 µM, and was found to be non‐hemolytic up to 500 µg/mL concentration.     

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).     

Synthesis and calcium channel modulation effects of isopropyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐phenylpyridine‐5‐carboxylates possessing ortho‐, meta‐, and para‐CH2S(O)nMe and –S(O)nMe (n = 0–2) phenyl substituents

A group of isopropyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐phenylpyridine‐5‐carboxylates ( 13–15 ) possessing ortho‐, meta‐, and para‐CH₂S(O)nMe and –S(O)nMe (n = 0–2) phenyl substituents were synthesized using a modified Hantzsch reaction. Calcium channel (CC) modulating activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) in vitro assays. This class of –CH₂S(O)nMe and –S(O)nMe (n = 0–2) compounds ( 13–15a–f ) exhibited weaker CC antagonist activity on GPILSM (IC₅₀ = > 1.1 × 10^–5 to 4.1 × 10^–6 M range) than the reference drug nifedipine (IC₅₀ = 1.4 × 10^–8 M). The oxidation state of the sulfur atom was a determinant of smooth muscle CC antagonist activity where the relative activity profile was generally thio ( 13 , ‐CH₂SMe, ‐SMe) and sulfonyl ( 15 , ‐CH₂SO₂Me, ‐SO₂Me) > sulfinyl ( 14 , ‐CH₂SOMe, ‐SOMe). The point of attachment of the phenyl substituent was a determinant of activity for the –CH₂SMe ( 13a–c ), ‐CH₂SOMe ( 14a–c ) and SOMe ( 14d–f ) isomers where the relative potency order was meta and para > ortho. Compounds in this group ( 13–15 ), unlike Bay K 8644 (EC₅₀ = 2.3 × 10^–7 M on GPILSM), did not exhibit an agonist effect on GPILSM. The meta‐CH₂SMe ( 13b ), ortho‐CH₂SMe ( 13c ), meta‐SMe ( 13e ), and ortho‐CH₂SO₂Me ( 15c ) C‐4 phenyl derivatives exhibited respectable in vitro cardiac positive inotropic activities (EC₅₀ = 1.00 × 10^–6 to 7.57 × 10^–6 M range) relative to the reference drug Bay K 8644 (EC₅₀ = 7.70 × 10^–7 M) in the GPLA assay. In contrast to Bay K 8644, which acts as an undesirable calcium channel agonist on smooth muscle (GPILSM), compounds 13b (IC₅₀ = 4.11 × 10^–6 M), 13c (IC₅₀ = 2.29 × 10^–5 M), 13e (IC₅₀ = > 1.20 × 10^–5 M) and 15c (IC₅₀ = 6.22 × 10^–6 M) exhibited a desirable simultaneous calcium channel antagonist effect on smooth muscle at a similar ( 13b , 15c ), or lower ( 13c , 13e ), concentration relative to its cardiac agonist EC₅₀ value. Model compounds such as 13b , 13c , 13e , and 15c , that exhibit dual cardioselective agonist / smooth muscle selective antagonist activities, represent a novel type of 1,4‐dihydropyridine CC modulators that offer a potential approach to drug discovery targeted toward the treatment of congestive heart failure and for use as probes to study the structure–function relationship of calcium channels. Drug Dev. Res. 51:177–186, 2000. © 2001 Wiley‐Liss, Inc.     

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,molecular docking studies,and biological evaluation of novel alkyl bis(4‐amino‐5‐cyanopyrimidine) derivatives

A series of bis(4‐amino‐5‐cyano‐pyrimidines) was synthesized and evaluated as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). To further explore the multifunctional properties of the new derivatives, their antioxidant and antibacterial activities were also tested. The results showed that most of these compounds could effectively inhibit AChE and BChE. Particularly, compound 7c exhibited the best AChE inhibitory activity (IC₅₀ = 5.72 ± 1.53 μM), whereas compound 7h was identified as the most potent BChE inhibitor (IC₅₀ = 12.19 ± 0.57 μM). Molecular modeling study revealed that compounds 7c, 7f , and 7b showed a higher inhibitory activity than that of galantamine against both AChE and BChE. Anticholinesterase activity of compounds 7h, 7b , and 7c was significant in vitro and in silico for both enzymes, since these compounds have hydrophobic rings (Br‐phenyl, dimethyl, and methoxyphenyl), which bind very well in both sites. In addition to cholinesterase inhibitory activities, these compounds showed different levels of antioxidant activities. Indeed, in the superoxide–dimethyl sulfoxide alkaline assay, compound 7j showed very high inhibition (IC₅₀ = 0.37 ± 0.28 μM). Also, compound 7l exhibited strong and good antibacterial activity against Staphylococcus epidermidis and Staphylococcus aureus, respectively. Taking into account the results of biological evaluation, further modifications will be designed to increase potency on different targets. In this study, the obtained results can be a new starting point for further development of multifunctional agents for the treatment of Alzheimer's disease.     

Design and synthesis of 4′‐((5‐benzylidene‐2,4‐dioxothiazolidin‐3‐yl)methyl)biphenyl‐2‐carbonitrile analogs as bacterial peptide deformylase inhibitors

Herein, we report the synthesis and screening of 4′‐((5‐benzylidene‐2,4‐dioxothiazolidin‐3‐yl)methyl)biphenyl‐2‐carbonitrile analogs 11(a–j) as bacterial peptide deformylase (PDF) enzyme inhibitors. The compounds 11b (IC₅₀ value = 139.28 μm ), 11g (IC₅₀ value = 136.18 μm ), and 11h (IC₅₀ value = 131.65 μm ) had shown good PDF inhibition activity. The compounds 11b (MIC range = 103.36–167.26 μg/mL), 11g (MIC range = 93.75–145.67 μg/mL), and 11h (MIC range = 63.61–126.63 μg/mL) had also shown potent antibacterial activity when compared with standard ampicillin (MIC range = 100.00–250.00 μg/mL). Thus, the active derivatives were not only PDF inhibitors but also efficient antibacterial agents. To gain more insight on the binding mode of the compounds with PDF enzyme, the synthesized compounds 11(a–j) were docked against PDF enzyme of Escherichia coli and compounds exhibited good binding properties. The results suggest that this class of compounds has potential for development and use in future as antibacterial drugs.     

Syntheses,calcium channel modulation effects,and nitric oxide release studies of O2‐alkyl‐1‐(pyrrolidin‐1‐yl) diazen‐1‐ium‐1,2‐diolate 4‐aryl(heteroaryl)‐1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxylates

A group of racemic 4‐aryl(heteroary)‐1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxy‐lates possessing a potential nitric oxide donor C‐5 O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester [alkyl=(CH₂)_n, n=1–4] substituent were synthesized using a modified Hantzsch reaction. Compounds having a C‐4 2‐trifluoromethylphenyl ( 16 ), 2‐pyridyl ( 17 ), or benzofurazan‐4‐yl ( 20 ) substituent generally exhibited more potent smooth‐muscle calcium channel antagonist activity (IC₅₀ values in the 0.55 to 38.6 μM range) than related analogs having a C‐4 3‐pyridyl ( 18 ), or 4‐pyridyl ( 19 ) substituent with IC₅₀ values > 29.91 μM, relative to the reference drug nifedipine (IC₅₀=0.0143 μM). The point of attachment of C‐4 isomeric pyridyl substituents was a determinant of antagonist activity where the relative potency profile was 2‐pyridyl > 3‐pyridyl and 4‐pyridyl. Subgroups of compounds 16a–d , 17a–d , and 20a–d having alkyl spacer groups of variable chain length [–CO₂(CH₂)_nO–, n=1–4] exhibited small differences in calcium channel antagonist potency. Replacement of the ester “methyl” moiety of Bay K 8644 by an O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate group provided the Bay K 8644 group of analogs 16a‐d that retained the desired cardiac positive inotropic effect. The most potent compound in this group, O²‐ethyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(2‐trifluoromethylphenyl)pyridine‐5‐carboxylate ( 16b , EC₅₀=0.096 μM) is about eightfold more potent positive inotrope (cardiac calcium channel agonist) than the reference compound Bay K 8644 (EC₅₀=0.77 μM). A similar replacement of the ester “isopropyl” group in the C‐4 benzofurazan‐4‐yl group of compounds by an O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester substituent provided compounds 20 (n=1 and 4) that were approximately equipotent cardiac positive inotropes with the parent reference compound PN 202‐791 ( 3 , EC₅₀=9.40 μM). The O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester moiety present in 1,4‐dihydropyridine calcium channel modulating compounds 16–20 is not a suitable ?NO donor moiety because the percent nitric oxide released upon in vitro incubation with either l ‐cysteine, rat serum, or pig liver esterase was less than 1%. Drug Dev. Res. 60:204–216, 2003. © 2003 Wiley‐Liss, Inc.     

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.     

Synthesis and mycobacterial evaluation of 5‐substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido‐[2,3‐d]pyrimidin‐4(3H)‐one derivatives

5‐Substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido[2,3‐d]pyrimidin‐4(3H)‐one derivatives were synthesized and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium aurum, Escherichia coli, and Staphylococcus aureus as well as a human monocyte‐derived macrophage (THP‐1), and murine macrophage (RAW 264.7) cell lines to assess their antibacterial and cytotoxic potential, respectively. The compounds showed activity in the range of 1.95–125 µg/ml against M. tuberculosis but showed no activity against M. aurum, E. coli, and S. aureus, indicating selectivity towards slow‐growing mycobacterial pathogens. The compounds exhibited very low to no cytotoxicity up to 500 µg/ml concentration against eukaryotic cell lines. The most potent molecule, 2l , showed a minimum inhibitory concentration of 1.95 µg/ml against M. tuberculosis H37Rv and a selectivity index of >250 against both the eukaryotic cell lines. Furthermore, 2l showed moderate inhibition of whole‐cell mycobacterial drug‐efflux pumps when compared to verapamil, a known potent inhibitor of efflux pumps. Thus, derivative 2l was identified as an antituberculosis hit molecule, which could be used to yield more potent lead molecules.     

2‐Pyridinyl‐4(3H)‐Quinazolinone: A Scaffold for Anti‐influenza A Virus Compounds

A series of 2‐pyridinyl‐3‐substituted‐4(3H)‐quinazolinones were synthesized, and their anti‐influenza A virus activities were determined using the cytopathic effect inhibition assay. Most of the compounds were potent with IC₅₀ values ranging from 51.6 to 93.0 μm , which are better than that of the currently marketed drug ribavirin. The molecular mechanisms of the new compounds were investigated using neuraminidase inhibition assay, cellular NF‐κB signaling pathway inhibition assay, and computational docking. Compound 4e , which is a N3 imidazol‐1‐ylpropyl‐substituted derivative of 2‐pyridinyl‐4(3H)‐quinazolinone, had the most potent anti‐influenza A virus activity in vitro, and inhibited both virus neuraminidase and cellular NF‐κB signaling pathway. In conclusion, 2‐pyridinyl‐4(3H)‐quinazolinone is a new scaffold for the design of potent anti‐influenza A virus compounds, offering an alternative approach to tackle influenza drug resistance.     

Synthesis of new arylazopyrazoles as apoptosis inducers: Candidates to inhibit proliferation of MCF‐7 cells

New 4‐arylazo‐3,5‐diamino‐1H‐pyrazole derivatives substituted in the 4‐aryl ring with the acetyl moiety were designed and synthesized. The antiproliferative activity of the novel arylazopyrazoles was examined against the MCF‐7 cell line. Among all target compounds, 8b (IC₅₀ 3.0 µM) and 8f (IC₅₀ 4.0 µM) displayed higher cytotoxicity as compared with the reference standard imatinib (IC₅₀ 7.0 µM). Further studies to explore the mechanism of action were performed on the most active hit of our library, 8b , via anti‐CDK2 kinase activity. It demonstrated good inhibitory effects for CDK2 (IC₅₀ 0.24 µM) with 62.5% inhibition, compared with imatinib. The cell cycle analysis in the MCF‐7 cell line revealed apoptosis induction by 8b and cell cycle arrest at the S phase. Docking in the CDK2 active site and pharmacophore modeling confirmed the affinity of 8b to the CDK2 active site. Absorption, distribution, metabolism, and excretion studies revealed that our target compounds are orally bioavailable, with no permeation through the blood–brain barrier.     

Design and synthesis of 1,2,4‐triazolo[1,5‐a]pyrimidine derivatives as PDE 4B inhibitors endowed with bronchodilator activity

A series of 1,2,4‐triazolo[1,5‐a]pyrimidine derivatives was designed, synthesized, and screened for their phosphodiesterase (PDE 4B) inhibitory activity and bronchodilation ability. Compound 7e showed 41.80% PDE 4B inhibition at 10 µM. Eight compounds were screened for their bronchodilator activity, where compounds 7f and 7e elicited promising bronchodilator activity with EC₅₀ values of 18.6 and 57.1 µM, respectively, compared to theophylline (EC₅₀ = 425 µM). Molecular docking at the PDE 4B active site revealed a binding mode and docking scores comparable to those of a reference ligand, consistent with their PDE 4B inhibition activity.     

Synthesis of 2‐(2‐oxo‐2H‐chromen‐4‐yl)acetamides as potent acetylcholinesterase inhibitors and molecular insights into binding interactions

Sixteen novel coumarin‐based compounds are reported as potent acetylcholinesterase (AChE) inhibitors. The most active compound in this series, 5a (IC₅₀ 0.04 ± 0.01 µM), noncompetitively inhibited AChE with a higher potency than tacrine and galantamine. Compounds 5d , 5j , and 5 m showed a moderate antilipid peroxidation activity. The compounds showed cytotoxicity in the same range as the standard drugs in HEK‐293 cells. Molecular docking demonstrated that 5a acted as a dual binding site inhibitor. The coumarin moiety occupied the peripheral anionic site and showed π‐π interaction with Trp278. The tertiary amino group displayed significant cation‐π interaction with Phe329. The aromatic group showed π‐π interaction with Trp83 at the catalytic anionic site. The long chain of methylene lay along the gorge interacting with Phe330 via hydrophobic interaction. Molecular docking was applied to postulate the selectivity toward AChE of 5a in comparison with donepezil and tacrine. Structural insights into the selectivity of the coumarin derivatives toward huAChE were explored by molecular docking and 3D QSAR and molecular dynamics simulation for 20 ns. ADMET analysis suggested that the 2‐(2‐oxo‐2H‐chromen‐4‐yl)acetamides showed a good pharmacokinetic profile and no hepatotoxicity. These coumarin derivatives showed high potential for further development as anti‐Alzheimer agents.     

Synthesis and evaluation as PDE4 inhibitors of pyrimidine‐2,4‐dione derivatives

A series of nitraquazone analogs with a pyrimidindione core was synthesized and tested for inhibitory activity on PDE4, selectivity versus PDE3 and PDE5 and for affinity towards the rolipram high‐affinity binding site (HARBS). The 5‐anilino derivatives 13–18 showed the best profile combining appreciable PDE4 inhibitory activity (IC₅₀ = 5–14 µM) with a good selectivity toward PDE3 and PDE5. The same compounds demonstrate low affinity for the HARBS site with IC₅₀ values of 12–69 µM (IC₅₀ for Rolipram = 3.6 nM). Drug Dev Res 72: 274–288, 2011. © 2010 Wiley‐Liss, Inc.     

Synthesis and calcium channel modulating effects of modified Hantzsch nitrooxyalkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(pyridinyl or 2‐trifluoromethylphenyl)‐5‐pyridinecarboxylates

A group of racemic nitrooxyalkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(pyridinyl or 2‐trifluoromethylphenyl)‐5‐pyridinecarboxylates 8a–o were synthesized using modified Hantzsch reactions. In vitro calcium channel antagonist activities, determined using a guinea pig ileum longitudinal smooth muscle (GPILSM) assay, showed that compounds 8a–o exhibited weaker calcium antagonist activity (10^–5 to 10^–7 M range) than the reference drug nifedipine (IC₅₀ = 1.43 × 10^–8 M). Compounds 8 possessing a C‐4 R¹ = 2‐pyridyl substituent were always more potent than the approximately equiactive analogs having an R¹ = 3‐pyridyl, 4‐pyridyl or 2‐CF₃‐C₆H₄‐substituent, within each subgroup of nitrooxyalkyl compounds [R² = – (CH₂)_nONO₂ (n = 2, 3, 4) or –CH(CH₂ONO₂)₂]. Although the length of the R² = –(CH₂)_nONO₂ substituent (n = 2–4) was not a determinant of smooth muscle calcium antagonist activity when the C‐4 R¹‐substituent was 2‐pyridyl, when R¹ was a 3‐pyridyl, 4‐pyridyl, or 2‐CF₃‐C₆H₄‐substituent, the relative potency order with respect to the R² = –(CH₂)_nONO₂ substituent was n = 3 and 4 > n = 2. Replacement of the isopropyl substituent of the ester moiety of the calcium antagonist (±)‐2‐pyridyl 3a by a –(CH₂)_nONO₂ (n = 2–4) moiety increased calcium antagonist activity on GPILSM by 8‐fold. In contrast, replacement of the isopropyl substituent of the ester moiety of the calcium agonists (±)‐3‐pyridyl 3b , (±)‐4‐pyridyl 3c or the methyl substituent of the ester moiety of Bay K8644 by a R² nitrooxyalkyl substituent resulted in abolition of their calcium agonist effects on GPILSM that is replaced by a smooth muscle calcium antagonist effect. These calcium antagonist data support the concept that incorporation of a nitrooxyalkyl ester substituent constitutes a valuable drug design strategy to enhance Hantzsch 1,4‐dihydropyridine calcium antagonist and/or abolish calcium agonist effects on smooth muscle. Replacement of the isopropyl ( 8b–c ), or the methyl ( 8d ) group by a –CH₂CH₂ONO₂ moiety resulted in retention of the cardiac positive inotropic effect where the relative potency order with respect to the C‐4 substituent was 2‐CF₃‐C₆H₆‐ (8d) > 3‐pyridyl (8b) ≈ 4‐pyridyl (8c). Model hybrid (calcium channel modulation, ·NO release) compounds, that exhibit dual cardioselective agonist / smooth muscle selective antagonist activities, represent a novel type of 1,4‐dihydropyridine CC modulator that offers a potential approach to drug discovery targeted toward the treatment of congestive heart failure and for use as probes to study the structure–function relationship of calcium channels. Drug Dev. Res. 51:225–232, 2000. © 2001 Wiley‐Liss, Inc.     

Benzoxazole/benzothiazole‐derived VEGFR‐2 inhibitors: Design,synthesis, molecular docking,and anticancer evaluations

A novel series of benzoxazole/benzothiazole derivatives 4a–c – 11a–e were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT‐116, and MCF‐7 cells. HCT‐116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 4c was found to be the most potent derivative against HepG2, HCT‐116, and MCF‐7 cells, with IC₅₀ values = 9.45 ± 0.8, 5.76 ± 0.4, and 7.36 ± 0.5 µM, respectively. Compounds 4b, 9f , and 9c showed the highest anticancer activities against HepG2 cells with IC₅₀ values of 9.97 ± 0.8, 9.99 ± 0.8, and 11.02 ± 1.0 µM, respectively, HCT‐116 cells with IC₅₀ values of 6.99 ± 0.5, 7.44 ± 0.4, and 8.15 ± 0.8 µM, respectively, and MCF‐7 cells with IC₅₀ values of 7.89 ± 0.7, 8.24 ± 0.7, and 9.32 ± 0.7 µM, respectively, in comparison with sorafenib as reference drug with IC₅₀ values of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively. The most active compounds 4a–c, 9b,c,e,f,h , and 11c,e were further evaluated for their VEGFR‐2 inhibition. Compounds 4c and 4b potently inhibited VEGFR‐2 at IC₅₀ values of 0.12 ± 0.01 and 0.13 ± 0.02 µM, respectively, which are nearly equipotent to the sorafenib IC₅₀ value (0.10 ± 0.02 µM). Furthermore, molecular docking studies were performed for all synthesized compounds to assess their binding pattern and affinity toward the VEGFR‐2 active site.