Exploring Tryptophan-based Short Peptides: Promising Candidate for Anticancer and Antimicrobial Therapies.

BACKGROUND: Ultra-short peptides are essential therapeutic agents due to their heightened selectivity and reduced toxicity. Scientific literature documents the utilization of dipeptides, tripeptides, and tetrapeptides as promising agents for combating cancer. We have created a range of tryptophan-based peptides derived from literature sources in order to assess their potential as anticancer drugs. METHODS: We present the results of our study on the antibacterial and anticancer effectiveness of 10 ultra-short peptides that were produced utilizing microwave-assisted solid phase peptide synthesis. The synthesized peptides underwent screening for in vitro antibacterial activity using the agar dilution method. RESULTS: HPLC, LC-MS, 1H NMR, and 13C NMR spectroscopy were used to analyze the synthesized peptides. In tests using the HeLa and MCF-7 cell lines, the synthesized peptides' anticancer efficacy was assessed. The study found that two peptides showed potential median inhibitory concentration (IC50) values of 3.9±0.13 µM and 1.8±0.09 µM, respectively, and showed more activity than the reference medication doxorubicin. CONCLUSION: The antibacterial activity of synthesized peptides 3b and 4b was found to be better than the other synthetic peptides. MIC value of roughly 5-50 µg/mL for peptides 3a, 4c, and 4d showed strong antifungal activity against Candida albicans. The synthesized peptides were also evaluated for their anticancer activity against HeLa and MCF-7 cell lines, and found that peptides 3e and 4e were more potent than other peptides against doxorubicin.

The Influence of Phytoconstituents for the Management of Antipsoriatic Activity in Various Animal Models.

It is possible for psoriasis to manifest at any point in a person's life, regardless of their age, gender, or geographic location. It is a chronic immune-linked inflammatory skin ill-ness that affects individuals of various racial and ethnic origins. It is recognized to be a long-lasting condition. Because of the significant contribution that natural products have made, there has been a significant advancement in the treatment of skin illnesses such as psoriasis. The biggest number of phytochemicals derived from a wide range of plants and herbs are now being used in a variety of applications throughout the whole world. Additionally, a number of phyto-chemicals, including aloe-emodin, psoralen, curcumin, and others, have been effectively ex-tracted in pure or clear form, and they have shown a great deal of efficacy in the treatment of psoriasis illness. There is evidence that a few herbal remedies are effective, and the occurrence of these phytochemicals provides more proof. When synthetic medications are used for chronic therapy, they may cause a variety of adverse consequences; hence, the exploration of natural pharmaceuticals can give a successful natural treatment with a minimal amount of adverse ef-fects. Within the scope of this concise review, a number of plant sources that possess anti-pso-riatic activity are investigated, and the antipsoriatic effects of these plant sources are shown on a number of animal models using particular pathways.

Unveiling the promise of pyrimidine-modified CDK inhibitors in cancer treatment.

Cyclin-dependent kinases (CDKs) constitute a vital family of protein-serine kinases, pivotal in regulating various cellular processes such as the cell cycle, metabolism, proteolysis, and neural functions. Dysregulation or overexpression of CDK kinases is directly linked to the development of cancer. However, the currently approved CDK inhibitors by the US FDA, such as palbociclib, ribociclib, Trilaciclib, Abemaciclib, etc., although effective, exhibit limited specificity and often lead to undesirable adverse effects. First and second-generation CDK inhibitors have not gained significant clinical interaction due to their high toxicity and lack of specificity. To address these challenges, a combined approach is being employed in the quest for newer CDK inhibitors aimed at mitigating toxicity and side effects associated with CDKIs. The discovery of therapeutic agents selectively targeting tumorous cells, such as CDK inhibitors, has demonstrated promise in treating various cancers, including breast cancer. Extensive literature reviews have facilitated the development of novel CDK inhibitors by combining medicinally preferred pyrimidine derivatives with other heterocyclic rings. Pyrimidine derivatives substituted with pyrazole, imidazole, benzamide, benzene sulfonamide, indole carbohydrazide, and other privileged heterocyclic rings have shown encouraging efficacy in inhibiting cyclin-dependent kinase activity. This review provides comprehensive data, including structure-activity relationship (SAR), anticancer activity, and kinetics studies of potent compounds. Additionally, molecular docking studies with compounds under clinical trial and patents filed on pyrimidine based CDK inhibitors in cancer treatment are included. This review serves as a valuable resource for further development of CDK kinase inhibitors for cancer treatment, offering insights into their efficacy, specificity, and potential clinical applications.

Recent Development in the Search for Epidermal Growth Factor Receptor (EGFR) Inhibitors based on the Indole Pharmacophore.

The signal transduction and cell proliferation are regulated by the epidermal growth factor receptor. The proliferation of tumor cells, apoptosis, invasion, and angiogenesis is inhibited by the epidermal growth factor receptor. Thus, breast cancer, non-small cell lung cancer, cervical cancer, glioma, and bladder cancer can be treated by targeting the epidermal growth factor receptor. Although third-generation epidermal growth factor receptor inhibitors are potent drugs, patients exhibit drug resistance after treatment. Thus, the search for new drugs is being continued. Among the different potent epidermal growth factor receptor inhibitors, we have reviewed the indole-based inhibitors. We have discussed the structure-activity relationship of the compounds with the active sites of the epidermal growth factor receptor receptors, their synthesis, and molecular docking studies.

An Insight on the Prospect of Quinazoline and Quinazolinone Derivatives as Anti-tubercular Agents.

Multiple potential drugs have been developed based on the heterocyclic molecules for the treatment of different symptoms. Among the existing heterocyclic molecules, quinazoline and quinazolinone derivatives have been found to exhibit extensive pharmacological and biological characteristics. One significant property of these molecules is their potency as anti-tubercular agents. Thus, both quinazoline and quinazolinone derivatives are modified using different functional groups as substituents for investigating their anti-tubercular activities. We present a summary of the reported anti-tubercular drugs, designed using quinazoline and quinazolinone derivatives, in this review.

Recent Updates on Structural Aspects of ALK Inhibitors as an Anticancer Agent.

Presently, several protein kinases have been discovered with the aim to treat various cancers. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that plays a role in the pathogenesis of a wide variety of human cancers known as ALCLs, NSCLC, ovarian cancer, breast cancer, colorectal cancer, neuroblastoma, etc. The fulllength ALK receptor is a classical receptor tyrosine kinase composed of an amino-terminal extracellular domain and an intracellular tyrosine kinase domain. Crizotinib is a strong oral small-molecule first tyrosine kinase inhibitor of ALK to be used in the treatment of ALK-dependent NSCLC. Due to the drug resistance of first generation ALK inhibitors, researchers are trying to design and synthesize novel ALK inhibitors with various heterocyclic rings in which 2,4- diarylaminopyrimidine derivatives with a specific N-(3-pyridinylmethyl)urea moiety, 2-amino-4-(1-piperidine) pyridine derivatives, 7-azaindole and carboxamide derivatives and some others produced potential compounds. To overcome drug resistance, to get better affinity and to reduce drug toxicity, there is an urgent need for novel ALK inhibitors. The present review describes the ALK signaling, their inhibitors and related structure activity relationships for the development of potential ALK inhibitors.

Artificial Intelligence (AI) in Drugs and Pharmaceuticals.

The advancement of computing and technology has invaded all the dimensions of science. Artificial intelligence (AI) is one core branch of Computer Science, which has percolated to all the arenas of science and technology, from core engineering to medicines. Thus, AI has found its way for application in the field of medicinal chemistry and heath care. The conventional methods of drug design have been replaced by computer-aided designs of drugs in recent times. AI is being used extensively to improve the design techniques and required time of the drugs. Additionally, the target proteins can be conveniently identified using AI, which enhances the success rate of the designed drug. The AI technology is used in each step of the drug designing procedure, which decreases the health hazards related to preclinical trials and also reduces the cost substantially. The AI is an effective tool for data mining based on the huge pharmacological data and machine learning process. Hence, AI has been used in de novo drug design, activity scoring, virtual screening and in silico evaluation in the properties (absorption, distribution, metabolism, excretion and toxicity) of a drug molecule. Various pharmaceutical companies have teamed up with AI companies for faster progress in the field of drug development, along with the healthcare system. The review covers various aspects of AI (Machine learning, Deep learning, Artificial neural networks) in drug design. It also provides a brief overview of the recent progress by the pharmaceutical companies in drug discovery by associating with different AI companies.

Cyclocondensation of Anthranilamide with Aldehydes on Gallium-Containing MCM-22 Zeolite Materials.

A gallium-containing MCM-22 (Mobil Composition of Matter No. 22) zeolite material was prepared using a simple hydrothermal method. Fourier transform infrared spectroscopy analysis and powder X-ray diffraction provide evidence of the formation of a pure MCM-22 phase framework and an MWW (MCM-tWenty-tWo) structure. Scanning electron microscopy images showed a uniform spherical shape, interpenetrating the platelet structure and a uniform particle size of approximately 6 µm. 71Ga nuclear magnetic resonance studies confirmed the presence of gallium in both the tetrahedral framework and the octahedral extra-framework environment. From the sorption studies, the presence of strong acidic sites and the microporous nature of the material were evident. The resultant Ga-MCM-22 material showed an excellent isolated yield of 95% in the synthesis of 2,3-dihydroquinazolin-4(1H)-ones by cyclocondensation of anthranilamide with aldehydes in ethanol. The scope of the reaction was further explored by employing various cyclic, aromatic, and aliphatic aldehydes with anthranilamide. The results provide a very good yield (85-95%). A significant advantage of the developed protocol includes high yield, use of a green solvent, and easy removal of the catalyst through filtration within a short reaction time.

Bioisosteric Replacement of Amide Group with 1,2,3-Triazoles in Acetaminophen Addresses Reactive Oxygen Species-Mediated Hepatotoxic Insult in Wistar Albino Rats.

Acetaminophen (AP) is a popularly recommended over-the-counter analgesic-antipyretic in clinical use. However, the drug is handicapped by the occurrence of hepatotoxic insult following acute ingestion. Consequently, AP-induced hepatotoxicity is often implicated in accidental or suicidal overdose. In the current study, we investigated the potential of bioisosteric replacement of amide in AP with 1,2,3-triazoles in curbing AP-induced hepatotoxicity. The therapeutic utility of synthesized bioisosteres was established by careful tailoring and optimization of the synthetic methodology along with detailed toxicological testing of pharmacologically potent acetaminophen-triazole derivatives (APTDs). Along the same lines, we herein report a series of 17 novel APTDs synthesized via aromatic substitution using sodium azide, l-proline, and copper iodide followed by click reaction with substituted alkynes using copper sulfate and sodium ascorbate. Pharmacological evaluation of synthesized APTDs revealed that, out of the series of 17 compounds, 5a and 5e were found to be most efficacious in exerting anti-inflammatory, analgesic, and antipyretic activity in an animal model. Further toxicity studies documented that, in both acute and sub-acute toxicology, AP administration caused significant hepatotoxicity, which was found to be a consequence of ROS-mediated oxidative stress. Potent APTDs (5a and 5e), on the other hand, revealed no adverse event in both acute and sub-toxicological analyses. Median lethal dose (LD50) and no observed adverse effect level (NOAEL) values for 5a and 5e were found to be >1000 mg/kg and 2000 mg/kg, respectively. The human equivalent dose, defining the maximum safe concentration of a compound in a human's physiology, was found to be 27.68 mg/kg for the most potent APTDs (5a and 5e). Thus, it can be concluded that triazole incorporation into AP nucleus produced conjugates devoid of hepatotoxic manifestations, having the added advantage of anti-inflammatory efficacy along with analgesic and antipyretic potency.

Electronegativity in Substituted-4(H)-quinazolinones Causes Anxiolysis without a Sedative-hypnotic Adverse Reaction in Female Wistar Rats.

OBJECTIVE: In the current study, the synthesis, characterization, and neuropharmacology of quinazolinone tethered with aromatic (3a-3i) and heteroaromatic substitution (3j, 3k, and 3l) as effective anxiolytic agents are reported. BACKGROUND: Anxiety and depression are often comorbid with neurological as well as other medical maladies. Clinically known anxiolytics (Benzodiazepines) are accompanied by untoward sedation and other CNS depressive actions. The quinazolinone moiety is a privileged pharmacophore with a wide pharmacological spectrum. Herein, the synthesis, characterization, and neuropharmacological evaluation of some 2-substituted quinazolinone derivatives are reported. METHODS: The synthesized compounds were characterized using 1H-NMR and TLC analysis. Behavioral analysis was performed using EPM (Elevated Plus Maze), OFT (Open Field Test), PIST (Pentobarbital Induced Sleep Test), FST (Forced Swim Test) and PCPA (p-chlorophenyl alanine) bioassay. To further justify the therapeutic claim, systemic and neurotoxicological analysis of the most potent members of the series was performed using OECD mandated protocols. The studies showed that the compounds had a wide therapeutic window with >1000 mg/kg and >500 mg/kg LD50 and NOAEL, respectively. RESULTS: The compounds with an electronegative group in the quinazolinone nucleus (3f, 3e, 3d, and 3c) induced anxiolysis devoid of sedative adverse reaction. Besides, anti-depressant efficacy of 3f, 3e, 3d, and 3c observed in rodents was a result of a decrease in anxiety level. It was found that the neurotoxicology of the potent members (3f, 3e, 3d, and 3c) advocated their wide therapeutic window with >1000 mg/kg LD50 and >5000 mg/kg NOAEL. CONCLUSION: Our findings of behavioral bioassays revealed that inducing an electronegative group into the quinazolinone nucleus yielded the most potent members of the series (3f, 3e, 3d, and 3c). The said compounds were found to produce anxiolysis and anti-depressive action without sedative-hypnotic side effects in rodent models. In summary, it can be stated that extending the studies in a clinical setting would furbish the contours of current anxiolytic therapy, especially in anxiety comorbid with medical maladies.

Synthesis, Pharmacological and Toxicological Screening of Penicillin-Triazole Conjugates (PNTCs).

A series of hybrid antimicrobial compounds were prepared by carboxylic acid protection of 6-aminopenicillanic acid using benzyl alcohol and thionyl chloride succeeded by azide displacement using trifluoromethanesulfonyl azide in dichloromethane. The azide thus formed was reacted with substituted alkynes to furnish benzyl-protected penicillin-triazole conjugates. Benzyl deprotection of the conjugates resulted in furnishing PNTCs under water methanol mixture using Pd/C as a catalyst. The PNTCs (7a-j) formed were screened for in vitro antibacterial potency against pathogenic strains of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pyogenes and antifungal potency against Candida albicans, Aspergillus niger, and Aspergillus clavatus. Further antimicrobial evaluation revealed compounds 7c, 7d, 7e, 7g, and 7i to be the most compounds of the series with minimum inhibitory concentration value for antibacterial in the range 0.5-50 µg/mL and for antifungal in the range 9-300 µg/mL. Toxicological analysis documented for compounds 7c, 7d, 7e, 7g, and 7i revealed compound 7i to be the most promising member of the series with 1000 and 500 mg/kg LD50, and no-observed-adverse-effect level to facilitate future clinical studies of the same.

Bio-isosteric replacement of amide group with 1,2,3-triazole in phenacetin improves the toxicology and efficacy of phenacetin-triazole conjugates (PhTCs).

AIM: Inflammatory algesia and pyresia are common pathological consequences of physiological defense. Phenacetin introduced as effective analgesic anti-pyretic agent, was proscribed from therapeutic use because of associated systemic toxicity. The aim of the study was to evaluate the potency of 1,2,3-triazole conjugation in reducing toxicity and increasing efficacy of the phenacetin nucleus. MAIN METHODS: The amide bond implicated as the cause of phenacetin toxicity was bioisosterically replaced with 1,2,3-triazoles to yield a series of PhTCs(PhTC1, PhTC2 and PhTC3). The toxicology of the synthesized conjugates in reference to phenacetin was evaluated in accordance with OECD test guidelines 420, 425 and 407. For the purpose of evaluating anti-inflammatory potency carrageenan induced paw edema and croton oil induced ear edema models were evaluated. Anti-nociceptive efficacy was assessed using Eddy's hot plate and acetic acid induced writhing experimental models. For anti-pyretic efficacy, the conjugates were submitted to Brewer's yeast antipyretic assay. KEY FINDINGS: Toxicological examination of PhTCs in comparison to phenacetin revealed that, phenacetin treatment caused considerable nephrotoxicity and hepatotoxicity in experimental models PhTCs were devoid of such toxic manifestations. Results of pharmacological assays showed that the entire series of PhTCs possessed better anti-inflammatory, anti-nociceptive and anti-pyretic potential than phenacetin. Furthermore it was revealed that the pharmacological profile of PhTC1 with triazole substitution at para position of the phenol ring exhibited potency even better than that exhibited by the reference standards. CONCLUSION: Bioisosteric replacement of amide bond by 1,2,3-triazole in the phenacetin moiety yields conjugates with superior efficacy and diminished toxicity, thus opening neo avenues in treatment of inflammatory syndromes.

Synthesis and systemic toxicity assessment of quinine-triazole scaffold with antiprotozoal potency.

A series of hybrid antiprotozoal compounds with quinine-triazolyl scaffold were prepared by copper catalyzed Huisgen 1,3-dipolar cycloaddition via O-mesylation with mesyl chloride followed by azide displacement. The synthesized azide derivative was made to react with various aromatic and aliphatic alkynes. The triazolyl-linked quinine scaffolds were synthesized under solvent-free mechanochemical ball milling conditions. Products (6a-s) were screened for in-vitro antimalarial and antileishmanial activity. Screening results indicated that out of the synthesized series of 19 products, compounds 6d, 6h, 6l, 6m, and 6n showed significant antimalarial (P. falciparum) and antileishmanial activities (L. donavani) with IC50 values 0.28, 0.28, 0.25, 0.33, 0.76 µM and 8.26, 4.4, 1.78, 3.95, and 4.06 µM, respectively. Further toxicological analysis established the Median lethal dose (LD50), No observed adverse effect level (NOAEL) and human equivalent dose (HED) of the most potent compounds by acute and sub acute toxicity studies performed in rodent animal model. The studies revealed that compounds (6d, 6h, 6l and 6m) did not reveal any toxic manifestation at dose 1000 mg/Kg and from which the corresponding HED was calculated to be 13.84 mg/kg.

Supramolecular gels from sugar-linked triazole amphiphiles for drug entrapment and release for topical application.

A simple molecular framework obtained by cross-linking a hydrophobic chain with S,S- and R,R-tetritol by the copper-catalysed azide-alkyne cycloaddition reaction is found to serve as an excellent bioisostere for self-assembly. The hexadecyl-linked triazolyl tetritol composite spontaneously self-assembles in n-hepane and methanol to form hierarchical organogels. Microscopic analyses and X-ray diffraction studies demonstrate eventual formation of nanotubes through lamellar assembly of the amphiphiles. A rheological investigation shows solvent-dictated mechanical properties that obey power law behavior similar to other low molecular weight gelators (LMOGs). The gel network was then utilized for the entrapment of drugs e.g. ibuprofen and 5-fluorouracil, with tunable mechanical behaviour under applied stress. The differential release profiles of the drugs over a period of a few hours as a result of the relative spatio-temporal location in the supramolecular network can be utilized for topical formulations.

Antileishmanial Drug Discovery: Synthetic Methods, Chemical Characteristics, and Biological Potential of Quinazolines and its Derivatives.

BACKGROUND: Leishmaniasis is a complex devastating disease that is widespread across the globe with 400 million people in 90 countries at a risk of acquiring leishmaniasis. It is caused by intracellular parasites belonging to genus Leishmania. OBJECTIVE: The therapeutic use of commonly available drugs like Pentostam, Glucantime, Amphotericin B, Paramomycin, and Miltefosine have has been declined due to their low efficacy, drug resistance and high toxicity. Therefore, a continuous effort is needed in order to find out less toxic and more successful drugs in future for the handling of leishmaniasis. RESULTS: Quinazoline derivatives are reported to have promising antileishmanial activities. A number of quinazoline derivatives were synthesized in the past three decades, by means of various synthetic pathways due to their ease of synthesis and favorable physicochemical properties. CONCLUSION: This review focuses on various synthetic procedures, chemical characteristics and antileishmanial activities of various quinazoline derivatives with respect to antileishmanial drug discovery.