Development Of New Chemical Entities Research Articles

Machine Learning for In Silico ADMET Prediction.

ADMET (absorption, distribution, metabolism, excretion, and toxicity) describes a drug molecule's pharmacokinetics and pharmacodynamics properties. ADMET profile of a bioactive compound can impact its efficacy and safety. Moreover, efficacy and safety are considered some of the major causes of clinical attrition in the development of new chemical entities. In past decades, various machine learning or quantitative structure-activity relationship (QSAR) methods have been successfully integrated in the modeling of ADMET. Recent advances have been made in the collection of data and the development of various in silico methods to assess and predict ADMET of bioactive compounds in the early stages of drug discovery and development process.

Techniques for Dissolution and Bioavailability Enhancement of Poorly Water-Soluble Drugs

Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired pharmacological response. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. A success of formulation development depends on how efficiently it makes the drug available at the site of action. Poorly soluble and dissolution profile creates problem in pharmaceutical industry for development of dosage form. The ability to increase aqueous solubility can thus be a valuable aid to increasing efficiency and/or reducing side effects (Adverse drug reaction) for drugs. This is true for parenterally, topically and orally administered solutions. Biopharmaceutical classification system (BCS) highlights the dissolution as rate limiting step for oral absorption of BCS class II and class IVdrugs. BCS class II and class IV drugs have low solubility.Increasing dissolution directly correlated to bioavailability of drug at site of action or systemic circulation. In this article we discuss, concept of dissolution, factors affecting dissolution,different techniques used for the enhancement of the solubility of poorly soluble drugs which include physical and chemical modifications of drug and other methods like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, complexation with hydrophilic excipients.
 

In-silico Inhibitory Potential of Triphala Constituents Against Cytochrome P450 2E1 for the Prevention of Thioacetamide-induced Hepatotoxicity

Background: Triphala, which is a combination of fruits of Terminalia chebula, Terminalia bellerica and Embilica officinalis generally recommended as herbal drug formulation in the Indian traditional medicine system.
 Study Design: To study the in-silico inhibitory potential of Triphala constituents against cytochrome P450 2E1 (CYP2E1) for the prevention of Thioacetamide-induced Hepatotoxicity
 Place and Duration of Study: The work has been performed at MUP's College of Pharmacy (B Pharm), Degaon, Risod, Washim, Maharashtra, India in between February 2021 to May 2021.
 Methodology: We have studied the inhibitory potential of Triphala on CYP2E1 by applying molecular docking tools. The major chemical constituents of Triphala i.e. gallic acid, chebulic acid, ellagic acid, epicatechin, syringic acid, and ascorbic acid were docked on CYP2E1.
 Results: Docking results revealed the very good inhibitory potential of Triphala in terms of binding affinity towards CYP2E1. All the chemical constituents have formed at least 2 and at most 6 hydrogen bonds with the crystal structure of CYP2E1. The binding energies (kcal/mol) of gallic acid, chebulic acid, ellagic acid, epicatechin, syringic acid, and ascorbic acid are -6.1, -7.1, -9.1, -8.3, -6.3, and -5.7, respectively. Ellagic acid has formed strong hydrogen bonds with Thr-303 and Thr-304 with bond length of 1.98 A0 and 2.26 A0 which confirms the excellent inhibition of CYP2E1.
 Conclusion: These findings can be used to control the CYP2E1-facilitated biotransformation and drug interactions in the development of new chemical entities. In future, these phytoconstituents can be used as lead molecules to overcome the cancer associated with oxidative stress resulting from the hyperactivity of CYP2E1.

Antibacterial potential of selected phytomolecules: An experimental study.

Antibiotic resistance is a snowballing international threat. Some of the antibiotics have lost their effectiveness due to overuse and underuse. Thus, there is an urgent need to tackle this global challenge, either by inhibiting the resistance mechanisms or by the development of new chemical entities. Thus, in the current study, the antibacterial activity of selected phytomolecules was investigated against bacterial strains, alone and in combination, with standard drugs. The antibacterial potential of these phytomolecules was explored using in vitro assays (microtiter assay, bacterial growth kinetics, percentage retardation of growth, and antimicrobial synergy study) and in vivo studies (zebrafish infection model). In vitro and in vivo studies have shown promising antibacterial effects against, both, Gram-positive and Gram-negative bacteria. Moreover, a cell viability assay also indicated the cytoprotective effect of these phytomolecules in combination with standard antibiotics (SABX). Thus, these phytomolecules could be a promising broad-spectrum antibacterial agent in combination with standard antibiotics.

Expedition to Phenanthrene Nucleus: A Two‐decade Research on Bench

AbstractThe phenanthrene nucleus is extensively found in diverse natural products and its versatility is not just limited to pharmaceutically beneficial molecules but has proved efficient in the development and synthesis of dyes, plastics, pesticides and explosives. Such a relevant nucleus has attracted researchers to probe into the construction of phenanthrene nucleus. The past two decades have witnessed continuous efforts in this direction with the exploration of various synthetic strategies enabling access to the privileged core. The review focuses on bringing the advances made in 20 years in these synthetic protocols and the mechanism involved in the generation of phenanthrene and its derivatives under one roof. In addition, it also provides a comparative study of the diverse approaches and vivid reactions employed for phenanthrene synthesis providing a better understanding and creating newer ideas towards the development of new chemical entities (NCEs).

Successful and Unsuccessful Prediction of Human Hepatic Clearance for Lead Optimization.

Development of new chemical entities is costly, time-consuming, and has a low success rate. Accurate prediction of pharmacokinetic properties is critical to progress compounds with favorable drug-like characteristics in lead optimization. Of particular importance is the prediction of hepatic clearance, which determines drug exposure and contributes to projection of dose, half-life, and bioavailability. The most commonly employed methodology to predict hepatic clearance is termed in vitro to in vivo extrapolation (IVIVE) that involves measuring drug metabolism in vitro, scaling-up this in vitro intrinsic clearance to a prediction of in vivo intrinsic clearance by reconciling the enzymatic content between the incubation and an average human liver, and applying a model of hepatic disposition to account for limitations of protein binding and blood flow to predict in vivo clearance. This manuscript reviews common in vitro techniques used to predict hepatic clearance as well as current challenges and recent theoretical advancements in IVIVE.

QcrB in Mycobacterium tuberculosis: The new drug target of antitubercular agents

Drug-resistance in mycobacterial infections is a major global health problem that leads to high mortality and socioeconomic pressure in developing countries around the world. From finding new targets to discovering novel chemical scaffolds, there is an urgent need for the development of better approaches for the cure of tuberculosis. Recently, energy metabolism in mycobacteria, particularly the oxidative phosphorylation pathway of cellular respiration, has emerged as a novel target pathway in drug discovery. New classes of antibacterials which target oxidative phosphorylation pathway either by interacting with a protein or any step in the pathway of oxidative phosphorylation can combat dormant mycobacterial infections leading to shortening of tuberculosis chemotherapy. Adenosine triphosphate synthase is one such recently discovered target of the newly approved antitubercular drug bedaquiline. Cytochrome bcc is another new target of the antitubercular drug candidate Q203, currently in phase II clinical trial. Research suggests that b subunit of cytochrome bcc, QcrB, is the target of Q203. The review article describes the structure, function, and importance of targeting QcrB throwing light on all chemical classes of QcrB inhibitors discovered to date. An understanding of the structure and function of validated targets and their inhibitors would enable the development of new chemical entities.

Quinazolin-4-One: A Varsatile Molecule

Background:Quinazolines and quinazolinones constitute a major class of biologically active molecules both from natural and synthetic sources. We will limit this review to compounds possessing the 4(3H)-quinazolinone skeleton, which is found in compounds displaying significant biological and pharmacological properties. The molecular design of potential lead compound is still a key line of approach for the discovery and development of new chemical entities. A combination of two or more chemical moieties into one is a common approach of operation and this can most likely result in the improvement of pharmacological activity and removal of unwanted side effects.Methods:We undertake search for peer-reviewed and research literature on quinazolinone moiety using different tools of literature survey. The quality of superior papers was assess using standard tools. The distinctiveness of screened papers was shorted and high-quality content was reorganiz and written in own language.Results:The review will be expressed in two main sections, the first section will be related to synthetic procedures and the second section includes the biological importance of Quinazoline derivatives. Total hundred (100) to one hundred and ten (110) research papers ware searched. Out of these, seventy-eight papers were included in the review, the majority of research papers were from international journals. Fifty fours papers defined the different synthetic schemes considering the general strategies using orthosubstituted anilines such as 2-aminobenzoic acid (anthranilic acid) and its analogues, or isatoic anhydride as starting materials, which are condensed with acid chlorides, imidates or aldehydes. Microwave irradiation was also proven to be very useful to improve the yields, and in particular, it has been successfully applied to the Niementowski procedure involving the fusion of anthranilic acid with formamide. The remaining part of the review focuses on biological importance of the 4(3H)-quinazolinone scaffold as therapeutic agents and a broad range of activities like antibacterial, antifungal, antiviral, anticonvulsant, antitumor, antihypertensive, analgesic and anti-inflammatory agents has been highlighted.Conclusion:The present review focuses on simplified, efficient and widespread literature of the methods of synthesis and diverse pharmacological activities of quinazoline and its derivatives have been highlighted.

Exploring the Multi-Target Performance of Mitochondriotropic Antioxidants against the Pivotal Alzheimer's Disease Pathophysiological Hallmarks.

Alzheimer disease (AD) is the most common neurodegenerative disease featuring progressive and degenerative neurological impairments resulting in memory loss and cognitive decline. The specific mechanisms underlying AD are still poorly understood, but it is suggested that a deficiency in the brain neurotransmitter acetylcholine, the deposition of insoluble aggregates of fibrillar β-amyloid 1–42 (Aβ42), and iron and glutamate accumulation play an important role in the disease progress. Despite the existence of approved cholinergic drugs, none of them demonstrated effectiveness in modifying disease progression. Accordingly, the development of new chemical entities acting on more than one target is attracting progressively more attention as they can tackle intricate network targets and modulate their effects. Within this endeavor, a series of mitochondriotropic antioxidants inspired on hydroxycinnamic (HCA’s) scaffold were synthesized, screened toward cholinesterases and evaluated as neuroprotectors in a differentiated human SH-SY5Y cell line. From the series, compounds 7 and 11 with a 10-carbon chain can be viewed as multi-target leads for the treatment of AD, as they act as dual and bifunctional cholinesterase inhibitors and prevent the neuronal damage caused by diverse aggressors related to protein misfolding and aggregation, iron accumulation and excitotoxicity.

Amit Joharapurkar wins industrial scientist award

Amit Joharapurkar, a general manager at Zydus Cadila in Ahmadabad, India, is the winner of the 2019 Indian Society of Chemists and Biologists Award of Appreciation for Industrial Scientists. Joharapurkar’s research is in the area of small-molecule drug discovery, which includes the development of prolyl hydroxylase inhibitor Desidustat. He has contributed to the discovery and development of new chemical entities at Zydus Cadila and has been actively involved in the development of seven new investigational drugs. He is also the recipient of 2018 Central Drug Research Institute Award for Excellence in Drug Research. Please send announcements of awards to l_wang@acs.org.

Molecular dynamics, viscoelastic properties and physical stability studies of a new amorphous dihydropyridine derivative with T-type calcium channel blocking activity

One of the greatest problems of pre-clinical development of new chemical entities is their poor aqueous solubility. Herein, we focus our attention on MD20 – a novel calcium channel blocker that selectively blocks T-type calcium channel (Cav3.2) over L-type calcium channel (Cav1.2). To avoid future problems with limited solubility of this compound, an amorphous form of MD20 was obtained and thoroughly investigated by various experimental techniques. The thermal properties of both crystalline and amorphous MD20 were examined by differential scanning calorimetry and thermogravimetry. Dielectric spectroscopy studies of MD20 at T < Tg revealed that this compound possesses as many as four secondary relaxation processes. The molecular dynamics of the supercooled sample was investigated by dielectric and mechanical spectroscopies. In this paper, a comparison of the relaxation dynamics of supercooled MD20 obtained from both of these experimental techniques is presented. On the basis of the dielectric studies, the time of physical stability of the investigated material (at T = 298 K) was predicted as 150 years. Finally, we have performed experimental long-term stability tests, which showed that amorphous MD20 did not reveal any signs of re-crystallization for at least 260 days.

Inhibitory Mechanism of An Anticancer Drug, Bexarotene Against Amyloid β Peptide Aggregation: Repurposing Via Neuroinformatics Approach.

Aggregation of Amyloid β (Aβ) peptide is a crucial feature of Alzheimer disease (AD) pathogenesis. In fact, Aβ peptides are misfolded and aggregated to frame Amyloid fibrils, which is considered as one of the major contributing events in the onset of AD. All these observations have prompted the researchers to design therapeutic molecules with robust anti-Aβ aggregation potential. Interestingly, in the last few decades, drug repurposing has turned into a fruitful and savvy approach for the treatment of several diseases. Bexarotene is an anticancer drug that has been under consideration for its ability to suppress Aβ-peptide aggregation. However, the exact mechanistic aspect of suppression of Aβ-peptide accumulation has not yet been completely revealed. In the present study, we have attempted to decipher the mechanistic aspects of the anti-aggregation potential of bexarotene by using the computational biology approach. We have observed the effect of 'Aβ-bexarotene' interaction on the aggregation ability of the Aβ-peptide and decoded the involvement of receptor for advanced glycation end products (RAGE) and beta-secretase (BACE-1). A deep structural analysis of Aβ upon binding with bexarotene revealed critical binding sites and structural twists involved in Aβ aggregation. It is evident from the present that bexarotene could significantly restrain the process of primary nucleation of Aβ. In addition, bexarotene showed a strong interaction with RAGE and BACE-1, suggesting them as plausible targets for the neuro-therapeutic action of bexarotene. Hence, we could safely suggest that bexarotene is a potent drug candidate that could reduce Aβ- peptide aggregation by applying different mechanistic pathways. These results might boost the portfolio of pharmaceutical companies looking for the development of new chemical entities against AD.

Repurposing of Existing Statin Drugs for Treatment of Microbial Infections: How Much Promising?

Today's microbial infections' resistance to approved drugs, the emergence of new infectious diseases and lack of vaccines, create a huge threat to human health. Thus, there is an urgent need to create novel antimicrobial agents, but the high cost and prolonged timeline of novel drug discovery and development is the major barrier to make new drugs. Therefore, there is a need for specific cost effective approaches in order to identify new drugs for the treatment of various microbial infections. Drug repurposition is an alternative technique to find existing clinically approved drugs for other indications. This approach may enhance the portfolio of Pharmaceutical companies by reducing the time and money required for the development of new chemical entity. In literature, various studies have reported some encouraging results regarding the antimicrobial use of existing statin drugs. Further, some clinical studies have also shown the protective effect of statin drugs in reduction of the morbidity and mortality due to many infectious diseases but complete understanding is still lacking. Thus, there is a need for better understanding of the use of statin drugs, especially in the context of antimicrobial effects. In this review, we try to summarize the use of statin drugs in various infectious diseases and their proposed antimicrobial mechanism of action. Further, current challenges and future perspectives of repurposition of statin drugs as antimicrobial agents have also been discussed.

A review on Nanocomposite Drug Delivery

Low aqueous solubility is the major problem come across the formulation development of new chemical entities as well as for the generic development. Supplementary than 40% New Chemical Entities developed in pharmaceutical industry are practically insoluble in water. Hence, there is a need for boosting the solubility and dissolution of such drugs. Enhancement of the solubility and dissolution of the practically insoluble drug was achieved by forming nanocomposites. Nanocomposities are formed by using synthetic polymers such as gelatin, chitosan, polyvinyl pyrollidone, carboxymethyl cellulose, etc. Selection of polymers was based on their surfactant and wetting properties. To check the solubility enhancement of drugs solubility studies is carried out. Nanocomposites are characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction studies, scanning electron microscopy and transmission electron microscopy. As the concentration of polymer in the composite increased the solubility and dissolution of poorly water soluble drug were enhanced. In end, new technology require substances showing novel properties and/or progressed performance in comparison to conventionally processed additives. In this context, nanocomposites are appropriate materials to meet the emerging needs bobbing up from medical and technologic advances. Keywords: nanocomposites, polymers, synthesis.

Solubility enhancement (Solid Dispersions) novel boon to increase bioavailability

The solubility of a solute is the maximum quantity of solute that can dissolve in a certain quantity of solvent or quantity of solution at a specified temperature. Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown. Solubility is essential for the therapeutic effectiveness of the drug, independent of the route of administration. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. Poorly soluble drugs are often a challenging task for formulators in the industry Conventional approaches for enhancement of solubility have limited applicability, especially when the drugs are poorly soluble simultaneously in aqueous and in non-aqueous media. Drug with poor water solubility cause slow dissolution rates, generally show erratic and incomplete absorption leading to low bioavailability when administered orally. Solubilization may be affected by cosolvent water interaction, micellar solubilization, reduction in particle size, inclusion complexes, solid dispersion, and change in polymorph. Some new technologies are also available to increase the solubility like micro emulsion, self-emulsifying drug delivery system and supercritical fluid technology. This present review details about the different approaches used for the enhancement of the solubility of poorly water-soluble drugs include particle size reduction, nanonization, pH adjustment, solid dispersion, complexation, co‐solvency, hydrotropy etc. The purpose of this article is to describe the techniques of solubilization for the attainment of effective absorption and improved bioavailability.&#x0D; Keywords: Solubility, Solubility Enhancement, bioavailability, solid dispersion, Solid Dispersion, Solubilization.

Metabolism‐Inspired Electrosynthesis

AbstractDrug metabolism is a critical stage in the development of new chemical entities to understand how the drug will behave in the body and to reveal potential toxic metabolites. In this Review, we discuss how a renaissance in the applications of synthetic electrochemistry can be employed both to identify drug metabolites (and mechanisms) and enable electrosynthetic preparation of drug metabolites for further analysis. Recent advances in electro‐oxidative drug reactions are reviewed together with a perspective on the future use of electrosynthesis to diversify lead stage drug molecules to enable rapid testing of advanced analogues. A focus on the remarkable advances in the last decade with the inclusion of seminal papers for contextual analysis are reviewed.

ANTIMICROBIAL INVESTIGATION AND BINDING MODE ANALYSIS OF SOME NEWLY SYNTHESIZED 4-AMINO-5-((ARYL SUBSTITUTED)-4H-1, 2, 4-TRIAZOLE-3-YL)-THIO LINKED HYDROXAMIC ACID DERIVATIVES

Objective: A series of 5-substituted-4-amino-1, 2, 4-triazole-linked hydroxamic acid derivatives have been synthesized and explored in vitro to evaluate antibacterial and antifungal activities.&#x0D; Methods: Different 5-phenyl group substituted-4-amino-1,2,4-triazole-3-thiol reacted with chlorine substituted hydroxamic acid to produce the desired compounds and characterized spectroscopically. Minimum inhibitory concentration (MIC), zone of inhibition (ZOI), growth kinetic studies, and scanning electron microscopy (SEM) were employed to elicit the antimicrobial efficacy of synthesized compounds against a wide range of bacterial and fungal strains.&#x0D; Results: Compounds 6a, 6b, 6d, and 6k (MIC of 25 μg/ml) have been found to be more potent against Klebsiella pneumoniae, Bacillus cereus, Bacillus pumilus, Micrococcus luteus, and Pseudomonas aeruginosa, compounds 6a-6d, 6k, and 6l (MIC of 25–50 μg/ml) have shown potent antibacterial efficacy against Klebsiella pneumonia, P. aeruginosa, and Vibrio cholera compare to the standard drug amoxicillin (MIC of 60 μg/ml, 65 μg/ml, and 25 μg/ml, respectively). Screening for the antifungal activity revealed that the compounds were found to be most active against Candida albicans (6a, 6b, and 6l), Candida tropicalis (6b and 6d), and Aspergillus niger (6a, 6b, 6d, and 6j) with MIC of 15–25 μg/ml. Bacteriostatic and fungistatic effect of titled compounds was revealed from growth kinetics study.&#x0D; Conclusion: Electron donating group at the 5-position of the 5-substituted-1,2,4-triazole-linked hydroxamic acid derivatives conferred the biological effectiveness of the synthesized compounds and also offer a therapeutically effective prototypical structure for further development of new chemical entities with superior antimicrobial activity.

SOLUBILITY ENHANCEMENT OF POORLY WATER SOLUBLE DRUGS BY VARIOUS TECHNIQUES

Solubility is not the ability to dissolve or thaw a substance; it may happen not only due to dissolution but also because of a chemical reaction. Solubility is the phenomenon of dissolution of solid in liquid phase to provide a homogenous system. Solubility is one of the vital factors for accomplishing desired concentration of drug in systemic circulation for pharmacological response. Low aqueous solubility is the major problem seen with formulation development of new chemical entities as well as for the generic development. With all new discovered chemical entities about 40% drugs are lipophilic and doesn’t shown therapeutic range due to their poor water solubility. Drug with poor water solubility shows slow dissolution rates, incomplete absorption and low bioavailability when taken orally. Drug solubility and bioavailability enhancement are the important in the formulation of pharmaceuticals. The Biopharmaceutics Classification System shows that Class II and IV drugs have low water solubility, poor dissolution, and low bioavailability. This review mentions different approaches used for the enhancement of the solubility of poorly water-soluble drugs that includes particle size reduction, pH adjustment, and solid dispersion. This describes the techniques of solubilizaton for the attainment of effective absorption and improved bioavailability.&#x0D; Keywords: Solubility, BCS classification, Bioavailability, Solid-dispersion.

A Cu2+ complex induces the aggregation of human papillomavirus oncoprotein E6 and stabilizes p53.

Papillomavirus oncoprotein E6 is a critical factor in the modulation of cervical cancer in humans. At the molecular level, formation of the E6-E6AP-p53 ternary complex, which directs p53's degradation, is the key instigator of cancer transforming properties. Herein, a Cu2+ anthracenyl-terpyridine complex is described which specifically induces the aggregation of E6 invitro and in cultured cells. For a hijacking mechanism, both E6 and E6AP are required for p53 ubiquitination and degradation. The Cu2+ complex interacts with E6 at the E6AP and p53 binding sites. We show that E6 function is suppressed by aggregation, rendering it incapable of hijacking p53 and thus increasing its cellular level. Therapeutic treatments of cervical cancer are currently unavailable to infected individuals. We anticipate that this Cu2+ complex might open up a new therapeutic avenue for the design and development of new chemical entities for the diagnosis and treatment of HPV-induced cancers.

A minimalistic approach to develop new anti-apicomplexa polyamines analogs

The development of new chemical entities against the major diseases caused by parasites is highly desired. A library of thirty diamines analogs following a minimalist approach and supported by chemoinformatics tools have been prepared and evaluated against apicomplexan parasites. Different member of the series of N,N′-disubstituted aliphatic diamines shown in vitro activities at submicromolar concentrations and high levels of selectivity against Toxoplasma gondii and in chloroquine-sensitive and resistant-strains of Plasmodium falciparum. In order to demonstrate the importance of the secondary amines, ten N,N,N′,N′-tetrasubstituted aliphatic diamines derivatives were synthesized being considerably less active than their disubstituted counterpart. Theoretical studies were performed to establish the electronic factors that govern the activity of the compounds.