Medicinal Chemistry最新文献

This review investigates the synthetic methods and anti-cancer activities of pyrazole compounds. Various synthetic approaches, including traditional organic synthesis and microwaveassisted synthesis, have been used to change the pyrazole core structure, resulting in new compounds with improved pharmacological properties. The paper also covers the mechanisms of action that underpin pyrazole derivatives' anti-cancer characteristics, focusing on interactions with major molecular targets implicated in cancer growth and proliferation. SAR insights help to rationally develop novel anti-cancer drugs. In conclusion, the review emphasizes the versatility of pyrazole derivatives as scaffolds for the discovery and development of new anti-cancer medicines. By understanding synthesis routes and unravelling anti-cancer potential, this study hopes to encourage new research endeavours focused on leveraging the therapeutic advantages of pyrazole paradigms in the fight against cancer.

Despite extensive research in the field of drug discovery and development, still there is a need to develop novel molecular entities. Literature reveals a substantial heterocyclic nucleus named, piperazine, which shows an immense therapeutic voyage. For several decades, molecules having the piperazine nucleus have entered the market as a drug exhibiting biological potential. It was known to possess antipsychotic, antihistamine, antianginal, antidepressant, anticancer, antiviral, cardioprotective, and anti-inflammatory activity with a specific basis for structural activity relationship. Thus, it is regarded as a key structural feature in most of the already available therapeutic drugs in the market. Reports also suggest that the extensive utilization of these currently available drugs having a piperazine nucleus shows increasing tolerance significantly day by day. In addition to this, various other factors like solubility, low bioavailability, cost-effectiveness, and imbalance between pharmacokinetics and pharmacodynamics profile limit their utilization. Focusing on that issues, various structural modification studies were performed on the piperazine moiety to develop new derivatives/analogs to overcome the problems associated with available marketed drugs. Thus, this review article aims to gain insight into the number of structural modifications at the N-1 and N-4 positions of the piperazine scaffold. This SAR approach may prove to be the best way to overcome the above-discussed drawbacks and lead to the design of drug molecules with better efficacy and affinity. Hence, there is an urgent need to focus on the structural features of this scaffold which paves further work for deeper exploration and may help medicinal chemists as well as pharmaceutical industries.

Long-term exposure to pesticides is associated with the incidence of cancer. With the exponential increase in the number of new pesticides being synthesized, it becomes more and more important to evaluate the toxicity of pesticides by means of simulated calculations. Based on existing data, machine learning methods can train and model the predictions of the effects of novel pesticides, which have limited available data. Combined with other technologies, this can aid the synthesis of new pesticides with specific active structures, detect pesticide residues, and identify their tolerable exposure levels. This article mainly discusses support vector machines, linear discriminant analysis, decision trees, partial least squares, and algorithms based on feedforward neural networks in machine learning. It is envisaged that this article will provide scientists and users with a better understanding of machine learning and its application prospects in pesticide toxicity assessment.

Objective: The chemical transformation of ursolic acid (UA) into novel C-3 aryl ester derivatives and in vitro and silico assessment of their antitubercular potential.

Background: UA is a natural pentacyclic triterpenoid with many pharmacological properties. Semisynthetic UA analogs have demonstrated enhanced anticancer, antimalarial, and antifilarial properties in our previous studies.

Methods: The C-30 carboxylic group of previously isolated UA was protected, and various C-3 aryl ester derivatives were semi-synthesized. The agar dilution method was used to evaluate the in vitro antitubercular efficacy of Mycobacterium tuberculosis (Mtb) H₃₇Ra. In silico docking studies of the active derivative were carried out against Mtb targets, catalase peroxidase (PDB: 1SJ2), dihydrofolate reductase (PDB: 4M2X), enoyl-ACP reductase (PDB: 4TRO), and cytochrome bc1 oxidase (PDB: 7E1V).

Results: The derivative 3-O-(2-amino,3-methyl benzoic acid)-ethyl ursolate (UA-1H) was the most active among the eight derivatives (MIC1 2.5 μg/mL) against Mtb H₃₇Ra. Also, UA-1H demonstrated significant binding affinity in the range of 10.8-11.4 kcal/mol against the antiTb target proteins, which was far better than the positive control Isoniazid, Ethambutol, and co-crystallized ligand (HEM). Moreover, the predicted hit UA-1H showed no inhibition of Cytochrome P450 2D6 (CYP2D6), suggesting its potential for favorable metabolism in Phase I clinical studies.

Conclusion: The ursolic acid derivative UA-1H possesses significant in vitro antitubercular potential with favorable in silico pharmacokinetics. Hence, further in vivo assessments are suggested for UA-1H for its possible development into a secure and efficient antitubercular drug.

The last decade has encountered an increasing demand for plant-based natural antibiotics. This demand has led to more research-based investigations for natural sources of antimicrobial agents and published reports demonstrating that plant extracts are widely applied in modern medicine, reporting potential activity that may be due to polyphenol compounds. Interestingly, the effects of polyphenols on the sensitivity of bacteria to antibiotics have not been well-studied. Hence, the current review encompasses the prospective application of plant-based phenolic extracts from plants of Indian origin. The emergence of resistance to antimicrobial agents has increased the inefficacy of many antimicrobial drugs. Several strategies have been developed in recent times to overcome this issue. A combination of antimicrobial agents is employed for the failing antibiotics, which restores the desirable effect but may have toxicity-related issues. Phytochemicals such as some polyphenols have demonstrated their potent activity as antimicrobial agents of natural origin to work against resistance issues. These agents alone or in combination with certain antibiotics have been shown to enhance the antimicrobial activity against a spectrum of microbes. However, the information regarding the mechanisms and structure-activity relationships remains elusive. The present review also focuses on the possible mechanisms of natural compounds based on their structure- activity relationships for incorporating polyphenolic compounds in the drug-development processes. Besides this work, polyphenols could reduce drug dosage and may diminish the unhidden or hidden side effects of antibiotics. Pre-clinical findings have provided strong evidence that polyphenolic compounds, individually and in combination with already approved antibiotics, work well against the development of resistance. However, more studies must focus on in vivo results, and clinical research needs to specify the importance of polyphenol-based antibacterials in clinical trials.

The worldwide impact of cancer is further compounded by the constraints of current anticancer medications, which frequently exhibit a lack of selectivity, raise safety apprehensions, result in significant adverse reactions, and encounter resistance mechanisms. The current situation highlights the pressing need to develop novel and more precise anticancer agents that prioritize safety and target specificity. Remarkably, more than 85% of drugs with physiological activity contain heterocyclic structures or at least one heteroatom. Nitrogen-containing heterocycles hold a significant position among these compounds, emerging as the most prevalent framework within the realm of heterocyclic chemistry. This article explores the medicinal chemistry behind these molecules, highlighting their potential as game-changing possibilities for anticancer medication development. The analysis highlights the inherent structural variety in nitrogen-containing heterocycles, revealing their potential to be customized for creating personalized anticancer medications. It also emphasizes the importance of computational techniques and studies on the relationships between structure and activity, providing a road map for rational medication design and optimization. Nitrogen- containing heterocycles are a promising new area of study in the fight against cancer, and this review summarises the state of the field so far. By utilizing their inherent characteristics and exploiting cooperative scientific investigations, these heterocyclic substances exhibit potential at the forefront of pioneering therapeutic approaches in combating the multifaceted obstacles posed by cancer.

One of the most effective therapeutic decencies in the treatment of Type 2 Diabetes Mellitus is the inhibition of α-glucosidase enzyme, which is present at the brush border of the intestine and plays an important role in carbohydrate digestion to form mono-, di-, and polysaccharides. Acarbose, Voglibose, Miglitol, and Erniglitate have been well-known α-glucosidase inhibitors in science since 1990. However, the long synthetic route and side effects of these inhibitors forced the researchers to move their focus to innovate simple and small heterocyclic scaffolds that work as excellent α-glucosidase inhibitors. Moreover, they are also effective against the postprandial hyperglycemic condition in Type 2 Diabetes Mellitus. In this aspect, this review summarizes recent progress in the discovery and development of heterocyclic molecules that have been appraised to show outstanding inhibition of α-glucosidase to yield positive effects against diabetes.

Background: Multicomponent reactions are highly useful in synthesizing natural products and bioactive molecules. Out of several MCRs, although utilized widely, some remain neglected in review articles. The Gewald and Groebke-Blackburn-Bienaymé (GBB) reactions are two such reactions. This comprehensive review assimilates applications of Gewald and Groebke-Blackburn- Bienayme reactions in synthesizing novel antimicrobial agents. It presents the antimicrobial properties of the synthesized molecules, providing an overview of their potential druggability.

Objective: Developing novel antimicrobial agents is the need of the hour. Toward this objective, the scientific community is developing new methods for constructing novel architectures with potential antimicrobial properties. This review will showcase the usefulness of the Gewald, Strecker, and Groebke-Blackburn-Bienaymé (GBB) reactions in synthesizing antimicrobial molecules.

Methods: The articles are searched by using the Sci-finder search tool and summarize the chemistry of their synthesis and antimicrobial evaluation of the molecules.

Results: This review focuses on synthesizing antimicrobial molecules using the Gewald, Strecker, and Groebke-Blackburn-Bienaymé (GBB) reactions. The antimicrobial activities of the synthesized molecules are also summarized in tables.

Conclusion: This review will briefly overview the application of the Gewald, Strecker, and Groebke- Blackburn-Bienaymé (GBB) reactions in synthesizing novel antimicrobial molecules. It contains several molecules with promising activity against resistant and non-resistant microbial strains. These promising molecules could be studied further to develop novel antibiotics.

Background: The current study recognizes the significance of estrogen receptor alpha (ERα) as a member of the nuclear receptor protein family, which holds a central role in the pathophysiology of breast cancer. ERα serves as a valuable prognostic marker, with its established relevance in predicting disease outcomes and treatment responses.

Methods: In this study, computational methods are utilized to search for suitable drug-like compounds that demonstrate analogous ligand binding kinetics to ERα.

Results: Docking-based simulation screened out the top 5 compounds - ZINC13377936, NCI35753, ZINC35465238, ZINC14726791, and NCI663569 against the targeted protein. Further, their dynamics studies reveal that the compounds ZINC13377936 and NCI35753 exhibit the highest binding stability and affinity.

Conclusion: Anticipating the competitive inhibition of ERα protein expression in breast cancer, we envision that both ZINC13377936 and NCI35753 compounds hold substantial promise as potential therapeutic agents. These candidates warrant thorough consideration for rigorous In vitro and In vivo evaluations within the context of clinical trials. The findings from this current investigation carry significant implications for the advancement of future diagnostic and therapeutic approaches for breast cancer.