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A series of novel amide functionalized trifluoromethyl substituted pyridine derivatives were prepared starting from pyridine 1 on reaction with bromoethylacetate followed by reaction with different primary aliphatic amines, cyclic secondary amines or L-amino acids under different set of conditions. All the synthesized compounds 4a-j and 5a-d were screened for anticancer activity against four cancer cell lines such as HeLa-Cervical cancer (CCL-2), COLO 205-Colon cancer (CCL-222) HepG2- Liver cancer (HB-8065), MCF7-Breast cancer (HTB-22). 4j and 5d showed good activity.

An efficient, economical synthetic route is developed for the antiviral drug favipiravir using a four-steps instead of a six-step protocol. Starting with 6-bromo-3-hydroxypyrazine-2-carboxamide the method offers an overall 65% molar yield. The prime intermediate 3,6-difluoropyrazine-2-carbonitrile was synthesized by reacting 3,6-dichloropyrazine-2-carbonitrile with potassium fluoride using tetrabutyl-ammonium bromide (TBAB) as a phase transfer catalyst in toluene and DMSO medium at reflux temperature (120 ºC). A simple purification method from fluoro intermediate was developed by making dicyclohexylamine salt and a neutral compound using hydrogen peroxide. The prepared pure favipiravir is fully characterized using NMR Mass and IR techniques. Validated analytical HPLC methods assessed the purity of the drug. The quality of the drug synthesized in terms of assay and impurities is well within the ICH and pharmacopeia standards.

Cancer is considered one of the leading causes of death globally, especially patients with lung, pancreatic, or brain tumors are most likely to die of cancer, and patients with prostate and breast cancer are at a high risk of noncancer death. As a result, there is ongoing research regarding developing new, safe, and efficient anticancer agents. Coumarin-based naturally occurring compounds possess a broad spectrum of activity in medicinal chemistry, such as anticancer, anti-inflammatory, antimicrobial, antioxidant agents, etc. Many researchers have synthesized coumarinbased novel therapeutic agents via molecular hybridization technique, which offers an excellent opportunity to develop novel compounds with improved biological activities by incorporating two or more pharmacophores. This review aims to shed light on the recent developments of coumarin-based anticancer hybrid derivatives and their Structure-Activity Relationships (SAR). This review serves as a medium that medicinal chemists could utilize to design and synthesize coumarin derivatives with significant pharmacological value as future anticancer agents.

Novel azole functionalized pyrido[2,3-d] pyrimidinone derivatives 6a-l were prepared starting from 2-Amino- 6-(thiophen-2-yl)-4-(trifluoromethyl)nicotinonitrile 1 reacting with trifluoroacetic acid in the presence of conc. H2SO4 and further reaction with bromoethyl acetate to obtain 3a and 3b. Compounds 3a and 3b further reacted with hydrazine hydrate to afford hydrazide compounds 4a and 4b. Compounds 4a and 4b on treating with phenylisothiocyanate give compound 5a and b. Compound 5a and 5b on reaction with different reagents (NaOH, H2SO4 and N2H4.H2O) produced different azole-substituted (triazolothione, thiadiazole, triazole) functionalized trifluoromethyl pyrido[2,3-d] pyrimidinone derivatives 6a-l respectively. All the products 6a–l were screened against gram +ve, gram –ve bacteria and fungal strains. Compounds 6ad showed promising activity against Bacillus subtilis microbial-type culture collection (MTCC) 121 at

Novel pyrazole tagged pyridine derivatives 5a-n synthesized starting from 3-cyano-4-trifluoromethyl-6- thiophenyl 2(1H) pyridone 1. Compound 1 on hydrolysis followed by decarboxylation resulted in 4-trifluoro-methyl-6- thiophenyl 2(1H)pyridone 2. Compound 2 treated with POCl3 to get 2- chloro-4-trifluoromethyl-6- thiophenyl pyridine 3 further reaction with hydrazine hydrate, which resulted in the formation of compound 4. Compound 4 on reaction with different substituted 1,3-diketones in ethanol reflux condition to afford pyrazole substituted pyridine derivatives 5a-n. All derivatives were tested against Gram-positive and Gram-negative bacterial strains and different Candida strains by well diffusion method, compounds 5k and 5l showed significant activity. The binding mode of 5k and 5l also studied by molecular docking studies.

Background: Human epidermal growth factor receptor 2 (Her2) gene located in human chromosome17, encodes Her2 tyrosine kinase protein, and is overexpressed in breast cancer cells. Her2 is activated on phosphorylation of tyrosine by adenosine triphosphate (ATP). Nonetheless, Her2 excessively partakes in the development and prognosis of specific types of aggressive breast cancers. Therefore, Her2 inhibition therapy is primary target for the treatment of aggressive breast cancer. At present, lapatinib is one of the Food and Drug Administration approved Her2 inhibitors used in cancer therapy. In molecular docking process, glabrene with slightly higher binding energy competitively bound to the active receptor site comparable to lapatinib and ATP. Therefore, glabrene could emerge as a potential candidate for restricting Her2 overexpressed breast cancer. Objective: The present study aimed to demonstrate the inhibitory activity of glabrene, an isoflavene and xenoestrogen found in liquorice root, along with known Her2 inhibitor, lapatinib. Methods: ATP, lapatinib, and glabrene were docked on human Her2 protein 3D structure which revealed glabrene as a competitive Her2 inhibitor akin to lapatinib. Results: The docking results suggested the binding site similarities of ATP, lapatinib, and glabrene. The binding energies of docked ATP, lapatinib, and glabrene complexes with Her2 were −9.1 kcal/mol, −10.5 kcal/mol, and −11.3 kcal/mol, respectively. Conclusion: The in silico docking simulation of ATP, lapatinib, and glabrene suggested that glabrene is likewise a competitive Her2 inhibitor.

Budesonide, a glucocorticosteroid, is used as anti-asthmatic drug that became generic in 2019. Existing preparation methods of budesonide require utilization of corrosive acids and involve expensive purification process. Thus, a new cost-effective continuous flow process for the synthesis of budesonide which belongs to the class of 16,17 acetals of pregnane core, is discussed in the present research findings. Flow reactor parameters such as flow rate, temperature, residence time, solution volumes, anti-solvents and reactor frequency are subjected to investigation on the preparation of molar ratio of budesonide epimers. Further, the suitable parameters entail for obtaining the desired molar ratio of epimers. In another aspect, particle size optimization studies are also performed to get the desired budesonide solid product. A continuous flow process for preparation of budesonide is identified from the present research investigation which can be readily transferred to industrial scale up.

Anti-cancer drug formulation Apalutamide 60mg tablets related substances method was developed and validated by using liquid chromatography gradient elution method. All the impurities and degradants were separated by using the Luna Omega 5μm Polar C18, (250 x 4.6) mm HPLC column with a 1.0 mLmin

Midostaurin (MTN), designated as an orphan medicinal product, is emerging as an important drug for treating acute myeloid leukemia and advanced systematic mastocytosis. The proposed method was developed and validated to evaluate the related impurities of MTN. The impurities were separated using a YMC Trait C18 ExRS column (150 × 4.6 mm, 3 μm). Mobile phase A consisted of a 10-mM concentration of phosphate buffer adjusted to pH 3.0 with diluted orthophosphoric acid, and mobile phase B consisted of 90% acetonitrile and 10% water. The optimized chromatographic conditions were as follows: flow rate, 0.5 mL min

Thermo-physical properties of hollow glass microsphere (HGM) filled silicone resin are analyzed by various mathematical models to optimize the formulation for a low-density high-temperature resistant composite. The study involves analyzing effective thermal conductivity, specific heat, and density for a two-phase particulate composite system by using the most popular expressions available in the literature at various volume fractions of HGM in the silicone resin matrix. Experiments are performed to compare theoretical results with the experimental data and identified the preferred composition with a density as low as 0.39 g/cc and thermal conductivity 0.116 W/m-K. The microstructural studies by SEM are done to explain the deviation in experimental and theoretical results. FEM analysis is done to understand the heat flow phenomenon in HGM filled silicone composites.

A series of novel amide tagged trifluoromethyl indole and pyrimido indole derivatives 4a-e & 5a-e and 6a-d & 7a-d were synthesized from 4-methyl-2-(methylamino)-6-(trifluoromethyl)isophthalonitrile (1) on reaction with bromoethyl acetate to obtain 2a and 2b isomers. Compound 2a treated with hydrazine hydrate followed by Schiff base reaction to get compounds 4a-e. In another way, compound 2a on reaction with aliphatic primary amine to get compounds 6a-d. For cyclization, compounds 4a-e & 6a-d treated with trifluoroacetic acid to obtain compounds 5a-e and 7a-d, respectively. All the synthesized compounds 4a-e & 5a-e and 6a-d & 7a-d were tested for anticancer activity against four human cancer cell lines such as A549-lung cancer (CCL-185), MCF7-breast cancer (HTB-22), DU145-prostate cancer (HTB-81) and HeLa-cervical cancer (CCL-2). Compounds 9e and 9f were found to have promising anticancer activity at micromolar concentration.

A three-component synthesis of novel 5-phenyl-2-(thiophen-2-yl)-4-(trifluoromethyl)-5Hindeno [1,2-b] [1,8] naphthyridin-6(11H)-one derivatives (4a-n) was prepared using 6-phenyl/ (thiophen- 2-yl)-4-(trifluoromethyl)pyridin-2-amine, 1H-indene-1,3(2H)-dione, and aryl aldehyde using 40% aq. HF with good yield. All the synthesized compounds were screened against Gram-positive and Gram-negative bacterial strains and different Candida strains by the well diffusion method. Compounds 4c, 4f, and 4g showed promising activity on Bacillus subtilis strain and compounds 4c and 4g showed promising activity towards Candida albicans strains.

The current study is designed to estimate mirabegron in the presence of high molecular weight polymers using a unique liquid chromatography method and sample preparation technique. The proposed method is significant because of the many analytical issues faced during the development studies. Based on the experimental results, we finally achieved the stability-indicating power of the method. The adequately prepared mobile phase was in the ratio of pH 2.0 buffer and acetonitrile (80:20) v/v, and the buffer pH 2.0 was prepared as follows: 8.7 ml of perchloric acid, 2 ml of triethylamine and 3.0 g sodium hydroxide into 1 L of water mixed well. The system suitability parameters were achieved using a Waters X-Bridge C

A series of thiazole linked Oxindole-5-Sulfonamide (OSA) derivatives were designed as inhibitors of RNA-dependent RNA polymerase (RdRp) activity of Dengue virus. These were synthesized and then evaluated for their efficacy in ex-vivo virus replication assay using human cell lines. Among 20 primary compounds in the series, OSA-15 was identified as a hit. A series of analogues were synthesized by replacing the difluoro benzyl group of OSA-15 with different substituted benzyl groups. The efficacy of OSA-15derivatives was less than that of the parent compound, except OSA-15-17, which has shown improved efficacy than OSA-15. The further optimization was carried out by adding dimethyl (DM) groups to both the sulfonamide and oxindole NH's to produce OSA-15-DM and OSA-15-17-DM. These two compounds were showing no detectable cytotoxicity and the latter was more efficacious. Further, both these compounds were tested for inhibition in all the serotypes of the Dengue virus using an ex-vivo assay. The EC

Ribosome assisted protein synthesis in all prokaryotes begins with a formylated methionine. Deformylation and demethionylation of these newly synthesized proteins are critical co-translational events carried out by peptide deformylase (PDF) and methionine aminopeptidase (MetAP) in all living cells. Since the mechanism of N-terminal modification is common between the infectious microbes and the host human cells, it is a challenge to identify selective inhibitors. Given that both MetAP and PDF are metalloenzymes, and have strong affinity for hydroxamic acids, we reasoned that the azaindole-based hydroxamic acids could inhibit the PDF enzymes. In the present study we describe the screening of a 17-compound library with 4- and 5- substituted azaindole hydroxamic acid derivatives against PDF enzyme from H. influenzae (HiPDF), M. tuberculosis (MtPDF) and human PDF (HsPDF). Several of these molecules showed nanomolar inhibition against HiPDF enzyme, best at 21 nM (15). On the other hand, none of these compounds inhibited the human enzyme while only two molecules showed moderate inhibition against Mtb enzyme. Surprisingly only 5-substituted azaindole derivatives inhibited the PDF enzymes. Some of the 5-substituted azaindole compounds inhibited the growth of different microbes indicating their potential application in antimicrobial therapy. Crystallographic and modeling studies provided the mechanistic view of regioselective inhibition.

Dengue virus (DENV) infection threatens the health and wellbeing of almost 100 million people in the world. Vectored by mosquitoes, DENV may cause a severe disease in human hosts called Dengue hemorrhagic fever (DHF)/Dengue shock syndrome (DSS), which is not preventable by any known drug. In the absence of a universally-accepted vaccine, a drug capable of inhibiting DENV multiplication is an urgent and unmet clinical need. Here we summarize inhibitory strategies by targeting either host biochemical pathways or virus-encoded proteins. A variety of approaches have been generated to design Directly-acting anti-virals or DAAs targeting different DENV proteins, with diverse success. Among them, DAAs targeting genome replicating viral enzymes have proven effective against many viruses including, Human Immuno-deficiency Virus and Hepatitis C Virus. DAAs may be derived either from existing compound libraries of novel molecules and plant secondary metabolites or devised through Computer-aided Drug design (CADD) methods. Here, we focus on compounds with reported DAA-activity against the DENV RNA-dependent RNA polymerase (RdRp), which replicate the viral RNA genome. The structure-activity relationship (SAR) and toxicity of the natural compounds, including secondary plant metabolites, have been discussed in detail. We have also tabulated novel compounds with known anti-RdRp activity. We concluded with a list of DAAs for which a co-crystal structure with RdRp is reported. Promising hit compounds are often discarded due to poor selectivity or unsuitable pharmacokinetics. We hope this review will provide a useful reference for further studies on the development of an anti-DENV drug.

A new series of 3,3ʹ-disubstituted chiral (S)-BINOL derivatives 6a–6k has been synthesized via the Kumada and Suzuki–Miyaura coupling reactions using (S)-BINOL as the initial compound. The Kumada coupling has been found to be superior in terms of yields and reaction time. All the synthesized compounds have been screened for their antibacterial activity against Gram-positive and Gram-negative organisms using Penicillin and Streptomycin as standards. The most potent antibacterial activity has been determined for compounds 6a,6b, 6c, and 6d with MIC values ranging from 1.17 to 4.68 μg/mL against all bacterial strains tested. Molecular docking studies has presented an insight into the binding pattern of the top active ligands with the respective target protein.

The present work describes a novel stability-indicating method development and validation for separation and identification of degradation products, known and genotoxic impurities in recently FDA a...

Favipiravir finished dosage was approved for emergency use in many countries to treat SARS-CoV-2 patients. A specific, accurate, linear, robust, simple, and stability-indicating HPLC method was developed and validated for the determination of degradation impurities present in favipiravir film-coated tablets. The separation of all impurities was achieved from the stationary phase (Inert sustain AQ-C18, 250 × 4.6 mm, 5-μm particle) and mobile phase. Mobile phase A contained KH

The synthesis of furano-rotenoid, pongarotene, by oxidative 1,2-aryl rearrangement of the sprirochromanone (11) using thallium(III) p-tosylate as key step has been described. Pongarotene (12) structure was confirmed by 2D NMR, HRMS and finally by X-ray crystallography. The sprirochromanones were synthesized by radical cyclization of chromone derivative (10). This methodology will be useful for the synthesis of naturally occurring rotenoids.

Imidazo[1,2-a]pyridine-based analogues have recently gained significant interest because of their wide spectrum of biological activities including anti-cancer potential, however the development of targeted therapeutic candidates against non-small cell lung cancer (NSCLC) is of utmost need due to its high prevalence and poor prognosis. Herein, we have aimed to synthesized novel imidazo [1,2-a] pyridine derivatives (IMPA) by coupling with 2-amino-4H-pyran to enhance bioactivity against NSCLC.We have designed and synthesized a series of fifteen novel imidazo [1,2-a] pyridine derivatives through molecular hybridization and studied their anti-cancer activity against in-vitro lung adenocarcinoma and 3D multicellular lung tumor spheroids.IMPA-2, IMPA-5, IMPA-6, IMPA-8, and IMPA-12 markedly induced cytotoxicity by notably increased NADPH oxidase (NOX) activity, which results in the induction of ROS-mediated apoptosis in A549 lung cancer cells. It caused impairment of mitochondrial membrane potential by increasing pro-apoptotic BAX, and BAK1 expressions, and decreasing anti-apoptotic BCL2 expression, along with the induction of caspase-9/3 activation, however, these attributes were compromised in presence of N-acetyl-L-cysteine (NAC), a free radical scavenger. Increased ROS production by IMPAs also promotes p53 mediated cell cycle arrest through the inactivation of p38MAPK. Reduction of tumor size in IMPAs-treated 3D multicellular lung tumor spheroids gave further validation.Beside cytotoxicity, IMPAs also inhibit lung cancer cell invasion and migration, suggesting their applicability in metastatic lung cancer. Therefore, IMPA derivatives could be used as potential anti-cancer agents in treating non-small cell lung cancer.

A simple stability-indicating method was developed and validated for the determination of progesterone (a steroid drug) in the semi-solid dosage form. All the impurities were separated from the main compound with a simple stationary phase (Eclipse XDB, C8, 150 × 4.6 mm, 5 μm). The mobile phase A contained phosphate buffer and acetonitrile in the ratio of 90:10, v/v, and mobile phase B contained purified water and acetonitrile in the ratio of 10:90, v/v. The optimized chromatographic conditions were as follows: flow rate, 1.0 mL min-1 ; UV detection, 241 nm; injection volume, 10 μL; and the column temperature, 30°C. The method was validated as per the current ICH Q2 guidelines. The recovery study and linearity ranges were established from 50 to 300% optimal concentrations. The method validation results were found between 98 and 102% for accuracy and r2 = 0.999 for linearity. Forced degradation in hydrolytic, oxidative, thermolytic, and photostability conditions was performed, and the stability indicating nature of the method was proved. Based on the validation and forced degradation results, the current method was found to be specific, precise, accurate, linear, robust, and stability-indicating method. The developed method was cost effective and easy to handle for quality control analysis.