Design, synthesis and evaluation of acridone-2-carbohydrazide derivatives as p-AKT Ser473 kinase inhibitors.

Aim: A series of benzylidene- and phenylethylidene-substituted acridone-2-carbohydrazide derivatives were designed, synthesized and evaluated for their cytotoxicity and response to p-AKT Ser473. Methods: The structures of the synthesized compounds were confirmed by spectroscopic techniques and evaluated for AKT enzyme inhibition activities. Molecular docking and in silico absorption, distribution, metabolism, elimination and toxicity studies were also performed. Results: Compounds 8k, 8v and 9h demonstrated good cytotoxicity against breast cancer cell lines. Especially, compounds 8v and 9h exhibited remarkable inhibition, with IC50 values of 1.75 and 2.40 µM, respectively. These compounds inhibited p-AKT Ser473 more specifically than total AKT in a dose-dependent manner. Moreover, they caused G0/G1-phase cell cycle arrest and cell apoptosis. Conclusion: This study identified compound 8v as a potent p-AKT Ser473 inhibitor.

Design, synthesis, modelling studies and biological evaluation of 1,3,4-oxadiazole derivatives as potent anticancer agents targeting thymidine phosphorylase enzyme.

A series of novel 1,3,4-oxadiazole derivatives with substituted phenyl ring were designed and synthesized with an objective of discovering newer anti-cancer agents targeting thymidine phosphorylase enzyme (TP). The 1,3,4-oxadiazole derivatives were synthesized by simple and convenient methods in the lab. Chemical structure of the all the synthesized compounds were characterized by IR, 1H NMR and mass spectral methods and evaluated for cytotoxicity by MTT method against two breast cancer cell lines (MCF-7 and MDA-MB-231). Further, results of TP assay identified that 1,3,4-oxadiazole molecules displayed anti-cancer activity partially by inhibition of phosphorylation of thymidine. The TP assay identified SB8 and SB9 as potential inhibitors with anti-cancer activity against both the cell lines. The molecular docking studies recognized the orientation and binding interaction of molecule at the active site amino acid residues of TP (PDB: 1UOU). Acute toxicity studies of compound SB8 at the dose of 5000 mg/kg has identified no signs of clinical toxicity was observed. The SARs study of synthesized derivatives revealed that the substitution of phenyl ring with electron withdrawing group at ortho position showed significant TP inhibitory activity compared to para substitution. The experimental data suggests that 1,3,4-oxadiazole with substituted phenyl can be taken as a lead for the design of efficient TP inhibitors and active compounds which can be taken up for further studies.

Targeting telomerase for its advent in cancer therapeutics.

Telomerase has emerged as an important primary target in anticancer therapy. It is a distinctive reverse transcriptase enzyme, which extends the length of telomere at the 3' chromosomal end, and uses telomerase reverse transcriptase (TERT) and telomerase RNA template-containing domains. Telomerase has a vital role and is a contributing factor in human health, mainly affecting cell aging and cell proliferation. Due to its unique feature, it ensures unrestricted cell proliferation in malignancy and plays a major role in cancer disease. The development of telomerase inhibitors with increased specificity and better pharmacokinetics is being considered to design and develop newer potent anticancer agents. Use of natural and synthetic compounds for the inhibition of telomerase activity can lead to an opening of new vistas in cancer treatment. This review details about the telomerase biochemistry, use of natural and synthetic compounds; vaccines and oncolytic virus in therapy that suppress the telomerase activity. We have discussed structure-activity relationships of various natural and synthetic telomerase inhibitors to help medicinal chemists and chemical biology researchers with a ready reference and updated status of their clinical trials. Suppression of human TERT (hTERT) activity through inhibition of hTERT promoter is an important approach for telomerase inhibition.

3D-QSAR and Molecular Docking Studies on Oxadiazole Substituted Benzimidazole Derivatives: Validation of Experimental Inhibitory Potencies Towards COX-2.

BACKGROUND: In past few decades, computational chemistry has seen significant advancements in design and development of novel therapeutics. Benzimidazole derivatives showed promising anti-inflammatory activity through the inhibition of COX-2 enzyme. OBJECTIVE: The structural features necessary for COX-2 inhibitory activity for a series of oxadiazole substituted benzimidazoles were explored through 3D-QSAR, combinatorial library generation (Combi Lab) and molecular docking. METHODS: 3D-QSAR (using kNN-MFA (SW-FB) and PLSR (GA) methods) and Combi Lab studies were performed by using VLife MDS Molecular Design Suite. The molecular docking study was performed by using AutoDockVina. RESULTS: Significant QSAR models generated by PLSR exhibited r2 = 0.79, q2 = 0.68 and pred_r2 = 0. 84 values whereas kNN showed q2 = 0.71 and pred_r2 = 0.84. External validation of developed models by various parameters assures their reliability and predictive efficacy. A library of 72 compounds was generated by combinatorial technique in which 11 compounds (A1-A5 and B1-B6) showed better predicted biological activity than the most active compound 27 (pIC50 = 7.22) from the dataset. These compounds showed proximal interaction with amino acid residues like TYR355 and/or ARG120 on COX-2(PDB ID: 4RS0). CONCLUSION: The present work resulted in the design of more potent benzimidazoles as COX-2 inhibitors with good interaction as compared to reference ligand. The results of the study may be helpful in the development of novel COX-2 inhibitors for inflammatory disorders.

An overview of tramadol and its usage in pain management and future perspective.

Patients with chronic non-malignant pain report impairment of physical and social life along with psychological state affecting their overall quality of life. The purpose of managing pain is to reduce the trauma and improve the patient comfort with better quality of life. Tramadol is a centrally acting weak µ-opioid receptor analgesic and is a racemic mixture of (+)-tramadol and (-)-tramadol enantiomers. Tramadol is used worldwide and is listed in many medical guidelines for pain management. The (+)-tramadol has greater affinity for µ-opioid receptor and provides additional prevention of 5- hydroxy tryptamine reuptake, while the (-)-tramadol is a successful noradrenaline reuptake inhibitor and intensifies its release by activating the auto receptor. Tramadol is prescribed to relieve moderate to severe pain management in patients. Tramadol does not show much serious adverse effects without any dependency potential in therapeutic doses as seen in other opioids, like morphine. Tramadol metabolite M1 also has µ-opioid receptor agonist activity, but it faces poor blood brain barrier permeability. In this review, we report the complete updated status of Tramadol along with its chemistry, synthesis, pharmacology, medicinal uses, adverse effects and its combinations available in the market. We have also covered Tramadol patents so that a complete overview provides a broader perspective for future designing of its derivatives and increase their potential use for pain management in terminal cancer patients.

Synthesis, thymidine phosphorylase inhibitory and computational study of novel 1,3,4-oxadiazole-2-thione derivatives as potential anticancer agents.

A series of novel 1,3,4-oxadiazole-2-thione derivatives were designed, synthesized and evaluated for in vitro anticancer activity against breast cancer (MCF-7) cell line and thymidine phosphorylase. The synthesis of target compounds was performed by cyclization reaction using aromatic amines and carbon disulphide to get mannich bases. The synthesized compound 2j exhibited the most potent anticancer activity against MCF-7 cell line. Compounds 2d, 2j, 2o and 2h showed potent thymidine phosphorylase inhibitory activity. The SAR study revealed that the substitution of phenyl ring with electron withdrawing group at R1 position and less bulky amines group at R2 position of 1,3,4-oxadiazole-2-thione ring showed significant growth inhibitory activity. Further in silico ADMET properties of synthesized compounds were calculated along with molecular docking to study the binding mode of the compounds in the active site of thymidine phosphorylase (TP). The molecular docking studies showed that amines group have good binding interaction on active site residues of TP such as compounds 2j and 2o exhibited hydrogen bond interaction with amino acid residues GLY152, THR151 and HIS116 of thymidine phosphorylase (PDB ID: 1UOU). The result of biological activity and docking study revealed that amines group at R2 point of 1,3,4-oxadiazole-2-thione moiety is essential for anticancer activity.

1,3,4-Oxadiazoles as Telomerase Inhibitor: Potential Anticancer Agents.

Cancer is a rapidly growing disease of current era which poses a major life threaten situation to human beings. Continuous research is going on in the direction to develop effective molecules for the treatment of the cancer. These efforts include searching of more active heterocyclic compounds possessing potential anticancer activity. The 1,3,4-Oxadiazole scaffold is a five member heterocyclic ring having versatile activities and created interest for synthetic organic and medicinal chemists for the designing of novel compounds having anticancer activity. The important mechanism behind tumor suppression by 1,3,4-Oxadiazole is related with the inhibition of different growth factors, enzymes and kinases etc. The current literature surveys revealed that 1,3,4-Oxadiazole is a promising lead for anti-cancer agents by the inhibition of telomerase activity. In cancerous cells telomerase enzyme is activated which maintains and restores the telomere which leads to cell proliferation. The telomerase inhibitors with enhanced specificity and improved pharmacokinetics have been considered for design and development of novel anti-cancer agents. This review focuses primarily on telomerase enzyme its function and mechanism of action. It also describes the interaction of telomerase enzyme with 1,3,4-Oxadiazole inhibitors including their structure activity relationships (SARs). With the knowledge of this molecular target, structural insights and SARs, this review may be helpful for (medicinal) chemists to design more potent, safe, selective and cost effective anti-cancer agents.

1,3,4-Oxadiazoles: An emerging scaffold to target growth factors, enzymes and kinases as anticancer agents.

Five member heterocyclic 1,3,4-oxadiazole nucleus find unique place in medicinal chemistry and plays significant role in producing anticancer activity. The small and simple 1,3,4-oxadiazole nucleus is present in various compounds involved in research aimed at evaluating new products that posses interesting pharmacological properties such as antitumour activity. Mono and 2,5-di-substituted-1,3,4-oxadiazole derivatives have attracted considerable attention owing to their effective biological activity and extensive use. The important mechanism involved during its tumour suppression is related with the inhibition of different growth factors, enzymes and kinases including telomerase enzyme, histone deacetylase (HDAC), methionine aminopeptidase (MetAP), thymidylate synthase (TS), glycogen synthase kinase-3 (GSK), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and focal adhesion kinase (FAK). The focused criteria of this review is to highlights the targeted inhibitory activity of 1,3,4-oxadiazole derivatives and their structure activity relationship to generate potential anticancer agents.