Antiproliferative activity of secondary metabolites isolated from Humboldtia unijuga Bedd.
AbstractHumboldtia unijuga Bedd. (Fabaceae), a tree species endemic to southern region of Western Ghats in India, is least explored for its chemical constituents and biological activities. Phytochemical analysis ofH. unijuga roots and stems resulted in the isolation of twenty-nine secondary metabolites with four new molecules,viz., methyl 3-(tetradecanoyloxy)olean-12-en-28-oate (3), lup-20(29)-en-3-yl 3-hydroxyheptadecanoate (26), methyl 3-(dodecanoyloxy)olean-12-en-28-oate (27), 28-oxoolean-12-en-3-yl myristate (28). Antiproliferative (cytotoxicity) activity of the twenty-nine isolated compounds was evaluated by MTT assay...
Source: Medicinal Chemistry Research - June 6, 2023 Category: Chemistry Source Type: research
Discovery of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of adaptor protein 2-associated kinase 1 for the treatment of pain
AbstractAdaptor protein 2-associated kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases and plays a role in modulating receptor endocytosis. AAK1 was identified as a potential therapeutic target for the treatment of neuropathic pain when it was shown that AAK1 knock out (KO) mice had a normal response to the acute pain phase of the mouse formalin model, but a reduced response to the persistent pain phase. Herein we report our early work investigating a series of pyrrolo[2,1-f][1,2,4]triazines as part of our efforts to recapitulate this KO phenotype with a potent, small molecule inhibitor of AAK...
Source: Medicinal Chemistry Research - June 3, 2023 Category: Chemistry Source Type: research
Design, synthesis, and antitumor activity evaluation of carbazole derivatives with potent HDAC inhibitory activity
In this study, we designed and synthesized a series of novel carbazole-hydroxamate analogues as HDAC inhibitors and evaluated their anti-tumor properties in vitro. Compared with vorinostat, the HDAC semi-inhibitory concentration of compounds3f and3g decreased 4 –13 folds, compounds8a and8c also showed strong inhibitory HDAC activity, and compound3g had a strong inhibitory effect on HDAC 1. The CCK8 assay showed that compounds3g displayed good antiproliferative activity on tested tumor cells. Flow cytometric and western blot assay showed that3g exerted anti-tumor activities by regulating the level of Ac-HH3 and activating...
Source: Medicinal Chemistry Research - June 2, 2023 Category: Chemistry Source Type: research
In silico and in vitro studies of novel cyanoacrylamides incorporating pyrazole moiety against breast and prostate carcinomas
We report novel cyanoacrylamide derivatives bearing the pyrazole moiety. The molecular structures of the prepared cyanoacrylamides were confirmed by the different spectral tools such as NMR, IR, and elemental analyses. The anticancer effect of all the newly prepared cyanoacrylamides was studied against four cancer cell lines (HEPG2, MCF7, PACA2, and PC3) as well as the normal cell line (BJ1). The best cytotoxic effect was shown against PC3, where compounds5f and5i revealed promising IC50 values (11.7 and 66.8 µM) respectively compared to doxorubicin (43.8 µM). In addition, the effective compounds were screened again...
Source: Medicinal Chemistry Research - June 1, 2023 Category: Chemistry Source Type: research
Antiproliferative effect, cell cycle arrest and apoptosis generation of novel 6-substituted N5-formyltetrahydropyrido[3,2-d]pyrimidine derivatives
AbstractBased on our previous work, a novel series of 6-substituted tetrahydropyrido[3,2-d]pyrimidinesc (6a-6k) bearing formyl group atN5-position were designed and synthesized. Most compounds were tested for their in vitro antitumor activity against five human cancer cell lines using methotrexate as a positive control. In preliminary antiproliferation assay, some compounds demonstrated micromolar inhibitory effects against all tumor cells. 6-(3,4,5-trimethoxyphenethyl)-5-formyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidine-2,4-diamine (6k) exhibited better antiproliferative activities with IC50 values of 16.6 and 8.5 μM t...
Source: Medicinal Chemistry Research - June 1, 2023 Category: Chemistry Source Type: research
Garcidepsidone B from Garcinia parvifolia: antimicrobial activities of the medicinal plants from East and North Kalimantan against dental caries and periodontal disease pathogen
This study explored the antibacterial activity of oral medicines utilized by indigenous peoples of East and North Kalimantan. We have selected ten medicinal plants commonly used in everyday life by the natives. We screened the samples using antimicrobial assays and GTase inhibition activity, then isolated, identified, and elucidated the mechanisms using HPLC, p-HPLC, NMR and MALDI TOF MASS. We obtained the most effective sample,Garcinia parvifolia, as antimicrobial activity againstStreptococcus sobrinus andPorphyromonas gingivalis, with MIC values of 0.5 mg/ml inhibition on both bacteria and MBC values of 0.5 and 1 mg...
Source: Medicinal Chemistry Research - May 30, 2023 Category: Chemistry Source Type: research
Amide- and bis-amide-linked highly potent and broadly active antifungal agents for the treatment of invasive fungal infections- towards the discovery of pre-clinical development candidate FC12406
AbstractMost fungal infections are common, localized to skin or mucosal surfaces and can be treated effectively with topical antifungal agents. However, while invasive fungal infections (IFIs) are uncommon, they are very difficult to control medically, and are associated with high mortality rates. We have previously described highly potent bis-guanidine-containing heteroaryl-linked antifungal agents, and were interested in expanding the range of agents to novel series so as to reduce the degree of aromaticity (with a view to making the compounds more drug-like), and provide broadly active high potency derivatives. We have ...
Source: Medicinal Chemistry Research - May 30, 2023 Category: Chemistry Source Type: research
Recent insights into antibacterial potential of benzothiazole derivatives
AbstractAntimicrobial resistance (AMR) is a worldwide concern among infectious diseases due to increased mortality, morbidity and treatment cost. According to WHO 2019 report, among the 32 antibiotics in the clinical trials, only six were classified as innovative and containing novel moiety. The remaining antibiotics from this list contain previously known moiety (WHO AMR 2019). Therefore, the development of novel antibiotics to control resistance problems is crucial. Benzothiazole derivatives are of great interest due to their wide range of biological activities and medicinal applications. Reported data indicated that ben...
Source: Medicinal Chemistry Research - May 29, 2023 Category: Chemistry Source Type: research
C-C bond cleavage reactions catalyzed by cytochrome P450 enzymes
AbstractCytochrome P450 (P450, CYP) enzymes are the major catalysts involved in drug metabolism, as well as general oxidations of vitamins, steroids, natural products, and industrial chemicals. The general catalytic mechanism involves a high valent FeO Complex termed Compound I (formally FeO3+) which can be used to explain most hydroxylations, dealkylations, epoxidations, and many other reactions. P450s also catalyze C-C bond formations and cleavages. Some of the latter are often seen with drugs and natural products, as well as with steroids. The steroid cleavage reactions have been studied in detail for many years, using ...
Source: Medicinal Chemistry Research - May 27, 2023 Category: Chemistry Source Type: research
Harnessing the necessary nitrogen atom in chemical biology and drug discovery
AbstractDespite 80 years of progress in modern small molecule drug discovery, medicinal chemists still struggle to minimize the number and duration of design cycles required to optimize hit and lead compounds into high-quality chemical probes or safe and efficacious clinical candidates. High-impact design elements are needed to make multiparameter optimization efforts more efficient and effective. The exchange of an aromatic methine group with a nitrogen atom is a minor bioisosteric structure modification that can lead to major improvements in a variety of pharmacological parameters. These improvements can enhance the effi...
Source: Medicinal Chemistry Research - May 27, 2023 Category: Chemistry Source Type: research
Structure-based optimization of aminothiadiazole inhibitors of AKT
We report here the discovery and structure-guided optimization of a novel series of AKT kinase inhibitors. Based on docking studies for the predicted active bound-conformation of2, a potent series ofN-substituted-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amines was developed. Compounds in the series achieve AKT pathway inhibition in cancer cells, as measured by inhibition of pathway proteins pGSK and pFKHR. Compound12 was further evaluated in a single dose PK/PD in vivo study in tumor-bearing mice and demonstrated inhibition of phosphorylation of the direct substrate GSK and pathway biomarker S6. (Source: Medicinal Chemistry Research)
Source: Medicinal Chemistry Research - May 25, 2023 Category: Chemistry Source Type: research
Novel potent and highly selective DDR1 inhibitors from integrated lead finding
AbstractDiscoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase and an attractive anti-fibrotic target. To identify novel DDR1 inhibitors, we used an integrated lead-finding approach relying in parallel on structure-based hybrid design and a focused screening campaign. Combining structural elements from both approaches allowed us to quickly overcome several compound liabilities and optimize the hits to advanced lead compounds. Despite a very high sequence conservation between DDR1 and DDR2, we were able to identify potent DDR1 inhibitors with close to 1000-fold selectivity against DDR2 as well a...
Source: Medicinal Chemistry Research - May 15, 2023 Category: Chemistry Source Type: research
Promising Schiff bases in antiviral drug design and discovery
AbstractEmerging and re-emerging illnesses will probably present a new hazard of infectious diseases and have fostered the urge to research new antiviral agents. Most of the antiviral agents are analogs of nucleosides and only a few are non-nucleoside antiviral agents. There is quite a less percentage of marketed/clinically approved non-nucleoside antiviral medications. Schiff bases are organic compounds that possess a well-demonstrated profile against cancer, viruses, fungus, and bacteria, as well as in the management of diabetes, chemotherapy-resistant cases, and malarial infections. Schiff bases resemble aldehydes or ke...
Source: Medicinal Chemistry Research - May 10, 2023 Category: Chemistry Source Type: research
Evaluation of homodimer 99mTc-HYNIC-E(SSSLTVPWY)2 peptide on HER2-over expressed breast cancer cells
AbstractThe evidence resulting from a previous preclinical study of dimer LTVPWY peptide (99mTc-DLY) has proved the capability of the tracer to recognize overexpressed-HER2 on ovarian SKOV-3 tumor more specifically than its monomer counterpart (99mTc-LY). In present work, we compared HER2-directed DLY and LY peptides conjugated to99mTc-HYNIC on SKBR-3 breast cancer cell to confirm HER2-targeting of99mTc-DLY in breast cancerous tumors. New dimer construction of99mTc-HYNIC-E(SSSLTVPWY)2 was labeled with a mixture of EDDA/tricine exchanging co-ligands. Afterward, it was utilized for evaluation of binding and specific binding ...
Source: Medicinal Chemistry Research - May 6, 2023 Category: Chemistry Source Type: research
An update on the discovery and development of reversible covalent inhibitors
AbstractSmall molecule drugs that covalently bind irreversibly to their target proteins have several advantages over conventional reversible inhibitors. They include increased duration of action, less-frequent drug dosing, reduced pharmacokinetic sensitivity, and the potential to target intractable shallow binding sites. Despite these advantages, the key challenges of irreversible covalent drugs are their potential for off-target toxicities and immunogenicity risks. Incorporating reversibility into covalent drugs would lead to less off-target toxicity by forming reversible adducts with off-target proteins and thus reducing...
Source: Medicinal Chemistry Research - April 29, 2023 Category: Chemistry Source Type: research
