A contemporary chemical entities infiltrating in the antimalarial therapy era: a comprehensive review.

Malaria, a life-threatening disease, is caused by parasitic single-celled microorganisms. It is specifically transmitted by the anopheles female mosquito of the Plasmodium family. There are a lot of drugs available in the market to treat this life-challenging disease. Chloroquine, a cheaper molecule that is available worldwide, is one of them. Drug resistance has been observed with chloroquine as well as with some other quinine derivatives and with artemisinin derivatives in the southeast region of Asia in countries like Cambodia, Thailand, Myanmar, and Vietnam country since 1957. After 1970, the drug resistance has been further increased and it has been expanded in several localities of India. Also, antimalarial agents, particularly chloroquine, have so many side effects such as nausea, vomiting, blurred vision, abdominal cramps, diarrhea, headache, appetite loss, deprivation of hearing, skin color change, baldness, reduced body weight, and seizures. Furthermore, this drug cannot be given to pregnant women. Hence, it is the right time to design and develop newer antimalarial agents so that this kind of drug resistance, as well as side effects of the drugs, can be overcome.

In Silico Analysis, Synthesis, and Biological Evaluation of Triazole Derivatives as H1 Receptor Antagonist.

INTRODUCTION: Histamine, a biological amine, is considered as a principal mediator of many pathological processes regulating several essential events in allergies and autoimmune diseases. Numerous derivatives have been developed that strive with histamine at the H1 receptor and prevent binding of histamine at the H1 receptor, thereby preventing allergic reactions. Molecules containing a triazole ring fused with six-membered ring systems are found to possess broad applications in the field of medicine and industry. The present study is an attempt to characterize the impact of the nature of the substituent introduced at 5 positions of the-4H-1,2,4-triazole-3-thiol on their capacities to bind with the H1 receptor. METHODS: Molecular docking (PDB ID: 3RZE) revealed that synthesized derivatives and target proteins were actively involved in binding with Tyr-108, Thr-112, Ala-216, and Phe-432 subunits. A pharmacophore model, new 5-(4-substituted phenyl)-4-(phenylamino)-4-H-1,2,4-triazole-3- thiols (5a-5h) were designed and evaluated for H1-blocking activity using isolated segments from the guinea pig ileum. RESULTS: According to in silico analysis, all the compounds have a topological polar surface area (TPSA) less than 140 Å squared, so they tend to easily penetrate cell membranes. The results show that most of the compounds are non-inhibitors of CYP450 substrates that play a fundamental role in drug metabolism. Compounds 5d (50.53±12.03), 5h (50.62±12.33) and 7a (55.07±12.41) are more active than others. CONCLUSION: Finally, these derivatives were screened for H1 receptor antagonist activity using guinea pig ileum, taking chlorpheniramine maleate as a standard. Most of the compounds were found to possess better antihistamine activity.

Design, Synthesis and Pharmacological Evalution of 1,3,4-Oxadiazole Derivatives as Collapsin Response Mediator Protein 1 (CRMP 1) Inhibitors.

OBJECTIVE: The series of 2-(4-Phenylamino)-N-(5-((4-nitrophenoxy)methyl) -1,3,4-oxadiazol- 2-yl)aceta-mide (5a-5e) and substituted N-(5-(Phenoxymethyl)-1,3,4-oxadiazol-2-yl)-2- (phenylamino)acetamide (5f-5i) was designed, synthesized and investigated for Collapsin Response Mediator Protein 1 (CRMP 1) inhibitors as small lung cancer. DESIGN: Design of compounds was determined by literature review and molecular docking studies in iGEMDOCK 2.0. MATERIALS AND METHODS: Novel 1, 3, 4 Oxadiazole derivatives were synthesized and characterized by melting point, TLC, IR Spectroscopy, Mass spectroscopy and 1H NMR. In vitro biological evaluation was performed on NCI-H2066 cell line for different concentrations 10-1000µM by telomeric repeat amplification protocol assay. The assay of telomerase in cellular extracts was modified from the PCR-based Telomeric-Repeat Amplification Protocol (TRAP), using the oligonucleotides TS and CX. RESULTS: Novel substituted 2-(4-Phenylamino)-N-(5-((4-nitrophenoxy)methyl)-1,3,4-oxadiazol-2- yl) acetamide (5a-5e) and substituted N-(5-(Phenoxymethyl)-1,3,4-oxadiazol-2-yl)-2-(phenylamino) acetamide (5f-5i) were synthesized, and characterized using spectral and analytical data. All compounds have shown considerable % inhibition of Cell Growth with respect to Bevacizumab, but compound 5a and 5f were equipotent with respect to activity as compared to standard Bevacizumab. CONCLUSION: Amongst the hybrids, p-nitro substituted derivative (5a) and p-chloro substituted (5f) showed the highest activity against human lung cancer cell line NCI-H2066 by TRAP assay.

In silico Analysis and Molecular Docking Studies of Novel 4-Amino-3- (Isoquinolin-4-yl)-1H-Pyrazolo[3,4-d]Pyrimidine Derivatives as Dual PI3-K/mTOR Inhibitors.

BACKGROUND: mTORC1/ PI3K control multiple anabolic pathways, including protein synthesis, ribosome production, lipogenesis, and nucleotide synthesis, are all important for cell and tissue growth. Sapanisertib and Dactolisib inhibit PI3K/AKT/mTOR pathway, an important signaling pathway for many cellular functions such as growth control, metabolism and translation initiation. METHODS: Dactolisib contains quinolin-3-yl-2,3-dihydroimidazo[4,5-c]quinolin scaffold and Sapanisertib contains benzo[d]oxazol-5-yl-1-ethyl-1H-pyrazolo[3,4-d]pyrimidinnucleous. From the reference to both of drug novel series of 4-Amino-3-(isoquinolin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin was developed by molecular docking. In sillico analysis was done with SWISSADME online tools. RESULTS: Among all the designed derivatives, compounds 6(-10.6 kcal/mol) , 12( -10.7 kcal/mol), 14( -10.2 kcal/mol), and 16(-10.2 kcal/mol) have a good binding affinity than others. Biological activity was predicted by Molinspirationonline software tool showing that all compounds are active on G- protein coupled receptor. In silico toxicity profile of designed compounds was performed using the SWISSADME program, indicating that all the compounds follow the Lipinski rule of five and do not penetrate Blood brain barrier. CONCLUSION: Series of pyrazolo[3,4-d]pyrimidin derivatives gives good binding affinity with pan- PI3-Kinese/Mtor inhibitors. The present study provided a better understanding of the molecular modeling requisite for maintaining and/or improving PI3K/mTOR inhibitors.

Molecular Docking, Synthesis and Biological Evaluation of Sulphonylureas/ Guanidine Derivatives as Promising Antidiabetic Agent.

BACKGROUND: A series of novel sulphonylureas/guanidine derivatives was designed, synthesized, and evaluated for the treatment of diabetes mellitus. In this study, the designed compounds were docked with AKR1C1 complexes by using glide docking program and docking calculations were performed to predict the binding affinity of the designed compounds with the binding pocket of protein 4YVP and QikProp program was used to predict the ADME/T properties of the analogues. METHODS: All the targeted derivatives were synthesized and purified by recrystallization. Synthesized compounds were characterized by various physicochemical and various spectroscopic techniques like melting point, thin layer chromatography, infrared spectroscopy (KBr pellets), mass spectroscopy(m/z), 1H NMR (DMSO-d6), and 13C NMR. The synthesized compounds were further studied for biological evolution by alloxan (150 mg/dl, intraperitonial) induced diabetic rat model for in-vivo studies. RESULT: Among all the synthesized derivatives, 5c and 5d were most potent as per binding energy. Compound 5i have shown a better plasma glucose reduction compared to glibenclamide. Hence, it will be further used as a lead compound to develop a more such kind of agent. CONCLUSION: The docking study revealed that in all designed sulphonylureas/ guanidine series of compounds 5c and 5d were found to be most potent compounds as per the binding energy compared to glibenclamide. With the help of detailed study of in vivo biological activity, we observed that compound 5i gives better result compared to glibenclamide as standard.