Synthesis,Cytotoxicity, and Pro‐Apoptosis Activity of Etodolac Hydrazide Derivatives as Anticancer Agents

Etodolac hydrazide and a novel series of etodolac hydrazide‐hydrazones 3 – 15 and etodolac 4‐thiazolidinones 16 – 26 were synthesized in this study. The structures of the new compounds were determined by spectral (FT‐IR, ¹H NMR, ¹³C NMR, HREI‐MS) methods. Some selected compounds were determined at one dose toward the full panel of 60 human cancer cell lines by the National Cancer Institute (NCI, Bethesda, USA). 2‐(1,8‐Diethyl‐1,3,4,9‐tetrahydropyrano[3,4‐b]indole‐1‐yl)acetic acid[(4‐chlorophenyl)methylene]hydrazide 9 demonstrated the most marked effect on the prostate cancer cell line PC‐3, with 58.24% growth inhibition at 10^?5 M (10 µM). Using the MTT colorimetric method, compound 9 was evaluated in vitro against the prostate cell line PC‐3 and the rat fibroblast cell line L‐929, for cell viability and growth inhibition at different doses. Compound 9 exhibited anticancer activity with an IC₅₀ value of 54 µM (22.842 µg/mL) against the PC‐3 cells and did not display any cytotoxicity toward the L‐929 rat fibroblasts, compared to etodolac. In addition, this compound was evaluated for caspase‐3 and Bcl‐2 activation in the apoptosis pathway, which plays a key role in the treatment of cancer.     

1H‐1,2,3‐Triazole tethered isatin‐moxifloxacin: Design,synthesis and in vitro anti‐mycobacterial evaluation

A series of novel 1H‐1,2,3‐triazole tethered isatin–moxifloxacin (MXF) hybrids 5a ‐ l with greater lipophilicity compared with the parent MXF were designed, synthesized and screened for their in vitro antimycobacterial activities against Mycobacterium tuberculosis (MTB) H₃₇Rv and multidrug‐resistant MTB (MDR–MTB) as well as their cytotoxicity on the VERO cell line. All the synthesized hybrids (MIC: 0.025‐0.78 μg/ml) showed considerable activities against MTB H₃₇Rv and MDR–MTB, and the most active conjugate 5c (MIC: 0.025 and 0.06 μg/ml) was 2 to >2048 times more potent in vitro than the three references MXF (MIC: 0.10 and 0.12 μg/ml), rifampicin (MIC: 0.39 and 32 μg/ml) and isoniazid (MIC: 0.05 and >128 μg/ml) against the two tested strains. All hybrids (CC₅₀: 4‐64 μg/ml) were much more cytotoxic than the parent MXF (CC50: 128 μg/ml), but the most active hybrid 5c (CC₅₀: 32 μg/ml) also displayed acceptable cytotoxicity, warranting further investigation.     

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.     

Study of the Cytotoxic and Bactericidal Effects of Sila‐substituted Thioalkyne and Mercapto‐thione Compounds based on 1,2,3‐Triazole Scaffold

A series of sila‐organosulphur compounds containing 1,2,3‐triazole cores were screened for their cytotoxic activity on human breast cancer cell line MCF‐7. Most of the tested compounds exhibited moderate‐to‐good activity against the cancer cells. Especially, the compound 4‐((2‐(trimethylsilyl)ethynylthio)methyl)‐1‐benzyl‐1H‐1,2,3‐triazole ( 3a) from series of sila‐substituted thioalkyne 1,2,3‐triazoles (STATs) and the compounds 3‐(1‐benzyl‐1H‐1,2,3‐triazol‐4‐yl)‐1‐mercapto‐1,1‐bis(trimethylsilyl)propane‐2‐thione ( 4a) and 1‐mercapto‐1,1‐bis(trimethylsilyl)‐3‐(1‐phenethyl‐1H‐1,2,3‐triazol‐4‐yl)propane‐2‐thione ( 4e) from series of sila‐substituted mercapto‐thione 1,2,3‐triazoles (SMTTs) exhibited promising cytotoxicity against MCF‐7 with IC₅₀ values of 35.17, 32.63 and 30.3 μg/mL, respectively. In addition, the possible mechanisms for inhibition of cell growth and induction of apoptotic cell death were explored by DAPI staining, cell cycle analysis and qRT‐PCR. The synthetic compounds were evaluated for their in vitro antibacterial activities, and as a result, the most prominent effects were observed for 3e and 4e . Especially, 3e was found to be quite active against all the tested strains with the MIC values ranging from 15 to 62 μg/mL, except P. aeruginosa. The results of the time‐kill assay suggested that the compound of 3e completely inhibited the growth of both gram‐negative bacteria, A. baumannii, and gram‐positive bacteria, S. aureus. In addition, SEM analysis confirmed morphostructural damage of the bacteria. Our findings could be applicable for developing dual‐targeting anticancer/antibacterial therapeutics.     

Design,Synthesis, and Antifungal Activity of Novel Conformationally Restricted Triazole Derivatives

A series of new triazole derivatives were designed and synthesized on the basis of the active site of lanosterol 14α‐demethylase from Candida albicans (CACYP51). 2‐(2,4‐Difluorophenyl)‐3‐(methyl‐(3‐phenoxyalkyl)amino)‐1‐(1H‐1,2,4‐triazol‐1‐yl)propan‐2‐ols show excellent in‐vitro activity against most of the tested pathogenic fungi. The MIC₈₀ value of compound 8a against Candida albicans is 0.01 μM, which provides a good starting template for further structural optimization. The binding modes of the designed compounds were investigated by flexible molecular docking. The compounds interacted with CACYP51 through hydrophobic, van‐der‐Waals, and hydrogen‐bonding interactions.     

Synthesis,molecular modeling,in vivo study,and anticancer activity of 1,2,4‐triazole containing hydrazide–hydrazones derived from (S)‐naproxen

A new series of 1,2,4‐triazole containing hydrazide–hydrazones derived from (S)‐naproxen ( 7a–m ) was synthesized in this study. The structures of these compounds were characterized by spectral (Fourier‐transform infrared spectroscopy, ¹H‐nuclear magnetic resonance (NMR), ¹³C‐NMR, and high‐resolution electron ionization mass spectrometry) methods. Furthermore, molecular modeling of these compounds was studied on human methionine aminopeptidase‐2. All synthesized compounds were screened for anticancer activity against three prostate cancer cell lines (PC3, DU‐145, and LNCaP) using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium colorimetric method. Compound 7a showed the best activity against the PC3, DU‐145 and LNCaP cancer cell lines with IC₅₀ values of 26.0, 34.5, and 48.8 μM, respectively. Compounds 7b , 7k , and 7m showed anticancer activity against cancer cell lines PC3 and DU‐145 with IC₅₀ values of 43.0, 36.5, 29.3 μM and 49.8, 49.1, 31.6 μM, respectively. Compounds 7f and 7g showed anticancer activity against PC3 cells with IC₅₀ values of 43.4 and 34.5 μM, respectively. To assess the biodistribution in mice of IRDye800, dye‐labeled compound 7a or 100 μM of free dye was injected intravenously into the mice's tail. In vivo images were taken with in vivo imaging system spectrum device at 60, 120, 180, 240, 300, and 360 min after injection. At the end of 360 min, ex vivo studies were carried out to determine in which organs the dye was accumulated in the urogenital system. Ex vivo studies showed that the accumulation of compound 7a in the prostate is greater than that of the free dye, and it is concluded that compound 7a may be promising for the treatment of prostate cancer.     

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 and in‐vitro antitumour activity of new naphthyridine derivatives on human pancreatic cancer cells

Objectives The aim of the study was to evaluate the antitumour effect in vitro of newly synthesized 7‐substituted 2,3‐dihydro‐1,8‐naphthyridines. Methods Characterization tools included cell viability assay, caspase 3/7 induction, DNA fragmentation, fibroblast growth factor type 1 receptor kinase inhibition, and in‐vitro antiangiogenic analysis. Key findings Treatment of MIA PaCa‐2 human pancreatic cancer cells with test compounds showed time‐ and concentration‐dependent cytotoxicity with IC50 values in the micromolar range. Compounds with an aminoalkyl or a diaminoalkyl side chain at the 7‐position exhibited remarkable cytotoxicity, whereas the presence of a methyl group or a cyclic amine in the same position led to a significant decrease in their biological activity. Cytotoxicity screening demonstrated that the most active was compound 11 (mean 50% inhibition of cell proliferation (IC50) 11 μM). This compound had an in‐vitro antitumour efficacy superior to 5‐fluorouracil (the lowest cell viability value after treatment (E_max) 0.2% and 19%, respectively) and proved to be less toxic than 5‐fluorouracil against non‐cancerous human oral epithelial cells. In addition, compound 11 induced apoptosis in MIA PaCa‐2 cells and it was able to promote antiangiogenic effects in vitro. Finally, its cytotoxicity was enhanced in pancreatic cancer cells stimulated with fibroblast growth factor, while no substantial effect was observed on human bronchial smooth muscle cells stimulated with the same growth factor. Conclusions These findings suggest that 1,8‐naphthyridine derivatives are a promising class of compounds in cancer research. In particular, the antitumour activity of compound 11 is worth further investigation.     

Design,Synthesis, Biological Evaluation,and Docking Study of Acetylcholinesterase Inhibitors: New Acridone‐1,2,4‐oxadiazole‐1,2,3‐triazole Hybrids

In this study, novel acridone‐1,2,4‐oxadiazole‐1,2,3‐triazole hybrids were designed, synthesized, and evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activity. Among various synthesized compounds, 10‐((1‐((3‐(4‐methoxyphenyl)‐1,2,4‐oxadiazol‐5‐yl)methyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl)acridin‐9(10H)‐one 10b showed the most potent anti‐acetylcholinesterase activity (IC₅₀ = 11.55 μm ) being as potent as rivastigmine. Also docking outcomes were in good agreement with in vitro results confirming the dual binding inhibitory activity of compound 10b .     

Fluorinated 1,2,4‐Triazolo[1,5‐a]pyrimidine‐6‐carboxylic Acid Derivatives as Antimycobacterial Agents

A series of fluorinated 1,2,4‐triazolo[1,5‐a]pyrimidine‐6‐carboxylic acid derivatives was designed and synthesized as fluoroquinolone analogues. The synthesized compounds were screened against Mycobacterium tuberculosis H₃₇R_v strain at 6.25 μg/mL concentration. Compound 4 , the 7‐oxo‐2‐(trifluoromethyl)‐4,7‐dihydro‐1,2,4‐triazolo[5,1‐a]pyrimidine‐6‐carboxylic acid was found to be a very potent inhibitor, being able to inhibit 92% growth of M. tuberculosis H₃₇R_v at 6.25 μg/mL concentration. At the same time, it proofed to be nontoxic to mammalian cells (IC₅₀ > 62.5 μg/mL in VERO cells).     

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.     

Design,Synthesis and Evaluation of Antidepressant Activity of Novel 2‐Methoxy 1, 8 Naphthyridine 3‐Carboxamides as 5‐HT3 Receptor Antagonists

A series of novel 1,8‐naphthyridine‐3‐carboxamides as 5‐HT₃ receptor antagonists were synthesized with an intention to explore the antidepressant activity of these compounds. The title carboxamides were designed using ligand‐based approach keeping in consideration the structural requirement of the pharmacophore of 5‐HT₃ receptor antagonists. The compounds were synthesized using appropriate synthetic route from the starting material nicotinamide. 5‐HT₃ receptor antagonism of all the compounds, which was denoted in the form of pA₂ value, was determined in longitudinal muscle myenteric plexus preparation from guinea‐pig ileum against 5‐HT₃ agonist, 2‐methyl‐5‐HT. Compound 8g (2‐methoxy‐1, 8‐naphthyridin‐3‐yl) (2‐methoxy phenyl piperazine‐1‐yl) methanone was identified as the most active compound, which expressed a pA₂ value of 7.67. The antidepressant activity of all the compounds was examined in mice model of forced swim test (FST); importantly, none of the compounds was found to cause any significant changes in the locomotor activity of mice at the tested dose levels. In FST, the compounds with considerably higher pA₂ value exhibited promising antidepressant‐like activity, whereas compounds with lower pA₂ value did not show antidepressant‐like activity as compared to the control group.     

Radiolabeling and in vitro evaluation of a new 5‐fluorouracil derivative with cell culture studies

The clinical impact and accessibility of ^99mTc tracers for cancer diagnosis would be greatly enhanced by the availability of a new, simple, and easy labeling process and radiopharmaceuticals. 5‐Fluorouracil is an antitumor drug, which has played an important role for the treatment of breast carcinoma. In the present study, a new derivative of 5‐Fluorouracil was synthesized as (1‐[{1′‐(1′′‐deoxy‐2′′,3′′:4′′,5′′‐di‐O‐isopropylidene‐β‐D‐fructopyranose‐1′′‐yl)‐1′H‐1′,2′, 3′‐triazol‐4′‐yl}methyl]‐5‐fluorouracil) ( E ) and radiolabeled with ^99mTc. It was analyzed by radio thin layer chromatography for quality control and stability. The radiolabeled complex was subjected to in vitro cell‐binding studies to determine healthy and cancer cell affinity using HaCaT and MCF‐7 cells, respectively. In addition, in vitro cytotoxicity studies of compound E were performed with HaCaT and MCF‐5 cells. The radiochemical purity of the [^99mTc]Tc E was found to be higher than 90% at room temperature up to 6 hours. The radiolabeled complex showed higher specific binding to MCF‐7 cells than HaCaT cells. IC₅₀ values of E were found 31.5 ± 3.4 μM and 20.7 ± 2.77 μM for MCF‐7 and HaCaT cells, respectively. The results demonstrated the potential of a new radiolabeled E with ^99mTc has selective for breast cancer cells.     

Nonclinical pharmacokinetics and metabolism of EPZ‐5676, a novel DOT1L histone methyltransferase inhibitor

(2R,3R,4S,5R)‐2‐(6‐Amino‐9H‐purin‐9‐yl)‐5‐((((1r,3S)‐3‐(2‐(5‐(tert‐butyl)‐1H‐benzo[d]imidazol‐2‐yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran‐3,4‐diol (EPZ‐5676) is a novel DOT1L histone methyltransferase inhibitor currently in clinical development for the treatment of MLL‐rearranged leukemias. This report describes the preclinical pharmacokinetics and metabolism of EPZ‐5676, an aminonucleoside analog with exquisite target potency and selectivity that has shown robust and durable tumor growth inhibition in preclinical models. The in vivo pharmacokinetics in mouse, rat and dog were characterized following i.v. and p.o. administration; EPZ‐5676 had moderate to high clearance, low oral bioavailability with a steady‐state volume of distribution 2–3 fold higher than total body water. EPZ‐5676 showed biexponential kinetics following i.v. administration, giving rise to a terminal elimination half‐life (t_1/2) of 1.1, 3.7 and 13.6 h in mouse, rat and dog, respectively. The corresponding in vitro ADME parameters were also studied and utilized for in vitro–in vivo extrapolation purposes. There was good agreement between the microsomal clearance and the in vivo clearance implicating hepatic oxidative metabolism as the predominant elimination route in preclinical species. Furthermore, low renal clearance was observed in mouse, approximating to f_u‐corrected glomerular filtration rate (GFR) and thus passive glomerular filtration. The metabolic pathways across species were studied in liver microsomes in which EPZ‐5676 was metabolized to three monohydroxylated metabolites (M1, M3 and M5), one N‐dealkylated product (M4) as well as an N‐oxide (M6). Copyright © 2014 John Wiley & Sons, Ltd.     

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

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

Effectiveness of Novel 5‐(5‐amino‐1‐aryl‐1H‐pyrazol‐4‐yl)‐1H‐tetrazole Derivatives Against Promastigotes and Amastigotes of Leishmania amazonensis

In this research, a series of substituted 5‐(5‐amino‐1‐aryl‐1H‐pyrazol‐4‐yl)‐1H‐tetrazoles were synthesized and evaluated for in vitro antileishmanial activity. Among the derivatives, examined compounds 3b and 3l exhibited promising activity against promastigotes and amastigotes forms of Leishmania amazonensis. The cytotoxicity of these compounds was evaluated on murine cells, giving access to the corresponding selectivity index (SI).     

Pyridine‐substituted thiazolylphenol derivatives: Synthesis,modeling studies,aromatase inhibition,and antiproliferative activity evaluation

Drugs used in breast cancer treatments target the suppression of estrogen biosynthesis. During this suppression, the main goal is to inhibit the aromatase enzyme that is responsible for the cyclization and structuring of estrogens either with steroid or non‐steroidal‐type inhibitors. Non‐steroidal derivatives generally have a planar aromatic structure attached to the triazole ring system in their structures, which inhibits hydroxylation reactions during aromatization by coordinating the heme group. Bioisosteric replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase the selectivity for aromatase enzyme inhibition. In this study, pyridine‐substituted thiazolylphenol derivatives, which are non‐steroidal triazole bioisosteres, were synthesized using the Hantzsch method, and physical analysis and structural determination studies were performed. The IC₅₀ values of the compounds were determined by a fluorescence‐based aromatase inhibition assay. Then, their antiproliferative activities on the MCF7 and HEK 293 cell lines were evaluated with the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. Furthermore, the crystal structure of human placental aromatase was subjected to a series of docking experiments to identify the possible interactions between the most active structure and the active site. Lastly, an in silico technique was performed to analyze and predict the drug‐likeness, molecular and ADME properties of the synthesized molecules.

     

A Novel Antifungal Agent with Broad Spectrum: 1‐(4‐Biphenylyl)‐3‐(1H‐imidazol‐1‐yl)‐1‐propanone

A series of (1‐substituted aryl)‐3‐(1H‐imidazol‐1‐yl)‐1‐propanones was synthesized through the N‐alkylation of imidazole with 3‐dimethylamino‐1‐(substituted aryl)‐1‐propanone hydrochlorides (ketonic Mannich bases). A second series of N¹‐substituted imidazoles was obtained by the reduction of the carbonyl function of the imidazole–ketones in the previous series by means of NaBH₄. All of the compounds were evaluated for antifungal activity against 16 strains of Candida, and 3‐(1H‐imidazol‐1‐yl)‐1‐(4‐biphenylyl)‐1‐propanone emerged as a broad‐spectrum antifungal agent. Several 3‐(1H‐imidazol‐1‐yl)‐1‐(2′‐(substituted benzyl)oxyphenyl)‐1‐propanones were also active towards Candida kefyr.     

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.

     

Antimalarial activity of newly synthesized chalcone derivatives in vitro

Twenty‐seven novel chalcone derivatives were synthesized using Claisen‐Schmidt condensation and their antimalarial activity against asexual blood stages of Plasmodium falciparum was determined. Antiplasmodial IC₅₀ (half‐maximal inhibitory concentration) activity of a compound against malaria parasites in vitro provides a good first screen for identifying the antimalarial potential of the compound. The most active compound was 1‐(4‐benzimidazol‐1‐yl‐phenyl)‐3‐(2, 4‐dimethoxy‐phenyl)‐propen‐1‐one with IC₅₀ of 1.1 μg/mL, while that of the natural phytochemical, licochalcone A is 1.43 μg/mL. The presence of methoxy groups at position 2 and 4 in chalcone derivatives appeared to be favorable for antimalarial activity as compared to other methoxy‐substituted chalcones. Furthermore, 3, 4, 5‐trimethoxy groups on chalcone derivative probably cause steric hindrance in binding to the active site of cysteine protease enzyme, explaining the relative lower inhibitory activity.