1,2,3-triazole tethered Indole-3-glyoxamide derivatives as multiple inhibitors of 5-LOX, COX-2 & tubulin: Their anti-proliferative & anti-inflammatory activity.

To evaluate the role of COX-2 and 5-LOX as dual inhibitors in controlling the cancer cell proliferation, a set of two series having 42 compounds of 1, 2, 3-Tethered Indole-3-glyoxamide derivatives were synthesized by employing click chemistry approach and were also evaluated for their in vitro cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) inhibitory activities with in vivo anti-inflammatory and in vitro anti-proliferative potencies. Among the compounds tested, compounds 11q and 13s displayed excellent inhibition of COX-2 (IC50 0.12 µM) with good COX-2 selectivity index (COX-2/COX-1) of 0.058 and 0.046 respectively. Compounds 11q and 13s also demonstrated comparable 5-LOX inhibitory activity with IC50 7.73 and 7.43 µM respectively to that of standard Norhihydroguaiaretic acid (NDGA: IC50 7.31 µM). Among all the selected cell lines, prostate cancer cell line DU145 was found to be susceptible to this class of compounds. Among all the tested compounds, compounds 11g, 11i, 11k, 11q, 13r, 13s and 13u demonstrated excellent to moderate anti-proliferative activity with IC50s ranging between 6.29 and 18.53 µM. Compounds 11q and 11g demonstrated better anti-proliferative activities against DU145 cancer cell line with IC50 values 8.17 and 8.69 µM respectively when compared to the standard drug etoposide (VP16; IC50 9.80 µM). Compounds 11g, 11k, 11q, 13s and 13u showed good dual COX-2/5-LOX inhibitory potentials with excellent anti-proliferative activity. Results from carrageenan-induced hind paw edema demonstrated that compounds 11b, 11l, 11q and 13q exhibited significant anti-inflammatory activity with 69-77% inhibition at 3 h, 75-82% inhibition at 5 h when compared to the standard drug indomethacin (66.6% at 3 h and 77.94% at 5 h). Ulcerogenic study revealed that compounds 11q and 13q did not cause any gastric ulceration. In vitro tubulin assay resuted that compound 11q interfered with microtubulin dynamic and act as tubulin polymerization inhibitor. In silico molecular docking studies demonstrated that compounds 11q and 13s are occupying the colchicines binding site of tubulin polymer and 11q illustrated very good binding affinities towards COX-2 and 5-LOX.

Synthesis of novel spiro[pyrazolo[4,3-d]pyrimidinones and spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,3'-indoline]-2',4(3H)-diones and their evaluation for anticancer activity.

An efficient and novel method for the preparation of spiro[pyrazolo[4,3-d]pyrimidin]-7'(1'H)-ones by the condensation of 4-amino-1-methyl-3-propylpyrazole-5-carboxamide with ketones under mild conditions using catalytic InCl3 was reported. This method has been extended for the synthesis of novel spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,3'-indoline]-2',4(3H)-dione which are having potential applications in medicinal chemistry. All the synthesized compounds were evaluated for their anti-proliferative properties in vitro against cancer cell lines and several compounds were found to be active. Further in vitro studies revealed that inhibition of sirtuins could be the possible mechanism of action of these molecules.

Design, synthesis and anticancer activity of N-(1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl derivatives.

Novel N-(1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl derivatives were designed, synthesized and their chemical structures were confirmed by 1H NMR, 13C NMR and Mass spectra. The anticancer activities of the newly synthesized compounds were evaluated in vitro against three human cancer cell lines including K562, Colo-205 and MDA-MB 231 by MTT assay. The screening results showed that five compounds (16b, 16d, 16i, 16p and 16q) exhibited potent cytotoxic activities with IC50 values between 20 and 40µM. Further in vitro studies revealed that inhibition of sirtuins could be the possible mechanism of action of these molecules.

Design, synthesis, and biological evaluation of hydrazone incorporated 1,2,4-triazines as anticonvulsant agents.

New hydrazone incorporated triazines were designed and synthesized using an appropriate synthetic route with regard to essential pharmacophores, and evaluated for their anticonvulsant activity through maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole-induced seizure (scPTZ) screenings. Among the tested compounds, 4-[{2-(5-(3-chlorobenzyl)-3-phenyl-1,2,4-triazine-6-yl)hydrazono}methyl]-N,N-dimethylaniline 6k (MES ED50 54.31, scPTZ ED50 92.01) and 4-[{2-(5-(4-chlorobenzyl)-3-phenyl-1,2,4-triazine-6-yl)hydrazono}methyl]-N,N-dimethylaniline 6r (MES ED50 46.05, scPTZ ED50 83.90) emerged as the most active anticonvulsant agents having GABAergic effects. Compounds 6k and 6r also showed lesser CNS depressant effect than the standard drug carbamazepine. To obtain further insights into the binding interactions of these molecules, molecular docking studies were carried out.

Design, synthesis, and high-throughput in vitro anti-cancer evaluation of novel 4-aminopyrazolo[3,4-d]pyrimidine derivatives: potential anti-cancer candidates against UO-31 renal cancer cells.

A novel series of 20 compounds containing 4-aminopyrazolo[3,4-d]pyrimidine core were synthesized, characterized and their chemical structures confirmed using spectroscopic techniques such as 1H NMR, 13C NMR, IR, and HRMS. The compound's growth inhibitory activities were evaluated against 60 human tumor cell lines from nine panels: leukemia, non-small cell lung cancer (NSCLC), colon, central nervous system (CNS), melanoma, ovarian, renal, prostate, and breast cancer. Among all the compounds, 11, 12c, 12d, 12f, and 12j are active against different cancer cell lines. Between all the cell lines, compounds 12c, 12d, 12f, 12j, and 11 showed good inhibitory activity against renal cancer cell lines. From the five-dose study, based on IC50 values, the order of activity of compounds against renal cancer cell lines was found to be 12c > 12f > 12c > 12j > 11 with 12c being the most potent, was better than sunitinib and sorafenib. Having been recognized as initial hits, these substances need additional pharmacological investigation.

Novel N-(3-ethynyl Phenyl)-6,7-bis(2-methoxyethoxy)Quinazoline-4-amine Derivatives: Synthesis, Characterization, Anti-cancer Activity, In-silico and DFT Studies.

BACKGROUND: Cancer is one of the most common reasons for mortality in the world. A continuous effort to develop effective anti-cancer drugs with minimum side effects has become necessary. The use of small-molecule drugs has revolutionized cancer research by inhibiting cancer cell survival and proliferation. Quinazolines are a class of bioactive heterocyclic compounds with active pharmacophores in several anti-cancer drugs. Such small molecule inhibitors obstruct the significant signals responsible for cancer cell development, thus blocking these cell signals to prevent cancer development and spread. OBJECTIVE: In the current study, novel quinazoline derivatives structurally similar to erlotinib were synthesized and explored as novel anti-cancer agents. METHODS: All the synthesized molecules were confirmed by spectroscopic techniques like 1H NMR, 13C NMR, and ESI-MS. Various techniques were applied to study the protein-drug interaction, DFT analysis, Hirshfeld surface, and target prediction. The molecules were screened in vitro for their anti-cancer properties against 60 human tumor cell lines. The growth inhibitory properties of a few compounds were studied against the MCF7 breast cancer cell line. RESULTS: The activity of compounds 9f, 9o, and 9s were found to be active. However, compound 9f is more active when compared with other compounds. CONCLUSION: Some synthesized compounds were active against different cancer cell lines. The in-vitro study results were found to be in agreement with the predictions from in-silico data. The selected molecules were further subjected to get the possible mechanism of action against different cancer cells.

Identification, Synthesis, and Characterization of Novel Baricitinib Impurities.

Baricitinib is a novel active pharmaceutical ingredient used in the treatment of rheumatoid arthritis, and it acts as an inhibitor of Janus kinase. During the synthesis of baricitinib, three unknown impurities were identified in several batches between 0.10 and 0.15% using high-performance liquid chromatography. The unknown compounds were isolated and identified as N-((3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-5-oxotetrahydrofuran-3-yl)methyl)ethane sulfonamide (lactone impurity, BCL), 2-(3-(4-(7H-[4,7'-bipyrrolo[2,3-d]pyrimidin]-4'-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (dimer impurity, BCD), and 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl) acetonitrile (hydroxymethyl, BHM). These compounds were synthesized and confirmed against the isolated samples. The structures of all the three impurities were confirmed by extensive analysis of 1H NMR, 13C NMR, and mass spectrometry. The lactone impurity formation was explained by a plausible mechanism. The outcome of this study was very useful for scientists working in process as well as in formulation development. To synthesize highly pure baricitinib drug substance, these impurities can be used as reference standards due to their potential importance.

Identification, Synthesis, and Characterization of Potential Oxidative Impurities of Venetoclax: Application of Meisenheimer Rearrangement.

Venetoclax is a potent BCL-2 inhibitor that is used for the treatment of several blood cancers. During the oxidative stress degradation of venetoclax, we observed the formation of two potential impurities at levels of about 8-10%, which have similar molecular weights. The two impurities were isolated and identified as 4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)carbamoyl)phenyl)-1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine 1-oxide (venetoclax N-oxide, VNO) and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methoxy)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (venetoclax hydroxylamine impurity, VHA). To confirm these two compounds, we have synthesized each impurity individually and analyzed it by high-performance liquid chromatography, mass spectrometry, 1H NMR, 13C NMR, and 2D NMR. VNO was synthesized by the oxidation of venetoclax using m-CPBA in dichloromethane to get the required N-oxide impurity. After the confirmation of the VNO impurity, the VNO impurity was heated with water at reflux in a sealed tube for 36 h to get the VHA impurity of about 6-8% after 36 h. After thorough analysis, it was confirmed that venetoclax N-oxide undergoes [1,2] Meisenheimer rearrangement to form the venetoclax hydroxylamine impurity. These two impurities may be relevant reference standards in manufacturing venetoclax Active Pharmaceutical Ingredient (API) (or) tablets.

InCl3-catalysed synthesis of 2-aryl quinazolin-4(3H)-ones and 5-aryl pyrazolo[4,3-d]pyrimidin-7(6H)-ones and their evaluation as potential anticancer agents.

A convenient and practical methodology for the synthesis of 2-aryl quinazolin-4(3H)-ones by the condensation of o-aminobenzamides with aromatic aldehydes under mild conditions using catalytic InCl(3) with good yields and high selectivities. This method has been extended for the synthesis of 5-aryl pyrazolo[4,3-d]pyrimidin-7(6H)-ones which have potential applications in medicinal chemistry. Many of these compounds were evaluated for their anti-proliferative properties in vitro against four cancer cell lines and several compounds were found to be active. Further in vitro studies indicated that inhibition of sirtuins could be the possible mechanism of action of these molecules.

Ethylenediamine diacetate (EDDA) mediated synthesis of aurones under ultrasound: their evaluation as inhibitors of SIRT1.

An improved synthesis of functionalized aurones has been accomplished via the reaction of benzofuran-3(2H)-one with a range of benzaldehydes in the presence of a mild base EDDA under ultrasound. A number of aurones were synthesized (within 5-30min) and the molecular structure of a representative compound determined by single crystal X-ray diffraction study confirmed Z-geometry of the C-C double bond present within the molecule. Some of the compounds synthesized have shown SIRT1 inhibiting as well as anti proliferative properties against two cancer cell lines in vitro. Compound 3a [(Z)-2-(5-bromo-2-hydroxybenzylidene) benzofuran-3(2H)-one] was identified as a potent inhibitor of SIRT1 (IC(50)=1µM) which showed a dose dependent increase in the acetylation of p53 resulting in induction of apoptosis.

Catalysis by molecular iodine: a rapid synthesis of 1,8-dioxo-octahydroxanthenes and their evaluation as potential anticancer agents.

Molecular iodine facilitated the reaction of 5,5-dimethyl-1,3-cyclohexanedione with aromatic aldehydes in iso-propanol affording a variety of 1,8-dioxo-octahydroxanthenes in high yields. Most of the compounds synthesized showed good anti-proliferative properties in vitro against three cancer cell lines and 9-(2-hydroxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione possessing a 2-hydroxy phenyl group at C-9 position was found to be promising. Further structure elaboration of the same compound and the crystal structure analysis and hydrogen bonding patterns of another compound that is, 9-(4-methoxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione prepared by using this methodology is presented.

Synthesis and pharmacological evaluation of N-substituted 2-(2-oxo-2H-chromen-4-yloxy)propanamide as cyclooxygenase inhibitors.

A series of novel N-substituted 2-(2-oxo-2H-chromen-4-yloxy)propanamide derivatives were synthesized via converting the readily available 4-hydroxy coumarin to the corresponding ethyl 2-(2-oxo-2H-chromen-4-yloxy)propanoate followed by hydrolysis and then reacting with different substituted amines. The molecular structures of two representative compounds, that is, 3 and 5l were confirmed by single crystal X-ray diffraction study. All the compounds synthesized were evaluated for their cyclooxygenase (COX) inhibiting properties in vitro. The compound 5i showed balanced selectivity towards COX-2 over COX-1 inhibition and good docking scores when docked into the COX-2 protein.

Ultrasound mediated catalyst free synthesis of 6H-1-benzopyrano[4,3-b]quinolin-6-ones leading to novel quinoline derivatives: their evaluation as potential anti-cancer agents.

A facile and catalyst free synthesis of 6H-1-benzopyrano[4,3-b]quinolin-6-ones has been accomplished via the reaction of 4-chloro-2-oxo-2H-chromene-3-carbaldehyde with various aromatic amines in the presence of ultrasound. Some of these compounds were converted to the corresponding 2-(3-(hydroxymethyl)quinolin-2-yl)phenols and further structure elaboration of a representative quinoline derivative is presented. Molecular structure of two representative compounds was confirmed by single crystal X-ray diffraction study. Many of these compounds were evaluated for their anti-proliferative properties in vitro against four cancer cell lines and several compounds were found to be active. Further in vitro studies indicated that inhibition of sirtuins could be the possible mechanism of action of these molecules.

Sequential coupling/desilylation-coupling/cyclization in a single pot under Pd/C-Cu catalysis: synthesis of 2-(hetero)aryl indoles.

A new one-pot synthesis of 2-(hetero)aryl indoles via sequential C-C coupling followed by C-Si bond cleavage and a subsequent tandem C-C/C-N bond forming reaction is described. A variety of functionalized indole derivatives were prepared by conducting this four step reaction under Pd/C-Cu catalysis. The methodology involved coupling of (trimethylsilyl)acetylene with iodoarenes in the presence of 10% Pd/C-CuI-PPh(3) and triethylamine in MeOH, followed by treating the reaction mixture with K(2)CO(3) in aqueous MeOH, and finally coupling with o-iodoanilides. The single crystal X-ray data of a synthesized indole derivative is presented. Application of the methodology, in vitro pharmacological properties of the synthesized compound, along with a docking study is described.

2,3-Diaryl-3H-imidazo[4,5-b]pyridine derivatives as potential anticancer and anti-inflammatory agents.

In this study we examined the suitability of the 3H-imidazo[4,5-b]pyridine ring system in developing novel anticancer and anti-inflammatory agents incorporating a diaryl pharmacophore. Eight 2,3-diaryl-3H-imidazo[4,5-b]pyridine derivatives retrieved from our in-house database were evaluated for their cytotoxic activity against nine cancer cell lines. The results indicated that the compounds showed moderate cytotoxic activity against MCF-7, MDA-MB-468, K562 and SaOS2 cells, with K562 being the most sensitive among the four cancer cell lines. The eight 2,3-diaryl-3H-imidazo[4,5-b]pyridine derivatives were also evaluated for their COX-1 and COX-2 inhibitory activity in vitro. The results showed that compound 3f exhibited 2-fold selectivity with IC50 values of 9.2 and 21.8 µmol/L against COX-2 and COX-1, respectively. Molecular docking studies on the most active compound 3f revealed a binding mode similar to that of celecoxib in the active site of the COX-2 enzyme.

Sulfur rich 2-mercaptobenzothiazole and 1,2,3-triazole conjugates as novel antitubercular agents.

A series of benzfused heterocyclic derivatives such as amide conjugates of 2-(benzo[d]thiazol-2-ylthio)acetic acid with aromatic/aliphatic/cyclic secondary amines (5a-5o & 8a-8m); 1,2,3-triazole conjugates of 2-mercaptobenzothiazoles and amide conjugates of indole-3-glyoxalic acid with cyclic secondary amines (14a-14g) have been synthesized and were screened for their antitubercular activity against Mycobacterium tuberculosis H37Rv strain by broth microdilution assay method. Compounds 8b, 8f, 8g and 8l inhibited the growth of the H37Rv strain at concentrations of 8 µg/mL. These compounds (8b, 8f, 8g and 8l) have been further identified as bactericidal and are completely killing the microbes at 32-64 µg/mL concentrations. Molecular docking studies of the active compounds reveal that these compounds are targeting DprE1 and may act as DprE1 inhibitors.

Synthesis of novel therapeutic agents for the treatment of multiple sclerosis: a brief overview.

Multiple sclerosis (MS) often results in chronic inflammatory and autoimmune disorders, and recent developments in understanding the disease pathogenesis has lead to newer therapeutic options for the treatment of the disease. The development of small molecule drugs with improved efficacy, better tolerability, and oral administration has received a new impetus with the discovery of newer classes of drugs. In this review, we have summarized the hitherto known synthetic strategies of fingolimod, laquinimod, cladribine, and teriflunomide reported in the literature which are the key small molecules and the first oral drug candidates for MS in various stages of clinical development or have been launched in the market.

Design and evaluation of new chemotherapeutics of aloe-emodin (AE) against the deadly cancer disease: an in silico study.

The Bcl-2 family proteins include pro- and antiapoptotic factors acting as critical arbiters of apoptotic cell death decisions in most circumstances. Evasion of apoptosis is one of the hallmarks of cancer, relevant to tumorigenesis as well as resistance to cytotoxic drugs, and deregulation of Bcl-2 proteins was observed in many cancers. Since Bax-mediated induction of apoptosis is a crucial mechanism in cancerous cells, we aimed at conducting in silico analysis on Bax in order to predict the possible interactions for anticancer agents. The present report depicts the binding mode of aloe-emodin and its structurally modified derivatives onto Bax. The structural information about the binding site of Bax for docked compounds obtained from this study could aid in screening and designing new anticancer agents or selective inhibitors for chemotherapy against Bax.

Experimental and computational studies on newly synthesized resveratrol derivative: a new method for cancer chemoprevention and therapeutics?

Nature has been a provenance of medicinal agents for thousands of years. Resveratrol (RESL) is a naturally occurring polyphenolic compound in food stuffs such as peanuts, seeds, berries, grapes, and beverages (red wine). RESL has received significant attention due to a plethora of in vitro and in vivo reports on its cancer chemopreventive and therapeutic properties. In the present study, diacetate RESL derivative (RESL43) was synthesized. The RESL43 displayed potent cytotoxicity and triggered apoptosis in U937 cells as evidenced by poly (ADP-ribose) polymerase (PARP) cleavage, DNA fragmentation, morphological changes, and activation of FasR and FasL genes. The electrophoretic mobility shift assay revealed the suppression NFkB activity in U937 cells after treatment with RESL43 in corroboration with the deactivation of NFkB dependent genes such as IL-8, TNFR, and TNFα. Furthermore, molecular docking and dynamics studies have shown that RESL and RESL43 might exert their inhibitory activity on NFkB by altering the intramolecular binding abilities between DNA and NFkB. Taken together, RESL43 can have greater putative activity than parental RESL in a context of cancer chemoprevention and therapeutics. We suggest that the diacetate resveratrol derivative RESL43 warrants further evaluation in preclinical and clinical bridging studies in the near future.

Synthesis and evaluation of resveratrol derivatives as new chemical entities for cancer.

Resveratrol has been shown to be active in inhibiting multistage carcinogenesis. The potential use of resveratrol in cancer chemoprevention or chemotherapy settings has been hindered by its short half-life and low bioavailability. Considering the above remarks, using resveratrol as a prototype, we have synthesized two derivatives of resveratrol. Their activity was evaluated using in vitro and in silico analysis. Biological evaluation of resveratrol analogues on U937 cells had shown that two synthesized analogues of resveratrol had higher rates of inhibition than the parental molecule at 10µM concentration. EMSA conducted for NF-kB revealed that these molecules significantly interfered in the DNA binding ability of NF-kB. It was found that these molecules suppressed the expression of TNFα, TNFR, IL-8, actin and activated the expression of FasL, FasR genes. To understand possible molecular mechanism of the action we performed docking and dynamic studies, using NF-kB as a receptor. Results showed that resveratrol, RA1 and RA2 interacted with the residues involved in DNA binding. Resveratrol analogues by interacting NF-kB might have prevented its translocation and also by interacting with the residues involved in DNA binding might have prevented the binding of NF-kB to DNA. This may be the reason for suppression of NF-kB binding to DNA.