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Targeting kinases with oncogenic driver mutations in malignancies with allosteric kinase inhibitors is a promising new treatment technique. EGFR inhibitors targeting the L858R/T790M/C797S mutation bearing thiazolidine-4-one scaffold were discovered, optimized, synthesized, and biologically evaluated. According to

Background: This paper reports the synthesis, Non-nucleoside reverse transcriptase inhibitory (NNRTIs) activity and computational studies of 2-((4-chloro-2-subtitutedphenoxy) methyl)-4-(furan-2-ylmethylene)-1-substituted Pyridine/-pyrimidine-1H-imidazol-5(4H)-ones. Methods: The imidazol-5-one analogs were synthesized by conventional method and characterized by FT-IR, NMR and mass spectral data. All compounds were evaluated for in-vitro NNRTI activity by using reverse transcriptase (RT) assay kit (Roche). The in-silico docking studies were conducted on RT enzyme to investigate binding site interactions of synthesized compounds. The MMGBSA method was also used to calculate the binding free energy between the inhibitors and RT enzyme. The MD simulation was further performed for the apo form of the RT enzyme and docked complex of compound A6-RT enzyme to better understand the stability of the protein-ligand complex. Results: The bioactivity analysis revealed that most of the synthesized compounds showed significant inhibitory activity against RT enzyme and the IC50 value was found to be in the range of 1.76-3.88 μM. The computational studies suggest that the docked compounds form the H-bonding with amino acid residue Lys101 and hydrophobic interactions with amino acid residues Tyr188, Tyr181, Trp229, and Tyr318, which act as the primary driving forces for protein-ligand interaction. Conclusion: The reported imidazol-5-one analogs can act as lead for further development of prospective RT inhibitors.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2), a novel member of the betacoronavirus family is a single-stranded RNA virus that has spread worldwide prompting the World Health Organization to declare a global pandemic. This creates an alarming situation and generates an urgent need to develop innovative therapeutic agents. In this context, an in silico molecular docking and molecular dynamics (MD) simulation study on the existing 58 antiviral and antimalarial compounds was performed on 3CLpro, PLpro and RdRp SARS-CoV-2 proteins. The antiviral compounds are best fitted in the binding pockets and interact more profoundly with the amino acid residues compared to antimalarial compounds. An HIV protease inhibitor, saquinavir showed a good dock score and binding free energy with varied binding interactions against 3CLpro and PLpro. While, adefovir, a nucleotide HBV DNA polymerase inhibitor exhibited good dock score and binding interactions against RdRp. Although, the antimalarial compounds showed relatively less dock score but were found to be crucial in displaying essential binding interactions with these proteins. The MD simulation runs for 100 ns on 3CLpro–saquinavir, PLpro–saquinavir and RdRp–adefovir complexes using Desmond revealed fairly stable nature of interactions. This study helped in understanding the key interactions of the vital functionalities that provide a concrete base to develop lead molecules effective against SARS-CoV-2. Communicated by Ramaswamy H. Sarma

The mutations concerned with non-small cell lung cancer involving epidermal growth factor receptor of tyrosine kinase family have primarily targeted. EGFR inhibitors binding allosterically to C797S mutant EGFR enzyme have been developed. Here, database building, library screening performing R-group enumeration and scaffold hopping technique for increasing the EGFR binding affinity of compounds have been carried out. Virtual screening was performed subjecting to HTVS, SP and XP docking protocol along with its relative binding free energy calculations. Molecular docking studies provided the information about binding pockets and interactions of molecules on mutant (PDB: 5D41) as well as wild type (PDB: 4I23) EGFR enzyme. This was supported with ADMET and molecular simulation studies. On the basis of glide score and protein-ligand interactions, highest scoring molecule was selected for molecular dynamic simulation providing a complete insight into the conformational stability. The virtually screened molecules can act as potential EGFR inhibitors in the management of drug resistance. Communicated by Ramaswamy H. Sarma.

Series of novel N-benzyl derivatives of 6-aminoflavone (9a–n) were synthesized and evaluated for anticancer and topoisomerase II enzyme inhibition activity. All the synthesized compounds were screened for in vitro anticancer activity against human breast cancer cell line (MCF-7) and human lung cancer cell line (A-549). Among the synthesized compounds, 9f and 9g were found to be the most potent anticancer agents against human breast cancer cell line (MCF-7) with IC50 values of 9.35 µM and 9.58 µM, respectively. Compounds 9b, 9c and 9n exhibited promising anticancer activity against human lung cancer cell line (A-549) with 43.71%, 46.48% and 44.26% inhibition at the highest concentration of 10 µM, respectively. Compounds 9c, 9f and 9g have ability to inhibit the topoisomerase II enzyme. Compound 9f showed most potent topoisomerase II enzyme inhibition activity with IC50 value of 12.11 µM. Further, these compounds have a high potential to be developed as a promising topoisomerase II inhibitors.

For developing novel therapeutic agents with good anticancer activities, a series of novel pyridine-pyrimidine hybrid phosphonate derivatives4(a-q) were synthesized by the Kabachnik-Fields method using CAN as catalyst. The compound 4o exhibited the most potent anticancer activity with an IC

Here in, we report the design, synthesis and in vitro anticancer activity of a novel series of 24 quinoline analogues of substituted amide and sulphonamide derivatives. The anticancer activity of the synthesised compounds was evaluated against the HCC827, H1975 (L858R/T790 M), A549 (WT EGFR), A-549 and BEAS-2B cell lines. The majority of quinoline compounds demonstrated a significant cytotoxic effect. Compound 21 was found to be the most potent, with IC

Background A small library of quinazolin-4-one clubbed thiazole acetates/acetamides lacking toxicity-producing functionalities was designed, synthesized, and evaluated for antidiabetic potential as glucokinase activators (GKA). Molecular docking studies were done in the allosteric site of the human glucokinase (PDB ID: 1V4S) enzyme to assess the binding mode and interactions of synthesized hits for best-fit conformations. All the compounds were evaluated by in vitro enzymatic assay for GK activation. Results Data showed that compounds 3 (EC50 = 632 nM) and 4 (EC50 = 516 nM) showed maximum GK activation compared to the standards RO-281675 and piragliatin. Based on the results of the in vitro enzyme assay, docking studies, and substitution pattern, selected compounds were tested for their glucose-lowering effect in vivo by oral glucose tolerance test (OGTT) in normal rats. Compounds 3 (133 mg/dL) and 4 (135 mg/dL) exhibited prominent activity by lowering the glucose level to almost normal, eliciting the results in parallel to enzyme assay and docking studies. Binding free energy, hydrogen bonding, and π–π interactions of most active quinazolin-4-one derivatives 3 and 4 with key amino acid residues of the 1V4S enzyme were studied precisely. Preliminary in-silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction was carried out using SwissADME and PreADMET online software which revealed that all the compounds have the potential to become orally active antidiabetic agents as they obeyed Lipinski's rule of five. Conclusion The results revealed that the designed lead could be significant for the strategic design of safe, effective, and orally bioavailable quinazolinone derivatives as glucokinase activators.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2), a novel member of the betacoronavirus family is a single-stranded RNA virus that has spread worldwide prompting the World Health Organization to declare a global pandemic. This creates an alarming situation and generates an urgent need to develop innovative therapeutic agents. In this context, an

Novel non-camptothecin (non-CPT) class of conformationally constrained, hitherto unknown 7,12-dihydrodibenzo[b,h][1,6] naphthyridine and 7H-Chromeno[3,2-c] quinoline derivatives have been designed, synthesized and evaluated for anti-cancer activity. In vitro anti-proliferation evaluation against human cancer cell lines (A549 and MCF-7) exhibited significant cytotoxicity. Among the derivatives (8–24), 8 (IC50 0.44 μM and IC50 0.62 μM) and 12 (IC50 0.69 μM and IC50 0.54 μM) were identified as the most promising candidate against A-549 and MCF-7 cancer cell lines respectively. Topo I inhibitory activity of 8 and 12 suggested that, they may be developed as potential anti-cancer molecules in future and rationalized by docking analysis with effective binding modes. Further, in silico ADME prediction studies of all derivatives were found promising, signifying the drug like properties. In precise, the present investigation displays a new strategy to synthesize and emphasis on anticancer activities of conformationally constrained dibenzo[b,h][1,6] naphthyridine derivatives and Chromeno[3,2-c] quinoline derivatives in the context of cancer drug development and refinement.

The inhibition of D-alanine-D-alanine ligase (Ddl) prevents bacterial growth, which makes this enzyme an attractive and viable target in the urgent search for novel effective antimicrobial drugs. In this work, a series of novel coumarin-linked pyrazoline inhibitors of D-alanine-D-alanine ligase were synthesized and evaluated as inhibitors of Escherichia coli DdlB ligase in order to target resistant strains of bacteria using environmentally benevolent β-cyclodextrin as a supramolecular catalyst via one-pot four component synthesis in water as a green reaction media. All the newly synthesized compounds have been characterized by elemental analysis and various spectroscopic methods. The new procedure has noteworthy advantages including easy work-up, short reaction times, high yields of products and column-free synthesis. The synthesized compounds were evaluated in vitro for their antimicrobial activity. Among the synthesized compounds, namely 3-(5-(4-hydroxy-3-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-2H-chromen-2-one (5f) was found to be the most potent D-alanine-D-alanine ligase enzyme inhibitor, with an IC50 value 106 μM, and the compound 3-(5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-2H-chromen-2-one (5g) was found to be the second-most potent inhibitor of the DdlB enzyme, with an IC50 value 111 μM against the standard D-cycloserine. In addition, SAR study provided evidence that the –OH, –CH3 and –OCH3 groups at the 4- and 3-position of the coumarins linked to the pyrazolines scaffold increased enzymatic inhibition, while the molecular docking study of most active compounds 5a, 5g, and 5j against DdlB enzyme of E. coli exhibited good binding properties. This work thus highlights the coumarin-linked pyrazoline motif as a very promising tool for the development of novel antimicrobial compounds acting through an interesting bactericidal mechanism of action.

Methods: A novel series of isoxazole (S21-S30) derivatives were designed, synthesized and screened for their anticancer activity against estrogen receptor-positive MCF-7 and negative MDA-MB-435 breast cancer cell lines. The synthesized derivative has the ability to inhibit the growth of the human breast cancer cell line at low concentrations. In vivo anticancer activity was performed on virgin female sprague dawley rats. Results: The result shows that compound S23 has more selectivity and marked estrogen modulator activity than the standard tamoxifen.

Background Due to the need and adverse effects associated with the available anti-inflammatory agents, an attempt was made to develop the new anti-inflammatory agents with better activity and lesser adverse effects. Objective Synthetic approaches based on chemical modification of NSAIDs have been undertaken with the aim of improving NSAIDs safety profile. Method In the present study, a series of thiazole derivatives (3a-3x) was synthesized and tested for its anti-inflammatory with analgesic and nitric oxide releasing properties. In this work, synthesis of molecules containing substituted diaryl ring on 5-membered thiazole ring with nitric oxide releasing moiety is described. Results Out of the twenty four synthesized compounds, five compounds showed considerable anti-inflammatory and analgesic activity in comparison with the standard. Most of the synthesized compounds showed considerable nitric oxide-releasing property. The molecular docking study was used to rationalize binding interaction at the active site and the result showed good binding interaction. Conclusion From the results of pharmacological studies, we conclude that the synthesized compounds have not only retained, but showed enhanced anti-inflammatory and analgesic profile.

The present method provides a wide scope and quick access to dihydropyrido[2,3-d:6,5-d′]dipyrimidinetetraone and pyrimido[4,5-d]pyrimidine derivatives in good to excellent isolated yields from a one-pot three-component reaction of aldehydes, barbituric acid and ammonium acetate/urea in DIPEAc at room temperature. Major advantages of the present methodology are: use of green solvent, short reaction time, catalyst free, compatibility with a wide range of substrates, ease of recovery, reusability of the reaction medium, and DIPEAc as an alternative solvent and catalyst. All the synthesized compounds (3a–k) and (4a–g) were evaluated for their in vitro anticancer and tyrosinase inhibitory activity. In vitro anticancer screening of the synthesized compounds was performed against MCF-7, HeLa and A-549 cancer cell lines and 3f, 3h and 3i showed good activity. The compounds 3a, 3c, 3f and 3i showed good in vitro anticancer activity against SK-MEL-2. The synthesized compounds were also tested on non-tumorigenic MCF-10A cell lines and were found to be selective towards their cancer cell lines. At the IC50 concentration of compound 3f there were typical morphological changes such as cell wall deformation, cell detachment, cell shrinkage and a reduced number of viable cells in MCF-7 cancer cell lines in comparison to control cells. Among the series, compounds 3f, 3h and 3i excellently inhibited the tyrosinase enzyme. A molecular docking study of the compounds was also performed and compounds showed overall very effective binding modes and good agglomeration in the active site by forming various interactions with active site residues. The in silico ADMET properties of the synthesized compounds showed that they possess worthy oral drug like properties.

In the development of novel antimicrobial agents, we synthesized novel O-alkylated chromones 4a–f by ultrasound-assisted method. The synthesized compounds were characterized by IR, 1H NMR, 13C NMR, MS, and elemental analysis. All compounds were assessed in vitro for their efficacy as antimicrobial agents against four bacteria (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa) and three fungi (Candida albicans, Candida glabrata, Candida tropicalis). In particular, compounds 4a, 4b, 4d, 4e, and 4f exhibited potent antimicrobial activity. Molecular docking study was used to rationalize binding interaction at the active site, and the result showed good binding interaction. The compounds were also processed for in silico ADME prediction, and the result showed that compounds could be exploited as an oral drug candidate.

Series of novel N-benzyl derivatives of 6-aminoflavone (9a-n) were synthesized and evaluated for anticancer and topoisomerase II enzyme inhibition activity. All the synthesized compounds were screened for in vitro anticancer activity against human breast cancer cell line (MCF-7) and human lung cancer cell line (A-549). Among the synthesized compounds, 9f and 9g were found to be the most potent anticancer agents against human breast cancer cell line (MCF-7) with IC

The obligatory testing of drug molecules and their impurities to protect users against toxic compounds seems to provide interesting opportunities for new drug discovery. Impurities, which proved to be non-toxic, may be explored for their own therapeutic potential and thus be a part of future drug discovery. The essential role of pharmaceutical analysis can thus be extended to achieve this purpose. The present study examined these objectives by characterizing the major degradation products of zileuton (ZLT), a 5-lipoxygenase (5-LOX) inhibitor being prevalently used to treat asthma. The drug sample was exposed to forced degradation and found susceptible to hydrolysis and oxidative stress. The obtained Forced Degradation Products (FDP's) were resolved using an earlier developed and validated Ultra-High-Pressure Liquid Chromatography Photo-Diode-Array (UHPLC-PDA) protocol. ZLT, along with acid-and alkali-stressed samples, were subjected to Liquid-chromatography Mass-spectrometry Quadrupole Time-of-flight (LC/MS-QTOF) studies. Major degradation products were isolated using Preparative TLC and characterized using Q-TOF and/or Proton nuclear magnetic resonance (1HNMR) studies. The information obtained was assembled for structural conformation. Toxicity Prediction using Komputer Assisted Technology (TOPKAT) toxicity analyses indicated some FDP's as non-toxic when compared to ZLT. Hence, these non-toxic impurities may have bio-affinity and can be explored to interact with other therapeutic targets, to assist in drug discovery. The drug molecule and the characterized FDP's were subjected to 3-Dimensional Extra Precision (3D-XP)-molecular docking to explore changes in bio-affinity for the 5-LOX enzyme (PDB Id: 3V99). One FDP was found to have a higher binding affinity than the drug itself, indicating it may be a suitable antiasthmatic. The possibility of being active at other sites cannot be neglected and this is evaluated to a reasonable extent by Prediction of Activity Spectra for Substances (PASS). Besides being antiasthmatic, some FDP's were predicted antineoplastic, antiallergic and inhibitors of Complement Factor-D.

A search for potent antiproliferative agents has prompted to design and synthesize aryloxy bridged and amide linked dimeric 1,2,3-triazoles (7a–j) by using 1,3-dipolar cycloaddition reaction between 2-azido-N-phenylacetamides (4a–e) and bis(prop-2-yn-1-yloxy)benzenes (6a–b) via copper (I)-catalyzed click chemistry approach with good to excellent yields. All the newly synthesized compounds have been screened for their in vitro antiproliferative activities against two human cancer cell lines. The compounds 7d, 7e, 7h, 7i and 7j have revealed promising antiproliferative activity against human breast cancer cell line (MCF-7), whereas, the compounds 7a, 7b, 7c, 7i and 7j were observed as potent antiproliferative agents against human lung cancer cell line (A-549). The active compounds against MCF-7 have been also analysed for their mechanism of action by the enzymatic study, which shows that the compounds 7d, 7h and 7j were acts as active EGFR tyrosine kinase phosphorylation inhibitors. In support to this biological study, the molecular docking as well as in silico ADME properties of all the newly synthesized hybrids were predicted.

A library of novel flavonoid derivatives with diverse heterocyclic groups was designed and efficiently synthesized. Structures of the newly synthesized compounds 4a-i and 8a-l have been characterized by 1H NMR, 13C NMR, MS and elemental analysis. Anticancer activities were evaluated against MCF-7, A549, HepG2 and MCF-10A by MTT based assay. Compared with the positive control Adriamycin, compounds 4a, 4b, 4c, 4d, 8d, 8e and 8j were found to be most active anti-proliferative compounds against human cancer cell line. We found that compounds 4a and 4c exhibited inhibition of enzyme topoisomerase II with IC50 values 10.28 and 12.38 μM, respectively. In silico docking study of synthesized compounds showed that compounds 4a and 4c have good binding affinity toward topoisomerase IIα enzyme and have placed in between DNA base pair at active site of enzyme. In silico ADME prediction results that flavonoid coumarin analogues 4a-i could be exploited as an oral drug candidate.

An approach is described to access 1,2,3-triazole-derived peptidyl vinyl sulfones as Trypanosoma brucei brucei inhibitors by using click chemistry, starting from a common azide intermediate. Among the triazole analogues, biotinylated inhibitors 11 and 12 offer possibilities as probes for the elucidation of target proteases for this compound class. The development of two syntheses of a 1,2,3-triazole-based vinyl sulfone 5 are also presented. This compound was accessed through a click reaction of a lysine-derived azide (itself accessed by diazo transfer), and a phenylalanine-derived alkyne synthesised by both Ohira–Bestmann and Corey–Fuchs-based alkynylation protocols. Several members of this family of compounds showed promising anti-trypanosomal activity. Unexpectedly, one of the most active compounds was allyl sulfone 24, which stems from the isomerisation of vinyl sulfone 5, and is presumably a reversible inhibitor. A docking study of the analogues in the active site of the parasitic cysteine protease rhodesain was carried out in order to gain an insight into their likely interactions with these enzymes.

In Search of novel antimicrobial agents with improved potency, we designed and synthesized a series of 3-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-2-(4-fluorophenyl)-4H-chromen-4-ones 5a–f using click chemistry. The structures of synthesized compounds were found using IR, 1H NMR, 13C NMR, and MS. All the synthesized compounds were assayed for their in vitro antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa and antifungal activity against Candida albicans, Candida glabrata, and Candida tropicalis by micro broth dilution method. The antimicrobial data suggested that from the series, compounds 3e, 4e, 5e, and 5f shows pronounced antimicrobial activity against the tested strain with low MIC value. Molecular docking study was used to rationalize binding interaction at the active site and the results showed good binding interaction.

A series of hetero-substituted sulphonamido-benzamide derivatives which can activate glucokinase (GK) were synthesized and screened in-vitro using Human GK activation assay and in-vivo following oral glucose tolerance test (OGTT) assays. All the molecules were docked into the active site of 1V4S receptor grid by XP docking method utilizing Schrodinger software to assess the binding interactions. Compounds 12 (EC50 = 495 nM) and 15 (EC50 = 522 nM), revealed maximum in-vitro GK activation. Selected compounds were subjected for in-vivo OGTT assay. The data revealed that same compounds 12 (135 mg/dL) showed maximum reduction in blood glucose level followed by compound 15 (142 mg/dL) at 120 min. The docking results as glide score, binding energy and interactions were reported and compounds with maximum pharmacological activity were studied precisely. In-silico ADME parameters, pharmacokinetic properties and toxicity studies were carried out and all compounds were found to have good bioavailability and nontoxic. Overall, the series of hetero-substituted sulphonamido-benzamide hybrids are safe and could be explored further for better therapeutic efficacy as GK activators.

In search of new active molecules against MCF-7, A549 and HepG2, tetrazole based pyrazoline and isoxazoline derivatives under both conventional and ultrasonic irradiation method were designed and efficiently synthesized. Structures of newly synthesized compounds 5a-h and 6a-h were characterized by 1H NMR, 13C NMR, MS and elemental analysis. Several derivatives were found to be excellent cytotoxic against MCF-7, A549 and HepG2 cell lines characterized by lower IC50 values (0.78–3.12 µg/mL). Compounds 5b and 5c demonstrated an antiproliferative effect comparable to that of CA-4. Western blot analysis revealed that, reported compounds accumulate more tubulin in the soluble fraction. Docking studies suggested that, binding of these compounds mimics at the colchicine site of tubulin. In vitro study revealed that the tetrazole based pyrazolines and isoxazolines may possess ideal structural requirements for further development of novel therapeutic agents.

A series of new sulfonamide analogues of 6/7-aminoflavones were synthesized by using molecular hybridization approach. These new sulfonamide analogues were screened for antiproliferative activity against human hepatocellular carcinoma (HepG-2), human lung cancer cell line (A-549), human colorectal adenocarcinoma (Caco-2) cancer cell lines. Compounds 5p, 5q, 5t, 5v, 5w and 5x exhibited good anticancer activity against selected cancer cell lines. These compounds were further evaluated to predict their ability to inhibit topoisomerase-II enzyme. Compound 5x has shown potent antiproliferative activity (IC50 value 0.98 µM) as compared to standard drug Adriamycin (IC50 = 0.94 µM) indicating that these compounds exhibits anticancer activity via inhibition of topoisomerase-II enzyme. Docking results also have supported above observations by indicating that compounds are held in the active pocket by combination of various hydrogen and hydrophobic interactions with Top II-DNA-etoposide enzyme.

The simple, multicomponent, water-mediated synthesis of benzothiazolo [2,3-b] quinazolin-1-ones were carried out from aminobenzthiazoles, cyclic β diketone, and aromatic aldehydes. The simplicity, easy work up, short reaction time, and use of environmentally benign water as a solvent are some advantages of this proposed method. The newly synthesized compounds were evaluated for cytotoxicity against a panel of human cancer cell lines (U-937, Hep-2, vero, and MCF-7). Among the synthesized compounds, the compounds 4a and 4d showed higher anticancer activity. The result of DNA fragmentation analysis showed that the compound 4d induced dose-dependent apoptosis. This preliminary study encouraged us to consider the compounds 4a and 4d as interesting leads for further optimization.

Non-nucleoside reverse transcriptase inhibitors have a definitive role and most commonly used in treatment of HIV-1 infection. A new series of 4-ethylidene/substituted-benzylidene-1-(4-hydroxy/chloro-6-methylpyrimidin-2-yl)-2-ethyl/phenyl-1H-imidazol-5(4H)-one were designed, synthesized, and evaluated for HIV-1 reverse transcriptase (RT) inhibitory activity. The results of in-vitro HIV-1 RT assay showed that some of the new compounds, such as 4c, 4d, 4e, 5a, and 5e effectively inhibit HIV-1 RT activity. 1-(4-Chloro-6-methylpyrimidin-2-yl)-4-(furan-2-ylmethylene)-2-methyl-1H-imidazol-5(4H)-one (5e) exerted most potent in-vitro HIV-1 RT inhibitory activity, among the group of compounds. Molecular docking studies were carried out to explore the binding affinity of imidazole-5-one analogs in active site of HIV-1 RT enzyme.

The 3D QSAR studies based on generation of common pharmacophore hypotheses (CPHs) were performed separately for the series of 1,2,3,4-tetrahydropyrimidin-5-yl-acetic acid and 2-(4-sulfonylphenyl)pyrimidine analogs for their in-vivo anti-inflammatory activity and in-vitro COX-2 inhibitory activity respectively. The main idea of selecting two different series was to develop two 3D QSAR models for same scaffold (1,2,3,4-tetrahydropyrimidine/pyrimidine) for same target, but with different aspects of activity. The aim of study was to screen designed compounds and select new compounds with increased COX-2 selectivity. The best 3D QSAR model from both group was employed as 3D search query to screen the designed 4,5,6-triphenyl-1,2,3,4-tetrahydropyrimidine derivatives. The new compounds showing good predicted activity were selected for experimental studies. Among the synthesized compounds, 5c and 5f showed highest anti-inflammatory activity.

Tubulins, an αβ heterodimers, the major component of microtubules, are important molecular target of numerous small molecule ligands for anticancer therapy. In this study, the molecular modeling studies were performed to develop predictive 3D-QSAR models using set of 32 compounds of benzoyl urea derivatives as tubulin-binding agents for antiproliferative activity. A five-point common pharmacophore hypotheses with one hydrogen bond acceptor (A), two hydrogen bond donors (D), one hydrophobic (H), and one ring (R) vector features were selected for alignment of all compounds. The 3D-QSAR models generated using training set of 21 compounds and test set of 11 compounds showed good partial least squares statistical results. The developed CPHs and 3D-QSAR models were validated further externally by predicting the activity of database of compounds from literature and comparing it with actual activity. Docking studies were also carried out for all compounds on colchicine-binding site of β-tubulin for studying of binding affinity of compounds for antiproliferative activity. The results of these molecular modeling studies are helpful to refine the pharmacophore for design of new potential compounds for antiproliferative activity.

Synthesis of new series of 1,2,4-triazole with 1,2,3-triazole and piperidine ring using ZrOCl(2) ·8H(2) O as a catalyst in ethanol has been described. The yields obtained are in the range of 80-85%. All the synthesized compounds (3a-3o) are novel and were evaluated for their in vitro antifungal activities using standard agar method. Docking study of the newly synthesized compounds was performed, and results showed that all new compounds have similar binding mode in the active site of fungal enzyme P450 cytochrome lanosterol 14α-demethylase.

2D and 3D quantitative structure-activity relationship studies have been carried out for establishing a correlation between the structural properties of benzyl urea derivatives and their anti-tumour activities. From this correlation, the new chemical entities were designed, and their activity and absorption, distribution, metabolism, excretion, and toxicity properties were also predicted. Finally, the most promising compounds from these screening were synthesized and biologically evaluated for their anti-cancer properties. Compound 1-(2, 4-dimethylphenyl)-3, 3-dimethyl-1-(2-nitrobenzyl) urea (7d) showed significant anti-proliferative activity (at 100 µg/mL) in human cancer cell lines-T-cell leukemia (Jurkat J6), myelogenous leukemia (K562), and breast cancer (MCF-7) compared to reference standard 5-flurouracil.

Since the last 41 years, Ibuprofen has been one of the most widely used Non-Steroidal Anti-Inflammatory Drug (NSAID) due to its anti-inflammatory actions. As all the NSAIDs are suffering from the deadlier GI toxicities, Ibuprofen also is no exception to these toxicities. The free –COOH group is thought to be responsible for the Gastrointestinal (GI) tract toxicity associated with all the traditional NSAIDs. Therefore, the main aim of this study was to develop new chemical entities as potential anti-inflammatory agents with less GI toxicities. In this article, synthesis of a series of Hybrid molecules containing important pharmacophore of Ibuprofen and substituted diaryl rings on 5-membered heterocycle similar to coxibs and Nitric oxide-releasing moiety are described. All the synthesized compounds were tested in vivo for their anti-inflammatory, analgesic, ulcerogenic properties, and histopathological studies and in vitro for their nitric oxide-releasing properties. Out of the six synthesized compounds, four compounds showed significant anti-inflammatory and analgesic activity which was compared with standard. All the synthesized compounds exhibited significant nitric oxide-releasing and reduced GI ulcerogenic activity.

Non-nucleoside reverse transcriptase inhibitors (NNRTI) has a definitive role and most commonly used in treatment of HIV infection. NNRTI act by binding to specific binding site (non-nucleoside binding pocket-NNBP) in reverse transcriptase (RT) enzyme. With the objective of developing efficient NNRTI, we have designed various Isatin analogs for effective treatment of AIDS and were subjected to molecular docking studies on five different crystal structures of RT complexed with five different ligands Nevirapine, Delaviridine, Efavirenz, Etravirine, and Rilpivirine. Combined dock-score of compound N21, N11, N23 was found to be comparable with standards indicated that Isatin analogs have good binding affinity for NNBP. Docking results suggested that these types of compounds could be binding in the NNRTI binding site in a similar mode to a known non-nucleoside inhibitors. ADME properties of Isatin analogs were also analyzed using Qikprop 2.5 tool of Schrodinger software.

Various substituted 1,5-diarylpyrazol-3-one derivatives were synthesized and screened for analgesic, anti-inflammatory activities, ulcerogenic potential and for their ability to release nitric oxide. Most compounds exhibited significant analgesic and anti-inflammatory activities. It was interesting to note that out of ten compounds, 7j (59.64%) was found to have anti-inflammatory activity greater than the standard drug Indomethacin (57.89%), whereas compound 7b (57.89%) was found to be equipotent to that of standard, Indomethacin. The pharmacological studies suggested that the presence of 4-nitro and 2-methoxy on phenyl ring at C5 of pyrazole has a significant anti-inflammatory activity and 4-chloro substitution on same phenyl ring was found to have decreased activity. However only a phenyl substituted derivative was found to have most potent activity. Compound 7j containing plane phenyl at C5 of pyrazole was found to have significant analgesic activity (56.86%) in acetic acid induced writhing model. Compounds 7d and 7i having 4-chloro substituted phenyl ring showed least analgesic activity (10.78%) and (6.86%) respectively. The compounds also showed significantly reduced GI-ulcerogenicity and gastroprotective results in histopathological studies i.e. they were found to be causing no mucosal injury. All the synthesized compounds were found to exhibit significant nitric oxide releasing activity, in both in vitro and in vivo models. Molecular docking studies served to be an important tool for the study of binding of compounds with that of a COX-2 enzyme. The results of the docking studies were found to endorse the result of experimental work. Thus, the rationale used to design the NCEs was found to produce the promising results as anticipated. Therefore it can be said that the strategy employed can serve as an important tool in future for the design and development of novel therapeutic agents of various categories too.

Tumor necrosis factor-α (TNF-α) converting enzyme (TACE) has been considered one of the principal therapeutic targets for the treatment of TNF-dependent pathologies. Several TACE inhibitors have been reported, but none of them has been successfully passed to phase II clinical trials. In the present work, we attempted to design highly selective new non-hydroxamate sulfonamide TACE inhibitors. The docking study was performed on one of the crystal structures of TACE, selected based on its resolution and R value, to tackle the flexibility issue of the active site. The results allowed us to distinguish the analogues with a higher binding affinity toward the active site of TACE and to identify the substituent of analogues needed for binding with the surrounding site of the enzyme. Finally the analogues were docked on crystal structures of six different matrix metalloproteinases (MMPs) for a selectivity study of TACE over MMPs. Some of these analogues were synthesized and subjected to preliminary testing for in vivo anti-inflammatory activity and TACE inhibitory activity.

Objective: synthesis of new 1, 3-diphenyl pyrazole derivatives 9(a-f) and 10(a-f) using molecular hybridization approach for antitubercular and cytotoxic studies.Methods: The structures of synthesized compounds were confirmed by 1H-NMR, 13C-NMR and mass spectra’s. The antitubercular activity of compounds and standard drugs were assessed against Mycobacterium tuberculosis using microplate Alamar Blue assay (MABA). The cytotoxic activities were performed by Sulforhodamine B (SRB) assay. The molecular docking and in silico ADME prediction were studied by using Schrodinger.Results: The results reveals that the compounds 9c, 9d, 10c and 10d exhibited substantial antitubercular potential with MIC < 20 μM. The cytotoxic studies revealed that the active compounds (9d, 10a, and 10d) are non-toxic to HeLa cancer cell lines with selectivity index >10. The molecular docking study was performed to study the binding orientation and affinity of synthesized compounds for InhA enzyme.Conclusion: The study explored that the 1, 3-diphenyl pyrazole hybrids coupled with well known antitubercular drugs could be a potential lead for antitubercular agents. In-silico molecular docking study helps to identify their corresponding intermolecular ligand-protein interactions with target enzyme. Also ADME prediction studies revealed that the compounds were in acceptable range to have pharmacokinetic parameters.

Herein, we report an environmentally friendly, rapid, and convenient one-pot ultrasound-promoted synthesis of 5-amino-2-(4-chlorophenyl)-7-substituted phenyl-8,8a-dihydro-7H-(1,3,4)thiadiazolo(3,2-α)pyrimidine-6-carbonitrile derivatives. The in-vitro anticancer activities of these compounds were evaluated against four human tumor cell lines. Among all the synthesized derivatives, compound 4i, which has substituent 3-hydroxy-4-methoxyphenyl is found to have the highest GI50 value of 32.7 μM, 55.3 μM, 34.3 μM, 28.9 μM for MCF-7, K562, HeLa and PC-3 cancer cell lines respectively. A docking study of the newly synthesized compounds were performed, and the results showed good binding mode in the active site of thymidylate synthase enzyme. ADME properties of synthesized compounds were also studied and showed good drug like properties The authors are thankful to the Fatima Rafiq Zakaria Chairman Maulana Azad Educational Trust and Zahid Zaheer, Incharge Principal, Y.B. Chavan College of Pharmacy, Rafiq Zakaria Campus, Aurangabad 431 001 (M.S.), India for providing the laboratory facility. In vitro SRB assay for anti-cancer activity evaluation of drugs was performed at Anti-Cancer Drug screening facility (ACDSF) at ACTREC, Tata Memorial Centre, Navi Mumbai and the authors are greatful to Jyoti Kode for her cooperation in in-vitro studies SI

A novel series of substituted imidazol-5-ones were designed, synthesized and evaluated for in vitro reverse transcriptase (RT) inhibition activity using reverse transcriptase assay kit (Roche, Colorimetric). It has been observed from in vitro screening that newly synthesized compounds possess RT inhibitory activity. Docking study was performed to study the binding orientation and affinity of synthesized compounds for RT enzyme.

We present here the Energetic pharmacophore model representing complementary features of the 1,2,3,4-tetrahydropyrimidine for selective cyclooxygenase-2 (COX-2) inhibition. For the development of pharmacophore hypothesis, a total of 43 previously reported compounds were docked on active site of COX-2 enzyme. The generated pharmacophore features were ranked using energetic terms of Glide XP docking for 1,2,3,4-tetrahydropyrimidine scaffold to optimize its structure requirement for COX-2 inhibition. The thirty new 4,5,6-triphenyl-1,2,3,4-tetrahydropyrimidine derivatives were synthesized and assessed for selective COX-2 inhibitory activity. Two compounds 4B1 and 4B11 were found to be potent and selective COX-2 inhibitors. The molecular docking studies revealed that the newly synthesized compounds can be docked into COX-2 binding site and also provide the molecular basis for their activity.

Synthesis of new series of 1,2,4-triazole with 1,2,3-triazole and piperidine ring using ZrOCl(2) ·8H(2) O as a catalyst in ethanol has been described. The yields obtained are in the range of 80-85%. All the synthesized compounds (3a-3o) are novel and were evaluated for their in vitro antifungal activities using standard agar method. Docking study of the newly synthesized compounds was performed, and results showed that all new compounds have similar binding mode in the active site of fungal enzyme P450 cytochrome lanosterol 14α-demethylase.