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.     

Fullerene Isoniazid Conjugate – A Tuberculostat with Increased Lipophilicity: Synthesis and Evaluation of Antimycobacterial Activity

A fullerene–isoniazid conjugate has been synthesized by 1, 3 dipolar cycloaddition reaction of fullerene (C₆₀) with isonicotinic acid (4‐formyl‐benzylidene) hydrazide and N‐methylglycine. The identity and purity of the compound was confirmed by elemental analysis, ¹H NMR, ¹³C NMR and MALDI‐TOF mass spectral analysis. Stable water suspension, in which the particles of the synthesized conjugate were made to aggregate in nanosize, was successfully tested for antimycobacterial activity against Mycobacterium avium and strains of Mycobacterium tuberculosis– H₃₇Rv & H6/99 at concentration as low as 0.50 μg/mL.     

Design,synthesis, and in vitro antimicrobial activity of hydrazide–hydrazones of 2‐substituted acetic acid

In this study, 30 hydrazide–hydrazones of phenylacetic ( 3 – 10 ) and hydroxyacetic acid ( 11 – 32 ) were synthesized by the condensation reaction of appropriate 2‐substituted acetic acid hydrazide with different aromatic aldehydes. The obtained compounds were characterized by spectral data and evaluated in vitro for their potential antimicrobial activities against a panel of reference strains of micro‐organisms, including Gram‐positive bacteria, Gram‐negative bacteria, and fungi belonging to the Candida spp. The results from our antimicrobial assays indicated that among synthesized compounds 3 – 32 , especially compounds 6 , 14, and 26 showed high bactericidal activity (MIC = 0.488–7.81 μg/ml) against reference Gram‐positive bacteria, and in some cases, their activity was even better than that of commonly used antibiotics, such as cefuroxime or ampicillin.     

Synthesis and Antibacterial Activity of a New Series of 3‐[3‐(Substituted Phenyl)‐1‐Isonicotinoyl‐1H‐Pyrazol‐5‐yl]‐2H‐Chromen‐2‐one Derivatives

A novel series of 3‐[3‐(substituted phenyl)‐1‐isonicotinoyl‐1H‐pyrazol‐5‐yl]‐2H‐chromen‐2‐one derivatives 4a – k have been synthesized by the reaction of 3‐[2,3‐dibromo‐3‐(substituted phenyl) propanoyl]‐2H‐chromen‐2‐one 3a – k and isonicotinic acid hydrazide in the presence of triethylamine in absolute ethanol, characterized by spectral data and screened for their in‐vitro antibacterial activity against Gram‐positive and Gram‐negative bacteria. Among the series, compounds 4e , 4i , and 4k displayed an encouraging antibacterial activity profile as compared to the reference drug ampicillin against tested bacterial strains.     

Facile Synthesis and In‐Vitro Antitumor Activity of Some Pyrazolo[3,4‐b]pyridines and Pyrazolo[1,5‐a]pyrimidines Linked to a Thiazolo[3,2‐a]benzimidazole Moiety

The key precursor E‐3‐(N,N‐dimethylamino)‐1‐(3‐methylthiazolo[3,2‐a]benzimidazol‐2‐yl)prop‐2‐en‐1‐one 4 was synthesized in good yield using Gold's reagent. The reaction of enaminone 4 with 5‐amino‐3‐aryl‐1‐phenylpyrazoles 5a , b in refluxing acetic acid in the presence of sulphuric acid, yielded pyrazolo[3,4‐b]pyridines 7a , b . Similarly, pyrazolo[1,5‐a]pyrimidines 10a , b and 14a – f were prepared by reaction of enaminone 4 with 5‐amino‐1H‐pyrazoles 8a , b and 12a – f , respectively. The structure of pyrazolo[1,5‐a]pyrimidine 10b was determined by X‐ray diffraction. The synthesized compounds were tested for their in‐vitro antitumor activity against the colon cancer cell line CaCo‐2; their cytotoxicity against the normal fibroblast cell line BHK was explored as well. Some of the tested compounds exhibited cell growth inhibitory activity. The significant antitumor activity of compound 14f against the CaCo‐2 cell line (IC₅₀ = 0.5 μg/mL) was coupled with a lower toxicity against BHK (IC₅₀ = 2.3 μg/mL).     

Design,synthesis, and evaluation of novel diphenyl ether derivatives against drug‐susceptible and drug‐resistant strains of Mycobacterium tuberculosis

In our efforts to develop druggable diphenyl ethers as potential antitubercular agents, a series of novel diphenyl ether derivatives ( 5a – f , 6a – f ) were designed and synthesized. The representative compounds showed promising in vitro activity against drug‐susceptible, isoniazid‐resistant, and multidrug‐resistant strains of Mycobacterium tuberculosis with MIC values of 1.56 μg/ml ( 6b ), 6.25 μg/ml ( 6a–d ), and 3.125 μg/ml ( 6b–c ), respectively. All the synthesized compounds exhibited satisfactory safety profile (CC₅₀ > 300 μg/ml) against Vero and HepG2 cells. Reverse phase HPLC method was used to probe the physicochemical properties of the synthesized compounds. This series of compounds demonstrated comparatively low logP values. pKa values of representative compounds indicated that they were weak acids. Additionally, in vitro human liver microsomal stability assay confirmed that the synthesized compounds possessed acceptable stability under study conditions. The present study thus establishes compound 6b as the most promising antitubercular agent with acceptable drug‐likeness.     

Synthesis of Novel Substituted Thiourea and Benzimidazole Derivatives Containing a Pyrazolone Ring as Anti‐Inflammatory Agents

Two series of new 1‐(alkyl/aryl)‐3‐{2‐[(5‐oxo‐4,5‐dihydro‐1H‐pyrazol‐3‐yl)amino]phenyl}thioureas 2a – h and 5‐[2‐(substituted amino)‐1H‐benzimidazol‐1‐yl]‐4H‐pyrazol‐3‐ols 3a – i were designed and synthesized as anti‐inflammatory agents. The cyclooxygenase inhibitory activity of the newly synthesized compounds was investigated. All the compounds showed non‐selective inhibition of COX‐1 and COX‐2 enzymes which was consistent with their docking results. Compounds 2c , 2f , 2g , 3b , and 3g that showed the highest COX‐2 inhibitory activity were selected for further in vivo testing as anti‐inflammatory agents using diclofenac as a reference drug. Two of the test compounds ( 2c and 3b ) showed potent anti‐inflammatory activity comparable to that of diclofenac with lower ulcerogenic effect relative to indomethacin. SAR study of the two series as cyclooxygenase inhibitors and anti‐inflammatory agents was also provided.     

Synthesis and antimycobacterial activity of novel 4-[5-(substituted phenyl)-1-phenyl-4,5-dihydro-1<Emphasis Type="Italic">H</Emphasis>-3-pyrazolyl]-2-methylphenol derivatives

In the present investigation, 4-hydroxy-3-methylacetophenone, on condensation with appropriate aldehydes in methanolic potassium hydroxide solution, yielded the corresponding chalcones (C_I-XI). These corresponding chalcones were reacted with phenyl hydrazide in glacial acetic acid, which led to the formation of novel 4-[5-(substituted phenyl)-1-phenyl-4,5-dihydro-1H-3-pyrazolyl]-2-methylphenol derivatives. All newly synthesized compounds were evaluated for their antimycobacterial activities against isoniazid-resistant Mycobacterium tuberculosis using agar dilution. 4-[5-(4-Fluoro phenyl)-1-phenyl-4,5-dihydro-1H-3-pyrazolyl]-2-methylphenol showed good antimycobacterial activity, with a minimum inhibitory concentration of 0.62 μg/ml.     

Antituberculosis activity of hydrazones derived from 4-fluorobenzoic acid hydrazide

A series of substitututed methylene/ethylene 4-fluorophenylhydrazide derivatives (3a–p) was synthesized with the aim of evaluating their antimycobacterial activity toward a strain of Mycobacterium tuberculosis H37Rv. Their chemical structures were confirmed by ¹H-nuclear magnetic resonance (NMR) and electrospray mass spectrometry (ES-MS) spectral data, and elemental analysis. The in vitro antimycobacterial evaluation was performed according to the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) antituberculosis drug discovery program. Compound 3a, 4-fluorobenzoic acid [(2,6-dichlorophenyl) methylene]hydrazide, showed the highest inhibitory activity of all the compounds under study.     

Synthesis and Antitubercular Screening of [(2‐Chloroquinolin‐3‐yl)methyl] Thiocarbamide Derivatives

A series of 1‐(substituted‐phenyl)‐1‐[(2‐chloroquinolin‐3‐yl)methyl]thiocarbamide and 1‐(substituted‐phenyl)‐1‐[(2‐chloroquinolin‐3‐yl)methyl]methylthiocarbamide derivatives was synthesized as antitubercular agent. The structure of quinolinyl amines and their thiocarbamide derivatives were established on the basis of IR, ¹H and ¹³C‐NMR and mass spectral data. All the compounds were tested in vitro for antimycobacterial activity against Mycobacterium tuberculosis (ATCC‐25177) in Lowenstein‐Jensen medium by well diffusion method and MIC by twofold serial dilution method. Results of the antitubercular screening revealed that compounds showed moderate to good antitubercular activity. Compound having two halogens in the phenyl rings viz. 3g , 3h , 4g, and 4h exhibited MIC of 50 μg/mL. The computational parameters relevant to absorption and permeation of target compounds were also calculated and found to be well correlated with antitubercular activity.     

Efficient Synthesis and Biological Evaluation of a Novel Series of 1,5‐Benzodiazepine Derivatives as Potential Antimicrobial Agents

A series of novel 1,5‐benzodiazepine derivatives were rationally designed and synthesized following the principle of the superposition of bioactive substructures by the combination of 1,5‐benzodiazepine, pyridine (phenyl), and an ester group. The structures of the target compounds were determined by ¹H NMR, ¹³C NMR, MS, IR, and elemental analysis. All the synthesized compounds were evaluated for their antimicrobial activities in vitro against the fungi C. neoformans, C. neoformans clinical isolates (ATCC 32264), C. albicans (ATCC 10231), Gram‐negative bacterium E. coli (ATCC 44752), and Gram‐positive bacterium S. aureus (ATCC 25923). The results of the bioactive assay demonstrated that most of the tested compounds exhibited variable inhibitory effects on the growth of the tested microorganisms. All the active compounds showed better antifungal activity than antibacterial activity. Notably, compound 2b displayed the highest activity (MIC = 30 μg/mL) against C. neoformans and (MIC = 31 μg/mL) against C. neoformans clinical isolates. In addition, compound 2a also showed excellent activity against C. neoformans and C. neoformans clinical isolates with minimum inhibitory concentration of 35 and 36 μg/mL, respectively. Compounds 2a and 2b were further studied by evaluating their cytotoxicities, and the results showed that they have relatively low level cytotoxicity for BV2 and 293T cell. Preliminary structure‐activity relationship study on three diverse sets (C‐2, C‐3, and C‐8 positions) of 1,5‐benzodiazepines was performed. The results revealed that the presence of a ‐CH₃ group at the C‐8 position had a positive effect on the inhibitory activity of these compounds. Additionally, the 2‐pyridyl group at the C‐2 position may be a pharmacophore and ‐COOC₂H₅ at C‐3 position is the best substituent for the maintenance of antimicrobial activities.     

PEG Mediated Synthesis and Biological Evaluation of Asymmetrical Pyrazole Curcumin Analogues as Potential Analgesic,Anti-Inflammatory and Antioxidant Agents

The new series of asymmetrical pyrazole curcumin analogues 4a – g were synthesized by using polyethylene glycol (PEG-400) as a green reaction medium and evaluated for their in vivo analgesic and in vitro antioxidant (H₂O₂, DPPH, Ferrous reducing power and Nitric oxide scavenging activity) and anti-inflammatory activities. All the compounds synthesized 4a – g showed the potential to demonstrate analgesic activity as compared to the standard ibuprofen. Among the tested series, compounds 4e and 4b exhibited good hydrogen peroxide scavenging activity as compared to the standard butylated hydroxy toluene (BHT). Compounds 4b , 4d , 4f , and 4g showed good DPPH free radical scavenging activity. Compounds 4b , 4c , 4d , 4e and 4g showed excellent ferrous-reducing power activity, whereas all the compounds showed better nitric oxide scavenging activity than standard ascorbic acid. Additionally, all the synthesized compounds were also screened for their in vitro anti-inflammatory activity. Compounds 4b , 4d , 4f and 4g showed good anti-inflammatory activity as compared to standard diclofenac sodium.     

Synthesis, antimycobacterial, antiviral, antimicrobial activities, and QSAR studies of nicotinic acid benzylidene hydrazide derivatives

A series of nicotinic acid benzylidene hydrazide derivatives (1–18) was synthesized and tested in vitro for biological evaluations. The antimycobacterial activity results indicated that the presence of electron-withdrawing halogen groups at para position of the phenyl ring improved their activity. The results of antiviral evaluation depicted that none of the synthesized derivatives inhibited the replication of viruses at subtoxic concentration. Further, the antimicrobial screening results indicated that compounds having OCH₃ and NO₂ substituents were the most active ones. QSAR investigations revealed that multi-target QSAR models were effective in describing the antimicrobial activity.     

Synthesis,biological evaluation,and molecular docking studies of novel 3‐aryl‐5‐(alkyl‐thio)‐1H‐1,2,4‐triazoles derivatives targeting Mycobacterium tuberculosis

A small library of new 3‐aryl‐5‐(alkyl‐thio)‐1H‐1,2,4‐triazoles was synthesized and screened for the antimycobacterial potency against Mycobacterium tuberculosis H₃₇Ra strain and Mycobacterium bovis BCG both in active and dormant stage. Among the synthesized library, 25 compounds exhibited promising anti‐TB activity in the range of IC₅₀0.03–5.88 μg/ml for dormant stage and 20 compounds in the range of 0.03–6.96 μg/ml for active stage. Their lower toxicity (>100 μg/ml) and higher selectivity (SI = >10) against all cancer cell lines screened make them interesting compounds with potential antimycobacterial effects. Furthermore, to rationalize the observed biological activity data and to establish a structural basis for inhibition of M. tuberculosis, the molecular docking study was carried out against a potential target MTB CYP121 which revealed a significant correlation between the binding score and biological activity for these compounds. Cytotoxicity and in vivo pharmacokinetic studies suggested that 1,2,4‐triazole analogues have an acceptable safety index, in vivo stability and bio‐availability.     

Synthesis and Antimycobacterial Activity of Triazene Derivatives of N-Arylcarbamates

A series of new triazene derivatives of N-arylcarbamates was synthesized via condensation of equimolar amounts of alkyl-N-(4-nitrosophenyl)carbamates with substituted hydrazines in ethanol. The antimycobacterial activity of the synthesized compounds was studied in vitro on cell cultures of Micobacterium tuberculosis and Micobacterium lufu. The reference drugs were isoniazid and dapsone. The chemical modification of isonicotinic acid hydrazide with the formation of triazene derivatives of N-arylcarbamates does not lead to a significant decrease in their antimycobacterial activity.__________Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 3, pp. 16 – 17, March, 2005.     

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.     

Design,Synthesis, Biological Evaluation,and Molecular Docking of Novel Benzopyran and Phenylpyrazole Derivatives as Akt Inhibitors

By inspiration of good Akt1 inhibitory and cytotoxic activity of our previously screened hits 1 and 2 , a series of novel benzopyrans 3a – c , 4 and phenylpyrazoles 5a – c , 6a – b , and 7 were designed, synthesized, and biologically evaluated for their in vitro Akt1 inhibitory and cytotoxic activity. The results revealed that all of these compounds showed moderate‐to‐excellent antiproliferative effects against the tested cancer cell lines (i.e. HL‐60, OVCAR, PC‐3, and HepG2). Among them, compounds 3a and 3c exhibited preferable Akt1 inhibitory activities (IC₅₀ of 3a and 3c are 6.18 and 5.28 μm , respectively), while compounds 4 , 5a – c , 6a – b , and 7 only showed weak Akt1 inhibitory activities. Consequently, we used molecular docking and dynamic simulation to propose a mode of binding between Akt1 and the 3c compound.     

Synthesis and biological evaluation of novel flavanone derivatives as potential antipsychotic agents

In this study, a series of novel flavanone derivatives were designed and synthesized, and the antipsychotic activities of the target compounds were evaluated in vitro and in vivo. The results showed that synthesized compounds 7a – 7g decreased the activity of dopamine D₂ receptors in HEK293 cells co‐transfected with D₂ receptor/G protein α16a, with IC₅₀ values of 0.051–0.35 μm . Compounds 7a – 7g inhibited the over‐production of nitric oxide stimulated by lipopolysaccharide/interferon‐γ in BV‐2 microglial cells. In mice, intragastric administration of 7d , 7e , and 7g reversed the increase in locomotor activity induced by MK‐801 (an antagonist of NMDA receptors) and decreased the hyperactivity of climbing behavior induced by apomorphine (a dopamine receptor agonist). These results suggest that some of the novel flavanone derivatives have potential antipsychotic effects and may be useful in the treatment of schizophrenia.     

Synthesis and in‐vitro Cytotoxic Evaluation of Novel Pyridazin‐4‐one Derivatives

A new series of N‐aryl‐4‐oxo‐1,4‐dihydro‐pyridazine‐3‐carboxylic acids has been synthesized by condensation of aryldiazonium with 4‐hydroxy‐6‐methyl‐2‐pyrone. Some of these compounds exhibited in‐vitro cytotoxic activity with moderate to excellent growth inhibition against the murine P815 mastocytoma cell line. Compound 5b showed an important cytotoxic activity against cell line P815 (IC₅₀ = 0.40 μg/mL).     

Synthesis and Antimycobacterial Activity of Novel Thiadiazolylhydrazones of 1‐Substituted Indole‐3‐carboxaldehydes

A series of novel thiocarbohydrazones of substituted indoles and their corresponding thiadiazole derivatives were prepared, and their structures were confirmed by different analytical and spectroscopic methods. The derivatives were prepared by a sequential synthetic strategy including substitution at N‐1 position of indole ring by various aliphatic and benzylic substituents, followed by condensation with thiocarbohydrazide, and finally cyclization by triethyl orthoformate. The derivatives were tested for their antimycobacterial activity against Mycobacterium bovis BCG, and the results revealed that among the synthesized compounds, thiadiazole derivatives 4e , 4f , 4n , 4p , 4q , and 4t exhibited the highest activity with IC₅₀ value of 3.91 μg/mL. The results indicate that the thiadiazole moiety plays a vital role in exerting antimycobacterial activity.