Mini Reviews in Medicinal Chemistry - Volume 19, Issue 7, 2019

The indole-3-carbinol (I3C) displays anti-cancer/proliferative activities against human cancer cells. Cellular proliferation is an event associated with the progress and its continuation. This manifest is described by variation in expression and/or functions of genes that are related with cell cycle relevant proteins. The constitutive activation of several signal transduction pathways stimulates cells proliferation as well. The immediate stages in cancer development are accompanied by a fibrogenic response and the progression of the hypoxic environment is in favor of survival and proliferatory functions of cancer stem cells. A main part for prevention of in cancer cells death may manifest through altering cell metabolism. Cellular proliferation and metastasis are reported to be supported with increased generation of responsible hormones (in hormone dependent malignancies), and further promotion the angiogenesis, with epithelial to mesenchymal transition. This may be facilitated by progression of autophagy phenomenon, as well as via taking cues from neighboring stromal cells. Several signaling pathways in association with various factors specific for cellular viability, including hypoxia inducible factor 1, NF-ΚB, insulin-like growth factor 1 (IGF-1) receptor, Human foreskin fibroblasts (HFF-1), phosphoinositide 3 kinase/Akt, Wnt, cell cycle related protein, with androgen and estrogen receptor signaling are reported to be inhibited by I3C. These evidences, in association with bioinformatics data represent very important information for describing signaling pathways in parallel with molecular targets that may serve as markers for early diagnosis and/or critical targets for designing and development of novel therapeutic regimes alone or combined with drugs, to prevent tumor formation and further progression. In particular, I3C and DIM have been extensively investigated for their importance against numbers human cancers both in vitro and in vivo. We aimed the present manuscript, current study, to review anticancer properties and the miscellaneous mechanisms underlying the antitumorigenicity in an in-depth study for broadening the I3C treating marvel.

Chrysin is a natural product of a flavonoid compound. Chemically, chrysin consists of two phenyl rings (A and B) and a heterocyclic ring (C). Biologically, chrysin exerts many different physiological activities. In recent years, with the in-depth development for more active drugs, the synthesis and biological activities of chrysin derivatives have been well studied. Besides, structure-activity relationship of chrysin revealed that the chemical construction meets the critical chemical structural necessities of flavonoids for numerous pharmacological activities. It is generally believed that modified chrysin could be more potent than unmodified chrysin. Different modification in the rings of chrysin could possess various degrees of biological activities. This review aims to summarize the mechanism for the activities of chrysin and its derivatives in different rings. We also explored the relationship between biological function and structure-activity of substituted chrysin derivatives with different functional groups. The influence of chrysin derivatives on the proliferation and apoptosis of cancer cells is also investigated. Development of novel drugs based on the biological functions of chrysin could better improve clinical outcomes of affected population, especially for tumor patients and diabetic patients.

Malaria is a potentially life-threatening disease, affecting approx. 214 million people worldwide. Malaria is caused by a protozoan, Plasmodium falciparum, which is transmitted through the Anopheles mosquito. Malaria treatment is becoming more challenging due to rising resistance against the antimalarial drug, chloroquine. Novel compounds that target aspects of parasite development are being explored in attempts to overcome this wide-spread problem. Anti-malarial drugs target specific aspects of parasite growth and development within the human host. One of the most effective targets is the inhibition of hematin formation, either through inhibition of cysteine proteases or through iron chelation. Metal-thiosemicarbazone (TSC) complexes have been tested for antimalarial efficacy against drug-sensitive and drug-resistant strains of P. falciparum. An array of TSC complexes with numerous transition metals, including ruthenium, palladium, and gold has displayed antiplasmodial activity. Au(I)- and Pd(II)-TSC complexes displayed the greatest potency; 4-amino-7-chloroquine moieties were also found to improve antiplasmodial activity of TSCs. Although promising metal-TSC drug candidates have been tested against laboratory strains of P. falciparum, problems arise when attempting to compare between studies. Future work should strive to completely characterize synthesized metal-TSC structures and assess antiplasmodial potency against several drug-sensitive and drugresistant strains. Future studies need to precisely determine IC50 values for antimalarial drugs, chloroquine and ferroquine, to establish accurate standard values. This will make future comparisons across studies more feasible and potentially help reveal structure-function relationships. Investigations that attempt to link drug structures or properties to antiplasmodial mechanism(s) of action will aid in the design of antimalarial drugs that may combat rising drug resistance.

2,4-thiazolidinedione (TZD) scaffold is a synthetic versatile scaffold explored by medicinal chemists for the discovery of novel molecules for the target-specific approach to treat or manage number of deadly ailments. PTP 1B is the negative regulator of insulin signaling cascade, and its diminished activity results in abolishment of insulin resistance associated with T2DM. The present review focused on the seven years journey (2012-2018) of TZDs as PTP 1B inhibitors with the insight into the amendments in the structural framework of TZD scaffold in order to optimize/design potential PTP 1B inhibitors. We have investigated the synthesized molecules based on TZD scaffold with potential activity profile against PTP 1B. Based on the SAR studies, the combined essential pharmacophoric features of selective and potent TZDs have been mapped and presented herewith for further design and synthesis of novel inhibitors of PTP 1B. Compound 46 bearing TZD scaffold with N-methyl benzoic acid and 5-(3-methoxy-4-phenethoxy) benzylidene exhibited the most potent activity (IC50 1.1 μM). Imidazolidine-2,4-dione, isosteric analogue of TZD, substituted with 1-(2,4-dichlorobenzyl)-5-(3-(2,4- dichlorobenzyloxy)benzylidene) (Compound 15) also endowed with very good PTP inhibitory activity profile (IC50 0.57 μM). It is noteworthy that Z-configuration is essential in structural framework around the double bond of arylidene for the designing of bi-dentate ligands with optimum activity.

Background: The indolo[2,3-b]quinoline framework is often found in various natural products displaying a range of pharmacological activities. This is an attractive template for the design and discovery of potential drugs especially for the identification of new anticancer agents. Methods: The synthesis of 6-substituted indolo[2,3-b]quinolones was undertaken and carried out using a ultrasound assisted method involving two sequential C-N bond forming reactions between 3-(2- bromophenyl)-2-chloroquinoline and amines in a single pot in the presence of Pd(OAc)2 and a ligand (S)-BINAP. All the synthesized compounds were tested in vitro against two cancer cell lines e.g. MCF7 and HepG2 along with non-cancerous HEK293 cell lines. Results: Two of these compounds showed promising and selective growth inhibition of MCF7 cell lines and one induced significant apoptosis in cancer (MCF7) cells. Conclusion: Compounds based on indolo[2,3-b]quinolone framework may be useful for the identification of new cytotoxic agents thereby potential cure for breast cancer.

Background: A series of 6, 6'-(1,4-phenylene)bis(4-(4-bromophenyl)pyrimidin-2-amine) derivatives has been synthesized by Claisen-Schmidt condensation and its chemical structures was confirmed by FT-IR, 1H/13C-NMR spectral and elemental analyses. The molecular docking study was carried out to find the interaction between active bis-pyrimidine compounds with CDK-8 protein. The in vitro antimicrobial potential of the synthesized compounds was determined against Gram-positive and Gram-negative bacterial species as well fungal species by tube dilution technique. Antimicrobial results indicated that compound 11y was found to be most potent one against E. coli (MICec = 0.67 μmol/mL) and C. albicans (MICca = 0.17 μmol/mL) and its activity was comparable to norfloxacin (MIC = 0.47 μmol/mL) and fluconazole (MIC = 0.50 μmol/mL), respectively. Conclusion: Anticancer screening of the synthesized compounds using Sulforhodamine B (SRB) assay demonstrated that compounds 2y (IC50 = 0.01 μmol/mL) and 4y (IC50= 0.02 μmol/mL) have high antiproliferative potential against human colorectal carcinoma cancer cell line than the reference drug (5- fluorouracil) and these compounds also showed best dock score with better potency within the ATP binding pocket and may also be used lead for rational drug designing.;