Synthesis,biological evaluation,and molecular docking studies of new pyrazol‐3‐one derivatives with aromatase inhibition activities

A new series derived from 4‐(2‐chloroacetyl)‐1,2‐dihydro‐1,5‐dimethyl‐2‐phenyl‐3H‐pyrazol‐3‐one was synthesized, characterized and its pharmacological activity toward aromatase enzyme inhibition was screened and compared to the reference native ligand letrozole. The most active compound of the series was 16 , showing IC₅₀ value of 0.0023 ± 0.0002 μm compared to letrozole with IC₅₀ of 0.0028 ± 0.0006 μm . In addition, compounds 26 and 36 exhibit good inhibition activities close to letrozole with IC₅₀ values 0.0033 ± 0.0001 and 0.0032 ± 0.0003 μm , respectively. Moreover, molecular docking studies were conducted to support the findings.     

Design and Synthesis of a New Class of 4‐Aminoquinolinyl‐ and 9‐Anilinoacridinyl Schiff Base Hydrazones as Potent Antimalarial Agents

A series of novel 4‐aminoquinolinyl and 9‐anilinoacridinyl Schiff base hydrazones have been synthesized and evaluated for their antimalarial activity. All compounds were evaluated in vitro for their antimalarial activity against chloroquine‐sensitive strain 3D7 and the chloroquine‐resistant K1 strain of Plasmodium falciparum and for cytotoxicity toward Vero cells. Compounds 17 , 20 , and 21 displayed good activity against the 3D7 strain with IC₅₀ values ranging from 19.69 to 25.38 nm . Moreover, compounds 16 , 17 , 21 , 24 , 32, and 33 exhibited excellent activities (21.64–54.26 nm ) against K1 strain and several compounds displayed β‐hematin inhibitory activity, suggesting that they act on the heme crystallization process such as CQ. Compounds were also found to be non‐toxic with good selectivity index.     

New Compounds Hybrids 1H‐1,2,3‐Triazole‐Quinoline Against Plasmodium falciparum

Malaria is one of the most prevalent parasitic diseases in the world. The global importance of this disease, current vector control limitations, and the absence of an effective vaccine make the use of therapeutic antimalarial drugs the main strategy to control malaria. Chloroquine is a cost‐effective antimalarial drug with a relatively robust safety profile, or therapeutic index. However, chloroquine is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of chloroquine‐resistant strains, which have also been reported for Plasmodium vivax. However, the activity of 1,2,3‐triazole derivatives against chloroquine‐sensitive and chloroquine‐resistant strains of P. falciparum has been reported in the literature. To enhance the anti‐P. falciparum activity of quinoline derivatives, we synthesized 11 new quinoline‐1H‐1,2,3‐triazole hybrids with different substituents in the 4‐positions of the 1H‐1,2,3‐triazole ring, which were assayed against the W2‐chloroquine‐resistant P. falciparum clone. Six compounds exhibited activity against the P. falciparum W2 clone, chloroquine‐resistant, with IC₅₀ values ranging from 1.4 to 46 μm . None of these compounds was toxic to a normal monkey kidney cell line, thus exhibiting good selectivity indexes, as high 351 for one compound ( 11 ).     

Piperazine‐linked 4‐aminoquinoline‐chalcone/ferrocenyl‐chalcone conjugates: Synthesis and antiplasmodial evaluation

A series of piperazine‐linked 4‐aminoquinoline‐chalcone/ferrocenyl‐chalcone conjugates were prepared with a view to evaluate their activities against Plasmodium falciparum. The synthesized conjugates had in vitro IC₅₀ values from 0.41 to 2.38 μm against chloroquine‐resistant and mefloquine‐sensitive W2 strain of P. falciparum. The submicromolar activities of most of the synthesized conjugates suggest that such molecular frameworks can act as therapeutic templates for the design and synthesis of new antimalarials.     

4‐Aminoquinoline‐Triazine‐Based Hybrids with Improved In Vitro Antimalarial Activity Against CQ‐Sensitive and CQ‐Resistant Strains of Plasmodium falciparum

A systematic chemical modification in the triazine moiety covalently attached via suitable linkers to 4‐amino‐7‐chloroquinolines yielded a series of new 7‐chloro‐4‐aminoquinoline‐triazine hybrids exhibiting high in vitro activity against W2 (chloroquine‐resistant) and D6 (chloroquine‐sensitive) strains of Plasmodium falciparum without any toxicity against mammalian cell lines (Vero, LLC‐PK11, HepG2). Many of the compounds ( 6, 8, 10, 11, 13, 14, 16, 27, 29 and 33 ) showed excellent potency against chloroquine sensitive and resistant strains. In particular, compounds 6, 8 , 14 , 16 and 29 were found to be significantly more active than chloroquine against the chloroquine‐resistant strains (W2 clone) of P. falciparum.     

Synthesis and Biological Evaluation of Heterocyclic Carboxylic Acyl Shikonin Derivatives

A series of shikonin derivatives ( 1 – 13 ) that were acylated selectively by various thiophene or indol carboxylic acids at the side chain of shikonin were synthesized, and their biological activities were also evaluated as potential tubulin inhibitors. Among them, compound 3 ((R)‐1‐(5,8‐dihydroxy‐1,4‐dioxo‐1,4‐dihydronaphthalen‐2‐yl)‐4‐methylpent‐3‐enyl 3‐(1H‐indol‐3‐yl)propanoate) and compound 8 ((R)‐1‐(5,8‐dihydroxy‐1,4‐dioxo‐1,4‐dihydronaphthalen‐2‐yl)‐4‐methylpent‐3‐enyl 2‐(thiophen‐3‐yl)acetate) exhibited good antiproliferative activity of A875 (IC₅₀ = 0.005 ± 0.001 μm , 0.009  ± 0.002 μm ) and HeLa (IC₅₀ = 11.84 ± 0.64 μm , 4.62  ± 0.31 μm ) cancer cell lines in vitro, respectively. Shikonin (IC₅₀ = 0.46 ± 0.002 μm , 4.80 ± 0.48 μm ) and colchicine (IC₅₀ = 0.75 ± 0.05 μm , 17.79 ± 0.76 μm ) were used as references. Meanwhile, they also showed the most potent growth inhibitory activity against tubulin (IC₅₀ of 3.96  ± 0.13 μm and 3.05 ± 0.30 μm , respectively), which were compared with shikonin (IC₅₀ =  15.20 ± 0.25 μm ) and colchicine (IC₅₀ = 3.50 ± 0.35 μm ). Furthermore, from the results of flow cytometer, we found compound 3 can really inhibit HeLa cell proliferation and has low cell toxicity. Based on the preliminary results, compound 3 with potent inhibitory activity in tumor growth may be a potential anticancer agent.     

7‐Chloroquinoline–isatin Conjugates: Antimalarial,Antitubercular, and Cytotoxic Evaluation

A series of twenty piperazine‐tethered 7‐chloroquinoline–isatin hybrids have been synthesized via either direct nucleophilic substitution or Cu(Ι)Cl‐mediated Mannich reaction. These new conjugates were evaluated for their antimalarial and antitubercular efficacy against a chloroquine‐resistant strain of Plasmodium falciparum and Mycobacterium tuberculosis, respectively, while the cytotoxic profiles were evaluated against 3T6 cell line, a permanent mouse embryonic fibroblast cell line. The most potent of the test compound with IC₅₀ of 0.22 μm against W2 strain of P. falciparum and 31.62 μm against the embryonic fibroblast cell line (cytotoxicity) displayed a high selective index of 143.73.     

Syntheses,Cholinesterases Inhibition,and Molecular Docking Studies of Pyrido[2,3‐b]pyrazine Derivatives

Cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), have a role in cholinergic deficit which evidently leads to Alzheimer's disease (AD). Inhibition of cholinesterases with small molecules is an attractive strategy in AD therapy. This study demonstrates synthesis of pyrido[2,3‐b]pyrazines ( 6a ‐ 6q ) series, their inhibitory activities against both cholinesterases, AChE and BChE, and molecular docking studies. The bioactivities data of pyrido[2,3‐b]pyrazines showed 3‐(3′‐nitrophenyl)pyrido[2,3‐b]pyrazine 6n a potent dual inhibitor among the series against both AChE and BChE with IC₅₀ values of 0.466 ± 0.121 and 1.89 ± 0.05 μm , respectively. The analogues 3‐(3′‐methylphenyl)pyrido[2,3‐b]pyrazine 6c and 3‐(3′‐fluorophenyl)pyrido[2,3‐b]pyrazine 6f were found to be selective inhibition for BChE with IC₅₀ values of 0.583 ± 0.052 μm and AChE with IC₅₀ value of 0.899 ± 0.10 μm , respectively. Molecular docking studies of the active compounds suggested the putative binding modes with cholinesterases. The potent compounds among the series could potentially serves as good leads for the development of new cholinesterase inhibitors.     

Synthesis and pharmacological evaluation of 2,3‐diphenyl acrylonitriles‐bearing halogen as selective anticancer agents

Eighteen novel 2,3‐diphenyl acrylonitrile derivatives bearing halogens were designed, synthesized, and evaluated for biological activity. Preliminary in vitro results indicated that the majority of the compounds with a para‐substituted halogen had considerable antiproliferative activity against five human cancer cell lines, including MGC‐803, AGS, and BEL‐7402, with IC₅₀ values in the range of 0.46–100 μm . No significant toxic effects on the non‐cancerous human liver cell line L‐02 were observed. The selective inhibitory activities against cancer cells were significantly better than that of the control lead compound CA‐4 and CA‐4P. Particularly, potent activities were found for the derivatives of 3‐(4‐halogen phenyl)‐2‐(3,4,5‐trimethoxyphenyl)acrylonitrile, such as 5c (4‐fluoro), 5f (4‐bromo), 5h (4‐chloro), and 5k (4‐trifluoro‐ methyl), for AGS with IC₅₀ values of 0.75 ± 0.24, 0.68 ± 0.21, 0.41 ± 0.05, and 1.49 ± 0.92 μm , respectively. The antiproliferative effects of 5f were attributed to cell‐cycle arrest in the G₂/M phase, induction of cellular apoptosis, suppression of cell migration, and inhibition of cell colony formation in AGS cells.     

Novel 1,3‐oxazine‐tetrazole hybrids as mushroom tyrosinase inhibitors and free radical scavengers: Synthesis,kinetic mechanism,and molecular docking studies

A variety of 5‐(2H‐tetrazol‐5‐yl)‐4‐thioxo‐2‐(substituted phenyl)‐4,5‐dihydro‐1,3‐oxazin‐6‐ones ( 3a–k ) have been synthesized from 1,3‐oxazine‐5‐carbonitriles ( 2a–k ). The protocol represents an efficient, facile, and novel route from easily available precursors to unprecedented structures that share 1,3‐oxazine and tetrazole motifs of utmost value. All the synthesized compounds ( 3a–k ) were evaluated for their inhibitory potential against mushroom tyrosinase. Results revealed that all examined 1,3‐oxazine‐tetrazole hybrids exhibited significant tyrosinase inhibitory activity while compound 3d having 2‐bromophenyl moiety was the most potent among the series with IC₅₀ value 0.0371 ± 0.0018 μM as compared to the reference kojic acid (IC₅₀ = 16.832 ± 0.73 μM). Inhibitory kinetics showed that compound 3d behaves as a competitive inhibitor. The molecular docking analysis was performed against target protein to investigate the binding mode. Moreover, compounds 3j and 3k displayed superior DPPH radical scavenging activity than other analogues.     

Design,synthesis and cytotoxic evaluation of nitric oxide‐releasing derivatives of isosteviol

Twenty‐six novel isosteviol derivatives coupled with two types of nitric oxide (NO) donors (furoxans and NONOates) were synthesized and screened for cytotoxic activities against four human cancer cell lines with sunitinib as the positive control. The results showed that seven furoxan‐based derivatives ( 8a , 8b , 8c , 8d , 8e , 9e , and 9f ) exhibited desirable cytotoxic activities, while NONOate‐based derivatives displayed poor potency because of unstability. Compared with sunitinib, compounds 8a and 8e were more active on all tested cell lines, especially in HCT116 ( 8a , IC₅₀ = 0.48 ± 0.02 μm ; 8e , IC₅₀ = 0.94 ± 0.01 μm ); compounds 8b and 8d were more potent on HCT116 (IC₅₀ = 3.39 ± 0.06 and 3.29 ± 0.03 μm ), HepG2 (IC₅₀ = 1.05 ± 0.03 and 5.37 ± 0.08 μm ), and SW620 (IC₅₀ = 1.33 ± 0.02 and 4.11 ± 0.05 μm ) cell lines, and 8c exhibited higher activities on HepG2 cells with an IC₅₀ = 4.76 ± 0.14 μm . NO‐releasing experiment of compounds 8a – e , 17a , 18a , 19a , and 21a reminded us that NO‐releasing amount of this series of isosteviol derivatives positively correlates with their cytotoxic activities.     

Design,Synthesis, and Biological Evaluation of 1‐(thiophen‐2‐yl)‐9H‐pyrido[3,4‐b]indole Derivatives as Anti‐HIV‐1 Agents

A novel series of 1‐(thiophen‐2‐yl)‐9H‐pyrido [3,4‐b]indole derivatives were synthesized using DL‐tryptophan as starting material. All the compounds were characterized by spectral analysis such as ¹H NMR, Mass, IR, elemental analysis and evaluated for inhibitory potency against HIV‐1 replication. Among the reported analogues, compound 7g exhibited significant anti‐HIV activity with EC₅₀ 0.53 μm and selectivity index 483; compounds 7e , 7i , and 7o displayed moderate activity with EC₅₀ 3.8, 3.8, and 2.8 μm and selectivity index >105, >105, and 3.85, respectively. Interestingly, compound 7g inhibited p24 antigen expression in acute HIV‐1_IIIB infected cell line C8166 with EC₅₀ 1.1 μm . In this study, we also reported the Lipinski rule of 5 parameters, predicted toxicity profile, drug‐likeness, and drug score of the synthesized analogues.     

Structure–activity relationship studies of benzyl‐, phenethyl‐, and pyridyl‐substituted tetrahydroacridin‐9‐amines as multitargeting agents to treat Alzheimer's disease

A library of substituted tetrahydroacridin‐9‐amine derivatives were designed, synthesized, and evaluated as dual cholinesterase and amyloid aggregation inhibitors. Compound 8e (N‐(3,4‐dimethoxybenzyl)‐1,2,3,4‐tetrahydroacridin‐9‐amine) was identified as a potent inhibitor of butyrylcholinesterase (BuChE IC₅₀ = 20 nm ; AChE IC₅₀ = 2.2 μm ) and was able to inhibit amyloid aggregation (40% inhibition at 25 μm ). Compounds 9e (6‐chloro‐N‐(3,4‐dimethoxybenzyl)‐1,2,3,4‐tetrahydroacridin‐9‐amine, AChE IC₅₀ = 0.8 μm ; BuChE IC₅₀ = 1.4 μm ; Aβ‐aggregation inhibition = 75.7% inhibition at 25 μm ) and 11b (6‐chloro‐N‐(3,4‐dimethoxyphenethyl)‐1,2,3,4‐tetrahydroacridin‐9‐amine, AChE IC₅₀ = 0.6 μm ; BuChE IC₅₀ = 1.9 μm ; Aβ‐aggregation inhibition = 85.9% inhibition at 25 μm ) were identified as the best compounds with dual cholinesterase and amyloid aggregation inhibition. The picolylamine‐substituted compound 12c (6‐chloro‐N‐(pyridin‐2‐ylmethyl)‐1,2,3,4‐tetrahydroacridin‐9‐amine) was the most potent AChE inhibitor (IC₅₀ = 90 nm ). These investigations demonstrate the utility of 3,4‐dimethoxyphenyl substituent as a novel pharmacophore possessing dual cholinesterase inhibition and anti‐Aβ‐aggregation properties that can be used in the design and development of small molecules with multitargeting ability to treat Alzheimer's disease.     

Discovery of Novel 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole Derivatives as Potential Anti‐Inflammatory Agents

A novel 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole derivative 5 with good anti‐inflammatory activity was identified from our in‐house library. Based on hit compound 5 , two series of 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole derivative 6a – g and 7a – h were designed and synthesized as novel anti‐inflammatory agents. Most of synthesized compounds exhibited good inhibitory activity on NO and TNF‐α production in LPS‐stimulated RAW 264.7 macrophages, in which the compound 6e showed most potent inhibitory activity on NO (IC₅₀ = 0.86 μm ) and TNF‐α (IC₅₀ = 1.87 μm ) production. Further evaluation revealed that compound 6e displayed more potent in vivo anti‐inflammatory activity than ibuprofen did on xylene‐induced ear oedema in mice. Additionally, Western blot analysis revealed that compound 6e could restore phosphorylation level of IκBα and protein expression of p65 NF‐κB in LPS‐stimulated RAW 264.7 macrophages.     

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.     

Discovery of novel pyrrolopyrimidine/pyrazolopyrimidine derivatives bearing 1,2,3‐triazole moiety as c‐Met kinase inhibitors

Six series of pyrrolo[2,3‐d]pyrimidine and pyrazolo[3,4‐d]pyrimidine derivatives bearing 1,2,3‐triazole moiety were designed and synthesized, and some bio‐evaluation was also carried out. As a result, four points can be summarized: Firstly, some of compounds exhibited excellent cytotoxicity activity and selectivity with the IC₅₀ values in single‐digit μm level. In particular, the most promising compound 16d showed equal activity to lead compound foretinib against A549, HepG2, and MCF‐7 cell lines, with the IC₅₀ values of 4.79 ± 0.82, 2.03 ± 0.39, and 2.90 ± 0.43 μm , respectively. Secondly, the SARs and docking studies indicated that the in vitro antitumor activity of pyrrolo[2,3‐d]pyrimidine derivatives bearing 1,2,3‐triazole moiety was superior to the pyrazolo[3,4‐d]pyrimidine derivatives bearing 1,2,3‐triazole moiety. Thirdly, three selected compounds ( 16d , 18d , and 20d ) were further evaluated for inhibitory activity against the c‐Met kinase, and the 16d could inhibit the c‐Met kinase selectively by experiments of enzyme‐based selectivity. What is more, 16d could induce apoptosis of HepG2 cells and inhibitor the cell cycle of HepG2 on G2/M phase by acridine orange staining and cell cycle experiments, respectively.     

Novel Selective Inhibitor of Leishmania (Leishmania) amazonensis Arginase

Arginase is a glycosomal enzyme in Leishmania that is involved in polyamine and trypanothione biosynthesis. The central role of arginase in Leishmania (Leishmania) amazonensis was demonstrated by the generation of two mutants: one with an arginase lacking the glycosomal addressing signal and one in which the arginase‐coding gene was knocked out. Both of these mutants exhibited decreased infectivity. Thus, arginase seems to be a potential drug target for Leishmania treatment. In an attempt to search for arginase inhibitors, 29 derivatives of the [1,2,4]triazolo[1,5‐a]pyrimidine system were tested against Leishmania (Leishmania) amazonensis arginase in vitro. The [1,2,4]triazolo[1,5‐a]pyrimidine scaffold containing R₁ = CF₃ exhibited greater activity against the arginase rather than when the substituent R₁ = CH₃ in the 2‐position. The novel compound 2‐(5‐methyl‐2‐(trifluoromethyl)‐[1,2,4]triazolo[1,5‐a]pyrimidin‐7‐yl)hydrazinecarbothioamide (30) was the most potent, inhibiting arginase by a non‐competitive mechanism, with the Ki and IC₅₀ values for arginase inhibition estimated to be 17 ± 1 μm and 16.5 ± 0.5 μm , respectively. These results can guide the development of new drugs against leishmaniasis based on [1,2,4]triazolo[1,5‐a]pyrimidine derivatives targeting the arginase enzyme.     

Synthesis of thiazolyl hydrazonothiazolamines and 1,3,4‐thiadiazinyl hydrazonothiazolamines as a class of antimalarial agents

Novel thiazolyl hydrazonothiazolamines and 1,3,4‐thiadiazinyl hydrazonothiazolamines were synthesized by a facile one‐pot multicomponent approach by the reaction of 2‐amino‐4‐methyl‐5‐acetylthiazole, thiosemicarbazide or thiocarbohydrazide and phenacyl bromides or 3‐(2‐bromoacetyl)‐2H‐chromen‐2‐ones in acetic acid with good to excellent yields. These new compounds were screened in vitro for their antimalarial activity; among them, four compounds, 4h, 4i, 4k, 4l , showed moderate activity with half‐maximal inhibitory concentration (IC₅₀) values of 3.2, 2.7, 2.7, and 2.8 and 3.2, 3.2, 3.1, and 3.5 μM against chloroquine‐sensitive and ‐resistant strains of Plasmodium falciparum, respectively. Compound 4l inhibited the ring stage growth of P. falciparum 3D7 at an IC₉₀ concentration of 12.5 µM in a stage‐specific assay method, where the culture is incubated with specific stages of P. falciparum for 12 hr, and no activity was found against the trophozoite and schizont stages, confirming that 4l may have potent action against the ring stage of P. falciparum.     

Synthesis and Biological Evaluation of Kojic Acid Derivatives Containing 1,2,4‐triazole as Potent Tyrosinase Inhibitors

A series of 5‐substituted‐3‐[5‐hydroxy‐4‐pyrone‐2‐yl‐methymercapto]‐4‐amino‐1,2,4‐triazole derivatives were synthesized by nucleophilic substitution reaction of 5‐hydroxy‐2‐chloromethyl ‐4H‐pyran‐4‐one with 5‐substituted‐3‐mercapto‐4‐amino‐1,2,4‐triazole, and their inhibitory effects on mushroom tyrosinase were evaluated. The results indicated that most of the synthesized compounds exhibited significant inhibitory activity. Specifically, 5‐(4‐chlorophenyl)‐3‐[5‐hydroxy‐4‐pyrone‐2‐yl‐methymercapto]‐4‐amino‐1,2,4‐triazole ( 6j ) exhibited the most potent tyrosinase inhibitory activity with IC₅₀ value of 4.50 ± 0.34 μm . The kinetic studies of the compound ( 6j ) demonstrated that the inhibitory effects of the compound on the tyrosinase were belonging to competitive inhibitors. Meanwhile, the structure–activity relationship was also discussed.     

Design,Synthesis and Biological Evaluation of Peptidyl Epoxyketone Proteasome Inhibitors Composed of β‐amino Acids

A series of novel di‐ and tripeptidyl epoxyketone derivatives composed of β‐amino acids were designed, synthesized and evaluated for their proteasome inhibitory activities and anti‐proliferation activities against two multiple myeloma cell lines RPMI 8226 and NCI‐H929 and normal cells (peripheral blood mononucleated cells). Among these tested compounds, tripeptidyl analogues showed much more potent activities than dipeptides, and four tripeptidyl compounds exhibited proteasome inhibitory activities with IC₅₀ values ranging from 0.97 ± 0.05 to 1.85 ± 0.11 μm . In addition, all the four compounds showed anti‐proliferation activities with IC₅₀ values at low micromolar levels against two multiple myeloma cell lines and weak activities against normal cells. Furthermore, Western blot analysis was performed to verify the proteasome inhibition induced by compounds 21d and 21e . All the experimental results validated that the β‐amino acid building block has the potential for the development of proteasome inhibitors.