Synthesis and Anticancer Activity of N-Aryl-5-substituted-1,3,4-oxadiazol-2-amine Analogues

In continuance of our search for anticancer agents, we report herein the synthesis and anticancer activity of some novel oxadiazole analogues. The compounds were screened for anticancer activity as per National Cancer Institute (NCI US) protocol on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers cell lines. N-(2,4-Dimethylphenyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-amine (4s) showed maximum activity with mean growth percent (GP) of 62.61 and was found to be the most sensitive on MDA-MB-435 (melanoma), K-562 (leukemia), T-47D (breast cancer), and HCT-15 (colon cancer) cell lines with GP of 15.43, 18.22, 34.27, and 39.77, respectively. Maximum GP was observed on MDA-MB-435 (melanoma) cell line (GP = 6.82) by compound N- (2,4-dimethylphenyl)-5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-amine (4u)

Computational approaches for the design of novel anticancer compounds based on pyrazolo[3,4-d]pyrimidine derivatives as trap1 inhibitor

In the present in-silico study, various computational techniques were applied to determine potent compounds against TRAP1 kinase. The pharmacophore hypothesis DHHRR_1 consists of important features required for activity. The 3D QSAR study showed a statistically significant model with R2 = 0.96 and Q2 = 0.57. Leave one out (LOO) cross-validation (R2 CV = 0.58) was used to validate the QSAR model. The molecular docking study showed maximum XP docking scores (−11.265, −10.532, −10.422, −10.827, −10.753 kcal/mol) for potent pyrazole analogs (42, 46, 49, 56, 43), respectively, with significant interactions with amino acid residues (ASP 594, CYS 532, PHE 583, SER 536) against TRAP1 kinase receptors (PDB ID: 5Y3N). Furthermore, the docking results were validated using the 100 ns MD simulations performed for the selected five docked complexes. The selected inhibitors showed relatively higher binding affinities than the TRAP1 inhibitor molecules present in the literature. The ZINC database was used for a virtual screening study that screened ZINC05297837, ZINC05434822, and ZINC72286418, which showed similar binding interactions to those shown by potent ligands. Absorption, distribution, metabolism, and excretion (ADME) analysis showed noticeable results. The results of the study may be helpful for the further development of potent TRAP1 inhibitors

An Insight into the Traditional Uses, Phytoconstituents and Pharmacological Activities of the Genus Tylophora

Traditional plants have huge demand as medicines to treat a wide range of illnesses. Tylophora is an important genus of medicinal plant in India, used to treat asthma and other ailments. The plants of this genus have been studied in vivo and in vitro for various pharmacological properties. In this article, we have given information regarding ethnomedicinal importance, phytochemistry and pharmacological uses of 18 species of Tylophora. Comprehensive information regarding different species of Tylophora were collected using different keywords in various electronic databases such as ACS, Google Scholar, PubMed, Science Direct, SciFinder, Web of Science, Springer Link, library search, J gate, Wiley, Semantic Scholar and ResearchGate since 1960 to 2023. Additionally, data was collected from some textbooks and chapters like Flora of India and Indian medicinal plants. This article highlights the traditional uses, phytochemistry, and pharmacological activities of the few studied taxa of Tylophora that would serve as a reference for pharmaceutical research. More than 100 compounds have been isolated from selected species of the genus Tylophora. Among them, phenanthroindolizidine alkaloids have received the most attention and are the most abundant active constituents of the plant. Other types of active components of genus Tylophora include C21 glycosides, secoiridoids, triterpenes, and furano alkaloids. These compounds have shown a variety of therapeutic activities like antiasthmatic, antitumour, antimicrobial, antidiabetic and antiallergic properties. This review can be an important scientific resource for further research

Design and synthesis of 3-(4-aminophenyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide/carbothioamide analogues as antitubercular agents

Emergence of multi-drug resistant tuberculosis (MDR-TB) and HIV-TB co-infections potentiate the development of newer antitubercular agents to combat against tuberculosis, a dreadful disease. In the present investigation a series of pyrazoline analogues were designed and synthesized based on the structure of known antitubercular agent thiacetazone, in hope of obtaining new and safe antitubercular agents. The target molecules were synthesized in two steps, starting with the condensation of 4-aminoacetophenone and p-anisidine in methanolic sodium hydroxide solution followed by the cyclization of intermediate chalcones with appropriate semicarbazide/thiosemicarbazide in glacial acetic acid. All the synthesized compounds were characterized by 1H NMR, IR and mass spectral data and the purity of the compounds was checked by elemental analysis. Their antimycobacterial activity was evaluated by two folds serial dilution method. 3-(4-Aminophenyl)-N-(4-chlorophenyl)-4,5-dihydro-5-(4-methoxyphenyl)pyrazole-1-carboxamide (4i) showed maximum activity against Mycobacterium tuberculosis H37Rv with minimum inhibitory concentration (MIC) of 7.41 μM

Synthesis and antimicrobial activity of N1-(3-chloro-4-fluorophenyl)-N4-substituted semicarbazone derivatives

A series of 16 N1-(3-chloro-4-fluorophenyl)-N4-substituted semicarbazone derivatives were synthesized and subjected to computational pharmacokinetic studies to predict molecular properties. All the title compounds (4a–p) followed the Lipinski “Rule of Five”. The synthesized compounds were characterized by elemental analyses and spectral data and the compounds (4a–p) were evaluated for antimicrobial activities. Among them the compound 2-(4-hydroxybenzylidene)-N-(3-chloro-4-fluorolphenyl)hydrazinecarboxamide (4f) was found to be the most active compound that showed good antibacterial activity while the compound 2-(4-methoxybenzylidene)-N-(3-chloro-4-fluorolphenyl)hydrazinecarboxamide (4g) was moderately active against fungal strains. We have noticed that the compounds, (4f, 4k and 4d) bearing OH and NO2 groups on the phenyl ring at position 4 exhibited good antibacterial activity while compound (4g) bearing OCH3 on the phenyl ring at position 4 exhibited moderate antifungal activity

Synthesis, Characterisation, and In Vitro Anticancer Activity of Curcumin Analogues Bearing Pyrazole/Pyrimidine Ring Targeting EGFR Tyrosine Kinase

In search of potential therapeutics for cancer, we described herein the synthesis, characterization, and in vitro anticancer activity of a novel series of curcumin analogues. The anticancer effects were evaluated on a panel of 60 cell lines, according to the National Cancer Institute (NCI) screening protocol. There were 10 tested compounds among 14 synthesized compounds, which showed potent anticancer activity in both one-dose and 5-dose assays. The most active compound of the series was 3,5-bis(4-hydroxy-3-methylstyryl)-1H-pyrazole-1-yl(phenyl)methanone (10) which showed mean growth percent of −28.71 in one-dose assay and GI50 values between 0.0079 and 1.86 µM in 5-dose assay

Synthesis and Anticancer Activity of N-Aryl-5-substituted-1,3,4-oxadiazol-2-amine Analogues

In continuance of our search for anticancer agents, we report herein the synthesis and anticancer activity of some novel oxadiazole analogues. The compounds were screened for anticancer activity as per National Cancer Institute (NCI US) protocol on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers cell lines. N-(2,4-Dimethylphenyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-amine (4s) showed maximum activity with mean growth percent (GP) of 62.61 and was found to be the most sensitive on MDA-MB-435 (melanoma), K-562 (leukemia), T-47D (breast cancer), and HCT-15 (colon cancer) cell lines with GP of 15.43, 18.22, 34.27, and 39.77, respectively. Maximum GP was observed on MDA-MB-435 (melanoma) cell line (GP=6.82) by compound N-(2,4-dimethylphenyl)-5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-amine (4u)

An Insight into the Structural Requirements and Pharmacophore Identification of Carbonic Anhydrase Inhibitors to Combat Oxidative Stress at High Altitudes: An In-Silico Approach

Carbonic anhydrases (CA) inhibitory action could be linked to the treatment of a number of ailments, including cancer, osteoporosis, glaucoma, and several neurological problems. For the development of effective CA inhibitors, a variety of heterocyclic rings have been investigated. Furthermore, at high altitudes, oxygen pressure drops, resulting in the formation of reactive oxygen and nitrogen species, and CA inhibitors having role in combating this oxidative stress. Acetazolamide contains thiadiazole ring, which has aroused researchers’ interest because of its CA inhibitory action. In the present study, we used a number of drug design tools, such as pharmacophore modeling, 3D QSAR, docking, and virtual screening on twenty-seven 1,3,4-thiadiazole derivatives that have been described as potential CA inhibitors in the literature. An atom-based 3D-QSAR analysis was carried out to determine the contribution of individual atoms to model generation, while a pharmacophore mapping investigation was carried out to find the common unique pharmacophoric properties required for biological activity. The coefficient of determination for both the training and test sets were statistically significant in the generated model. The best QSAR model was chosen based on the values of R2 (0.8757) and Q2 (0.7888). A molecular docking study was also conducted against the most potent analogue 4m, which has the highest SP docking score (−5.217) (PDB ID: 6g3v). The virtual screening revealed a number of promising compounds. The screened compound ZINC77699643 interacted with the amino acid residues, Pro201 and Thr199, in the virtual screening study (PDB ID: 6g3v). These interactions demonstrated the significance of the CA inhibitory activity of the compound. Furthermore, ADME study revealed useful information regarding compound’s drug-like properties. Therefore, the findings of the present investigation could aid in the development of more potent CA inhibitors, which could benefit the treatment of oxidative stress at high altitudes

Toward the Discovery of a Novel Class of Leads for High Altitude Disorders by Virtual Screening and Molecular Dynamics Approaches Targeting Carbonic Anhydrase

For decades, carbonic anhydrase (CA) inhibitors, most notably the acetazolamide-bearing 1,3,4-thiadiazole moiety, have been exploited at high altitudes to alleviate acute mountain sickness, a syndrome of symptomatic sensitivity to the altitude characterized by nausea, lethargy, headache, anorexia, and inadequate sleep. Therefore, inhibition of CA may be a promising therapeutic strategy for high-altitude disorders. In this study, co-crystallized inhibitors with 1,3,4-thiadiazole, 1,3-benzothiazole, and 1,2,5-oxadiazole scaffolds were employed for pharmacophore-based virtual screening of the ZINC database, followed by molecular docking and molecular dynamics simulation studies against CA to find possible ligands that may emerge as promising inhibitors. Compared to the co-crystal ligands of PDB-1YDB, 6BCC, and 6IC2, ZINC12336992, ZINC24751284, and ZINC58324738 had the highest docking scores of −9.0, −9.0, and −8.9 kcal/mol, respectively. A molecular dynamics (MD) simulation analysis of 100 ns was conducted to verify the interactions of the top-scoring molecules with CA. The system’s backbone revealed minor fluctuations, indicating that the CA–ligand complex was stable during the simulation period. Simulated trajectories were used for the MM-GBSA analysis, showing free binding energies of −16.00 ± 0.19, −21.04 ± 0.17, and −19.70 ± 0.18 kcal/mol, respectively. In addition, study of the frontier molecular orbitals of these compounds by DFT-based optimization at the level of B3LYP and the 6-311G(d,p) basis set showed negative values of the HOMO and LUMO, indicating that the ligands are energetically stable, which is essential for forming a stable ligand–protein complex. These molecules may prove to be a promising therapy for high-altitude disorders, necessitating further investigations