Computational modelling strategies in exploring triazolopyridazine PIM1 kinase inhibitors as anticancer agents.

Background: PIM (Proviral Integration site for Moloney Murine Leukemia virus) kinases are members of the class of kinase family serine/ threonine kinases, which play a crucial role in cancer development. As there is no drug in the market against PIM-1, kinase has transpired as a budding and captivating target for discovering new anticancer agents targeting PIM-1 kinase.

Aim: The current research pondered the development of new PIM-1 kinase inhibitors by applying a ligand-based and structure-based drug discovery approach involving 3D QSAR, molecular docking, and dynamics simulation.

Topical advances in PIM kinases and their inhibitors: Medicinal chemistry perspectives.

Cytosolic PIM kinases are the members of serine/ threonine family play a crucial role in the cancer progression and development. Overexpression of PIM kinases is observed in various types of cancers including prostate, hematological, pancreatic, breast carcinoma and likewise. PIM kinases have now been considered as limelight target for the discovery of new molecules as novel anticancer agents as no drug is in the market targeting PIM kinases.

Design, Synthesis and Pharmacological Evaluation of Some C Heterocyclic-Substituted Ciprofloxacin Derivatives as Chimeric Antitubercular Agents.

A series of new C heterocyclic-substituted ciprofloxacin derivatives were prepared from ciprofloxacin acid hydrazide as possible chimeric molecules. They were evaluated for their possible in vitro antibacterial (agar cup/bore diffusion method) and antitubercular (Lowenstein-Jensen (LJ) slant method) activities. The results indicated that all the test compounds are highly effective against all the bacterial strains and have shown excellent anti-tubercular activity against normal, multidrug resistant and extensively drug resistant strains of Mycobacterium tuberculosis.

Substituted Benzamides from Anti-inflammatory and p38 Kinase Inhibitors to Antitubercular Activity: Design, Synthesis and Screening.

Background: Twenty one amide compounds possessing phenoxy/benzyloxy/pyridinyl groups have been synthesized by benzoylation of respective amines in presence of base with moderate to encouraging yields. Upon confirmation of structure, compounds were subjected for p38 kinase inhibitory, anti-inflammatory, antimicrobial and antitubercular activities.

Method: Anti-inflammatory activity was determined using carrageenan induced rat paw edema model while p38 kinase inhibitory activity was studied using ELISA method and serial dilution method was employed to determine MICs.

Design, Synthesis and Evaluation of New 2, 6-Dihydroimidazo[1, 2-c]Pyrimido[5, 4-e]-Pyrimidine-5(3H)-thiones as Possible Antihistaminic/Antiasthmatic Agents.

A series of new 10-(alkylamino)-8-methyl-2, 6-dihydroimidazo[1, 2-c]pyrimido[5, 4-e]pyrimidine-5(3H)-thiones (4a-g) were subjected to molecular property prediction (drug-likeness, lipophilicity and solubility parameters) using Osiris Property Explorer, ALOGPS 2.1, Molinspiration and ACD/Chemsketch 12.0 software programmes.

Molecular docking studies and in vitro screening of new dihydropyridine derivatives as human MRP1 inhibitors.

The overexpression of multidrug resistance protein 1 (MRP1) by tumor cells results in multidrug resistance (MDR) to structurally unrelated anticancer drugs. Circumvention of MDR by combination of chemosensitizers with antitumor compounds is a new field of investigation in cancer chemotherapy. Much effort has been put-in recently to identify the modulators/inhibitors of MRP1 to overcome the MDR.

Synthesis, antibacterial and antimycobacterial activities of some new 4-aryl/heteroaryl-2,6-dimethyl-3,5-bis-N-(aryl)-carbamoyl-1,4-dihydropyridines.

A novel class of 4-aryl/heteroaryl-2,6-dimethyl-3,5-bis-N-(phenyl/substituted phenyl)-carbamoyl-1,4-dihydropyridines has been synthesized by simple, economical and eco-friendly, modified Hantzsch condensation reaction making use of N-arylacetoacetamides, aryl or heteroaryl aldehydes and ammonium acetate. The newly synthesized compounds were characterized by their spectral (IR, 1H NMR, Mass), elemental analyses data and evaluated for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv ATCC 27294 and antibacterial activity against different Gram +ve and Gram -ve bacteria. The preliminary screening results revealed that some of the compounds possess promising antimicrobial activity.

Facile synthesis and antibacterial, antitubercular, and anticancer activities of novel 1,4-dihydropyridines.

A series of twenty new 4-substituted-2,6-dimethyl-3,5-bis-N-(heteroaryl)-carbamoyl-1,4-dihydropyridines have been prepared from a three-component one-pot condensation reaction of N-heteroaryl acetoacetamide, an aromatic/heteroaromatic aldehyde, and ammonium acetate under four different experimental conditions. Except for the conventional method, all the experimental conditions were simple, eco-friendly, economical, and the reactions were rapid and high-yielding. The methods employed have been compared in terms of yields, cost, and simplicity.

Synthesis and Pharmacological Evaluation of (6-Substituted 4-Oxo-4H-chromene-3 yl) methyl N-substituted Aminoacetates.

A series of the title compounds were synthesized and characterized by spectral data. All the compounds were evaluated for in vitro antihistaminic activity by inhibition of isotonic contractions induced by histamine on isolated guinea pig ileum and the compound 6-k showed significant activity. A few compounds have also been screened for in vivo bronchodilatory activity.

Molecular modeling studies of phenoxypyrimidinyl imidazoles as p38 kinase inhibitors using QSAR and docking.

p38 Kinase plays a vital role in inflammation mediated by tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta) pathways and inhibitors of p38 kinase provide effective approach for the treatment of inflammatory diseases. Pyridinyl and pyrimidinyl imidazoles, selectively inhibit p38alpha MAP kinase, are useful in the treatment of inflammatory diseases like rheumatoid arthritis. Three dimensional quantitative structure-activity relationship studies (3D-QSAR) involving comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA) and molecular docking were performed on 44 phenoxypyrimidinyl imidazole p38 kinase inhibitors to find out the structural relationship with the activity.

Strategies to design pyrazolyl urea derivatives for p38 kinase inhibition: a molecular modeling study.

The p38 protein kinase is a serine-threonine mitogen activated protein kinase, which plays an important role in inflammation and arthritis. A combined study of 3D-QSAR and molecular docking has been undertaken to explore the structural insights of pyrazolyl urea p38 kinase inhibitors. The 3D-QSAR studies involved comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA).

Novel targets for antiinflammatory and antiarthritic agents.

Inflammation is a complex pathological condition associated with exaggerated human immune system involving various activated immune cells and bio-molecules. Treatment of inflammatory diseases particularly chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease etc. has been a big challenge for scientists as there are no safe drugs available for cure.

Quaternary salts of 4,3' and 4,4' bis-pyridinium monooximes. Part 2: synthesis and biological activity.

In continuation of our investigations of unsymmetrical bisquaternary monooximes, we synthesized four new series of compounds bridged by hexyl, heptyl, octyl and nonyl groups. All eight monooximes viz., dibromides of 1-(4-hydroxyiminomethylpyridinium)6-(3/4-carbamoylpyridinium)hexane, 1-(4-hydroxyiminomethylpyridinium)-7-(3/4-carbamoylpyridinium)heptane, 1-(4-hydroxyiminomethylpyridinium)-8-(3/4-carbamoylpyridinium)octane, 1-(4-hydroxyiminomethylpyridinium)-9-(3/4-carbamoylpyridinium)nonane as well as the corresponding bis-oximes were synthesized and characterized by spectral data.