Synthesis, In vivo, and In silico Evaluation of New Pyrazoline- Benzothiazole Conjugates as Orally Administered Antiepileptic Agents.

New 2-(4-benzothiazol-2-yl-phenoxy)-1-(3,5-diphenyl-4,5-dihydro-pyrazol-1-yl)-ethanones (9a-o) have been designed and synthesized. The antiepileptic potential of the synthesized compounds has been tested by following standard animal screening models which include maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) models. The study concluded that compounds 9c, 9d, 9f, 9i, 9n, and 9o possessed good antiepileptic potential when compared with standard drugs like carbamazepine and phenytoin. The results of the rotarod performance test also established them without any neurotoxicity. The motor impairment test yielded that the synthesized compounds are also good antidepressants. In-silico studies have been performed to determine the eligibility of synthesized compounds as orally administered molecules and interactions with the target proteins. The result of in-silico studies reinforced results obtained by in vivo study of the synthesized compounds along with their possible mechanism of antiepileptic action i.e. via inhibiting voltage-gated sodium channels (VGSCs) and gamma-aminobutyric acid-A receptor.

Bisphenol-F and Bisphenol-S (BPF and BPS) Impair the Stemness of Neural Stem Cells and Neuronal Fate Decision in the Hippocampus Leading to Cognitive Dysfunctions.

Neurogenesis occurs throughout life in the hippocampus of the brain, and many environmental toxicants inhibit neural stem cell (NSC) function and neuronal generation. Bisphenol-A (BPA), an endocrine disrupter used for surface coating of plastic products causes injury in the developing and adult brain; thus, many countries have banned its usage in plastic consumer products. BPA analogs/alternatives such as bisphenol-F (BPF) and bisphenol-S (BPS) may also cause neurotoxicity; however, their effects on neurogenesis are still not known. We studied the effects of BPF and BPS exposure from gestational day 6 to postnatal day 21 on neurogenesis. We found that exposure to non-cytotoxic concentrations of BPF and BPS significantly decreased the number/size of neurospheres, BrdU+ (proliferating NSC marker) and MAP-2+ (neuronal marker) cells and GFAP+ astrocytes in the hippocampus NSC culture, suggesting reduced NSC stemness and self-renewal and neuronal differentiation and increased gliogenesis. These analogs also reduced the number of BrdU/Sox-2+, BrdU/Dcx+, and BrdU/NeuN+ co-labeled cells in the hippocampus of the rat brain, suggesting decreased NSC proliferation and impaired maturation of newborn neurons. BPF and BPS treatment increases BrdU/cleaved caspase-3+ cells and Bax-2 and cleaved caspase protein levels, leading to increased apoptosis in hippocampal NSCs. Transmission electron microscopy studies suggest that BPF and BPS also caused degeneration of neuronal myelin sheath, altered mitochondrial morphology, and reduced number of synapses in the hippocampus leading to altered cognitive functions. These results suggest that BPF and BPS exposure decreased the NSC pool, inhibited neurogenesis, induced apoptosis of NSCs, caused myelin degeneration/synapse degeneration, and impaired learning and memory in rats.

Synthetic Approaches, Biological Activities, and Structure-Activity Relationship of Pyrazolines and Related Derivatives.

It has been established that pyrazolines and their analogs are pharmacologically active scaffolds. The pyrazoline moiety is present in several marketed molecules with a wide range of uses, which has established its importance in pharmaceutical and agricultural sectors, as well as in industry. Due to its broad-spectrum utility, scientists are continuously captivated by pyrazolines and their derivatives to study their chemistry. Pyrazolines or their analogs can be prepared by several synthesis strategies, and the focus will always be on new greener and more economical ways for their synthesis. Among these methods, chalcones, hydrazines, diazo compounds, and hydrazones are most commonly applied under different reaction conditions for the synthesis of pyrazoline and its analogs. However, there is scope for other molecules such as Huisgen zwitterions, different metal catalysts, and nitrile imine to be used as starting reagents. The present article consists of recently reported synthetic protocols, pharmacological activities, and the structure-activity relationship of pyrazoline and its derivatives, which will be very useful to researchers.

Insight into the Synthesis, Biological Activity, and Structure-activity Relationship of Benzothiazole and Benzothiazole-hydrazone Derivatives: A Comprehensive Review.

Heterocyclic compounds constitute the most important part of medicinal as well as organic chemistry. Most of the marketed drugs possess therapeutic activity because of the presence of heterocyclic scaffolds as part of their structure. A slight change in the structure of the heterocyclic moieties may result in a major change in the therapeutic response of the drug candidate. Among all heterocycle compounds, the compounds containing nitrogen and sulfur atoms serve as a unique resource for drug development, such as benzothiazoles. Benzothiazole is a benzofused heterocyclic that is widely reported as a constituent of naturally occurring chemicals and chiefly responsible for their pharmacological potential. It was also reported that the pharmacological activity of BTA may also be influenced by its coupling with aldehydes, ketones, or hydrazines to form respected benzothiazole-hydrazone derivatives. The present comprehensive review consists of various synthesis methods, biological activities, and structure-activity relationships of and targets of benzothiazole and benzothiazole-hydrazone derivatives to provide a wide range of information to medicinal chemists for future research work.

Camphor and Menthol as Anticancer Agents: Synthesis, Structure-Activity Relationship and Interaction with Cancer Cell Lines.

Cancer is a type of human cell degenerative disease that has afflicted a large number of people for years. Cancer is caused due to the abnormal proliferation of cells in any part of the body. Most of the prescribed anticancer drugs are synthetic in nature and have been reported with enormous adverse effects. The researchers are very much enthusiastic about the use of natural compounds and their derivatives, which have been reported with less toxicity. Natural compounds have emerged as promising synergistic compounds with potential anticancer effects. In vitro anticancer activity of natural compounds with special reference to camphor and menthol has been investigated against different cancer cell lines. It has been found that camphor and menthol derivatives have potential cytotoxic activity. The present literature review outlines the various methods for the synthesis of camphor and menthol derivatives, which have potential cytotoxic activity. It highlights various cancer cell lines, which are the target of these camphor and menthol derivatives as ligands, along with structure-activity studies.

Recent Insights on Synthetic Methods and Pharmacological Potential in Relation with Structure of Benzothiazoles.

Benzothiazole is a bicyclic heterocyclic compound that contains benzene fused with 1, 3- thiazole ring. Several researches established the potential of benzothiazoles as important moiety in various adverse pharmacological conditions. Benzothiazole and its derivatives have been in use and marketed as anti-microbial, anti-inflammatory, anti-diabetic, anti-oxidant, anti-convulsant, antitumor, etc. The variations in pharmacological potentials of benzothiazole and its derivatives have been rational with their chemical structure. Nowadays, hybridization of two or more pharmacophores to synthesize a single molecule with potent pharmacological action is used. This helps to synergize pharmacological properties, make interaction possible with many targets, or minimize the adverse effects associated with them. Several synthetic approaches have been reported for benzothiazole and its derivatives. In this present review article, we focused on recently adopted synthetic approaches for the synthesis of the benzothiazole nucleus and its derivatives. The structure-activity relationship in relation to different pharmacological activities has also been highlighted to provide a good understanding to the researchers for future research on benzothiazoles.

Qualitative and quantitative assessment of sperm miRNAs identifies hsa-miR-9-3p, hsa-miR-30b-5p and hsa-miR-122-5p as potential biomarkers of male infertility and sperm quality.

BACKGROUND: In contrast with the preceding stages of the germ cells, spermatozoa are unusually rich in small non-coding RNAs in comparison to the coding RNAs. These small RNAs may have had an essential role in the process of spermatogenesis or may have critical roles in the post-fertilization development. Sporadic efforts have identified a few differentially expressed miRNAs in infertile individuals, which do not replicate in other studies. METHODS: In order to identify miRNAs signatures of infertility or poor sperm quality, we compared miRNA differential expression data across nine datasets, followed by their analysis by real-time PCR in a case-control study. This was followed by the validation of potential biomarkers in yet another set of cases and controls. For this, total RNA was isolated from 161 sperm samples. miRNA expression levels in infertile cases and fertile controls were measured using TaqMan real-time PCR. Meta-analyses of two miRNAs (hsa-miR-9-3p and hsa-miR-122-5p) were performed using Comprehensive Meta-Analysis Software (version 2). All statistical analyses were performed with the help of GraphPad Prism Software (version 8). RESULTS: Literature search identified seven miRNAs (hsa-let-7a-5p, hsa-miR-9-3p, hsa-miR-22-5p, has-miR-30b-5p, hsa-miR-103-3p, hsa-miR-122-5p and hsa-miR-335-5p) showing consistent dysregulation in infertility across a minimum of four studies. In the discovery phase, six miRNAs showed strong association with infertility with four (hsa-miR-9-3p, hsa-miR-30b-5p, hsa-miR-103-3p and hsa-miR-122-5p) showing consistent differential regulation across all sub-groups. Receiver operating characteristic (ROC) curve analysis showed that the area under curve of > 0.75 was achieved by three (hsa-mir-9-3p, hsa-miR-30b-5p and hsa-miR-122-5p) miRNAs. In the validation phase, these three miRNAs showed consistent association with infertility (hsa-mir-9-3p, hsa-miR-30b-5p, and hsa-miR-122-5p). Meta-analysis on hsa-miR-122-5p showed its significant quantitative association with infertility [Hedge's g = -2.428, p = 0.001 (Random effects)]. CONCLUSIONS: Three miRNAs (hsa-miR-9-3p, hsa-miR-30b-5p and hsa-miR-122-5p) have strong linkage with infertility and a high potential as sperm quality biomarkers.