Synthetic account on indoles and their analogues as potential anti-plasmodial agents.

Malaria caused by P. falciparum, has been recognized as one of the major infectious diseases causing the death of several patients as per the reports from the World Health Organization. In search of effective therapeutic agents against malaria, several research groups have started working on the design and development of novel heterocycles as anti-malarial agents. Heterocycles have been recognized as the pharmacophoric features for the different types of medicinally important activities. Among all these heterocycles, nitrogen containing aza-heterocycles should not be underestimated owing to their wide therapeutic window. Amongst the aza-heterocycles, indoles and fused indoles such as marinoquinolines, isocryptolepines and their regioisomers, manzamines, neocryptolenines, and indolones have been recognized as anti-malarial agents active against P. falciparum. The present work unleashes the synthetic attempts of anti-malarial indoles and fused indoles through cyclocondensation, Fischer-indole synthesis, etc. along with the brief discussions on structure-activity relationships, in vitro or in vivo studies for the broader interest of these medicinal chemists, working on their design and development as potential anti-malarial agents.

Systematic virtual screening in search of SARS CoV-2 inhibitors against spike glycoprotein: pharmacophore screening, molecular docking, ADMET analysis and MD simulations.

In the absence of efficient anti-viral medications, the coronavirus disease 2019 (COVID-19), stemming from severe acute respiratory syndrome coronavirus-2 (SARS CoV-2), has spawned a worldwide catastrophe and global emergency. Amidst several anti-viral targets of COVID-19, spike glycoprotein has been recognized as an essential target for the viral entry into the host cell. In the search of effective SARS CoV-2 inhibitors acting against spike glycoprotein, the virtual screening of 175,851 ligands from the 2020.1 Asinex BioDesign library has been performed using in silico tools like SiteMap analysis, pharmacophore-based screening, molecular docking using different levels of precision, such as high throughput virtual screening, standard precision and extra precision, followed by absorption, distribution, metabolism, excretion and toxicity analysis, and molecular dynamics (MD) simulation. Following a molecular docking study, seventeen molecules (with a docking score of less than - 6.0) were identified having the substantial interactions with the catalytic amino acid and nucleic acid residues of spike glycoprotein at the binding site. In investigations using MD simulations for 10 ns, the hit molecules (1 and 2) showed adequate compactness and uniqueness, as well as satisfactory stability. These computational research findings have offered a key starting point in the field of design and development of novel SARS CoV-2 entry inhibitors with appropriate drug likeliness.

A review on synthetic account of 1,2,4-oxadiazoles as anti-infective agents.

Most of the currently marketed drugs consist of heterocyclic scaffolds containing nitrogen and or oxygen as heteroatoms in their structures. Several research groups have synthesized diversely substituted 1,2,4-oxadiazoles as anti-infective agents having anti-bacterial, anti-viral, anti-leishmanial, etc. activities. For the first time, the present review article will provide the coverage of synthetic account of 1,2,4-oxadiazoles as anti-infective agents along with their potential for SAR, activity potential, promising target for mode of action. The efforts have been made to provide the chemical intuitions to the reader to design new chemical entity with potential of anti-infective activity. This review will mark the impact as the valuable, comprehensive and pioneered work along with the library of synthetic strategies for the organic and medicinal chemists for further refinement of 1,2,4-oxadiazole as anti-infective agents.

Design, synthesis, and biological evaluation of benzo[d]imidazole-2-carboxamides as new anti-TB agents.

Tuberculosis is the leading cause of death globally among infectious diseases. Due to the development of resistance of Mycobacterium tuberculosis to currently used anti-TB medicines and the TB-HIV synergism the urgent need to develop novel anti-mycobacterial agents has been realized. The drug-to-target path has been the successful strategy for new anti-TB drug development. All the six drug candidates that have shown promise during the clinical trials and some of these being approved for treatment against MDR TB are the results of phenotype screening of small molecule compound libraries. In search of compounds belonging to novel pharmacophoric class that could be subjected to whole cell assay to generate new anti-TB leads the benzo[d]imidazole-2-carboxamide moiety has been designed as a novel anti-TB scaffold. The design was based on the identification of the benzimidazole ring as a prominent substructure of the FDA approved drugs, the structural analysis of reported anti-TB benzimidazoles, and the presence of the C-2 carboxamido functionality in novel bioisoteric anti-TB benzothiazoles. Twenty seven final compounds have been prepared via NH4Cl-catalyzed amidation of ethyl benzo[d]imidazole-2-carboxylates, as the required intermediates, obtained through a green "all water" one-pot synthetic route following a tandem N-arylation-reduction-cyclocondensation procedure. All of the synthesised target compounds were assessed for anti-TB potential using H37Rv ATCC27294 strain. Thirteen compounds were found with better MIC (0.78-6.25 µg/mL) than the standard drugs and being non-cytotoxic nature (<50% inhibition against RAW 264.7 cell lines at 50 µg/mL). The compound 8e exhibited best anti-TB activity (MIC: 2.15 µM and selectivity index: > 60) and a few others e.g., 8a, 8f, 8k and 8o are the next best anti-TB hits (MIC: 1.56 µg/mL). The determination and analysis of various physiochemical parameters revealed favorable druglike properties of the active compounds. The compounds 8a-l and 8o, with MIC values of ≤ 6.25 µg/mL, have high LipE values (10.66-11.77) that are higher than that of the suggested value of > 6 derived from empirical evidence for quality drug candidates and highlight their therapeutic potential. The highest LipE value of 11.77 of the best active compound 8e with the MIC of 0.78 µg/mL indicates its better absorption and clearance as a probable clinical candidate for anti-TB drug discovery. These findings highlight the discovery of benzimidazole-2-carboxamides for further development as new anti-TB agents.

In search of SARS CoV-2 replication inhibitors: Virtual screening, molecular dynamics simulations and ADMET analysis.

Severe acute respiratory syndrome has relapsed recently as novel coronavirus causing a life threat to the entire world in the absence of an effective therapy. To hamper the replication of the deadly SARS CoV-2 inside the host cells, systematic in silico virtual screening of total 267,324 ligands from Asinex EliteSynergy and BioDesign libraries has been performed using AutoDock Vina against RdRp. The molecular modeling studies revealed the identification of twenty-one macrocyclic hits (2-22) with better binding energy than remdesivir (1), marketed SARS CoV-2 inhibitor. Further, the analysis using rules for drug-likeness and their ADMET profile revealed the candidature of these hits due to superior oral bioavailability and druggability. Further, the MD simulation studies of top two hits (2 and 3) performed using GROMACS 2020.1 for 10 ns revealed their stability into the docked complexes. These results provide an important breakthrough in the design of macrocyclic hits as SARS CoV-2 RNA replicase inhibitor.

In search of RdRp and Mpro inhibitors against SARS CoV-2: Molecular docking, molecular dynamic simulations and ADMET analysis.

Corona Virus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome coronavirus (SARS CoV-2) has been declared a worldwide pandemic by WHO recently. The complete understanding of the complex genomic structure of SARS CoV-2 has enabled the use of computational tools in search of SARS CoV-2 inhibitors against the multiple proteins responsible for its entry and multiplication in human cells. With this endeavor, 177 natural, anti-viral chemical entities and their derivatives, selected through the critical analysis of the literatures, were studied using pharmacophore screening followed by molecular docking against RNA dependent RNA polymerase and main protease. The identified hits have been subjected to molecular dynamic simulations to study the stability of ligand-protein complexes followed by ADMET analysis and Lipinski filters to confirm their drug likeliness. It has led to an important start point in the drug discovery and development of therapeutic agents against SARS CoV-2.

Benzimidazoquinazolines as new potent anti-TB chemotypes: Design, synthesis, and biological evaluation.

In search for new molecular entities as anti-TB agents, the benzimidazoquinazoline polyheterocyclic scaffold has been designed adopting the scaffold hopping strategy. Thirty-two compounds have been synthesized through an improved tandem decarboxylative nucleophilic addition cyclocondensation reaction of o-phenylenediamine with isatoic anhydride followed by further cyclocondensation of the intermediately formed 2-(o-aminoaryl)benzimidazole with trialkyl orthoformate/acetate. The resultant benzimidazoquinazolines were evaluated in vitro for anti-TB activity against M. tuberculosis H37Rv (ATCC27294 strain). Fourteen compounds exhibiting MIC values in the range of 0.4-6.25 µg/mL were subjected to cell viability test against RAW 264.7 cell lines and were found to be non-toxic (<30% inhibition at 50 µg/mL). The active compounds were further evaluated against INH resistant Mtb strains. The most active compound 6x [MIC (H37Rv) of 0.4 µg/mL] and the compound 6d [MIC (H37Rv) of 0.78 µg/mL] were also found to be active against INH resistant Mtb strain with MIC values of 12.5 and 0.78 µg/mL, respectively.

Rationalization of Benzazole-2-carboxylate versus Benzazine-3-one/Benzazine-2,3-dione Selectivity Switch during Cyclocondensation of 2-Aminothiophenols/Phenols/Anilines with 1,2-Biselectrophiles in Aqueous Medium.

The cyclocondensation reaction of 2-aminothiophenols with 1,2-biselectrophiles such as ethyl glyoxalate and diethyl oxalate in aqueous medium leads to the formation of benzothiazole-2-carboxylates via the 5-endo-trig process contrary to Baldwin's rule. On the other hand, the reaction of 2-aminophenols/anilines produced the corresponding benzazine-3-ones or benzazine-2,3-diones via the 6-exo-trig process in compliance with Baldwin's rule. The mechanistic insights of these cyclocondensation reactions using the hard-soft acid-base principle, quantum chemical calculations (density functional theory), and orbital interaction studies rationalize the selectivity switch of benzothiazole-2-carboxylates versus benzazine-3-ones/benzazine-2,3-diones. The presence of water facilitates these cyclocondensation reactions by lowering of the energy barrier.

Synthesis, biological evaluation and structure-activity relationship of 2-styrylquinazolones as anti-tubercular agents.

2-Styrylquinazolones are reported as a novel class of potent anti-mycobacterial agents. Forty-six target compounds have been synthesized using one pot reaction involving isatoic anhydride, amine, and triethyl orthoacetate followed by aldehyde to construct the 2-styrylquinazolone scaffold. The anti-mycobacterial potency of the compounds was determined against H37Rv strain. Twenty-six compounds exhibited anti-Mtb activity in the range of 0.40-6.25µg/mL. Three compounds 8c, 8d and 8ab showed MIC of 0.78µg/mL and were found to be non-toxic (<50% inhibition at 50µg/mL) to HEK 293T cell lines with the therapeutic index >64. The most potent compound 8ar showed MIC of 0.40µg/mL with the therapeutic index >125. An early structure activity relationship for this class of compounds has been established. The computational studies indicate the possibility of these compounds binding to the penicillin binding proteins (PBPs).

In silico investigation of potential phytoconstituents against ligand- and voltage-gated ion channels as antiepileptic agents.

The most promising anticonvulsant phytocompounds were explored in this work using docking, molecular dynamic (MD) simulation, and Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) approaches. A total of 70 phytochemicals were screened against α-amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-d-aspartate (NMDA), voltage-gated sodium ion channels (VGSC), and carbonic anhydrase enzyme II (CA II) receptors, and the docking results were compared to the reference drug phenytoin. Amentoflavone displayed the highest affinity for AMPA and VGSC receptors, with docking scores of - 10.4 and - 10.1 kcal/mol, respectively. Oliganthin H-NMDA and epigallocatechin-3-gallate-CA II complexes showed docking scores of - 10.9 and - 6.9 kcal/mol, respectively. All four complexes depicted a high dock score compared to the phenytoin complex at the binding site of the corresponding proteins. The MD simulation investigated the stabilities and favorable conformation of apoproteins and ligand/reference-bound complexes. The results revealed that proteins AMPA, VGSC, and CA II were more efficiently stabilized by lead phytochemicals than phenytoin binding. Additionally, principal component analysis and MM-PBSA results suggested that these lead phytocompounds have good compactness and strong binding free energy. Further, physicochemical and pharmacokinetic studies revealed that these final lead phytochemicals would be suitable for oral intake, have sufficient intestinal permeability, and have the ability to cross the blood-brain barrier (BBB). Comprehensively, this study predicted amentoflavone as the best lead phytochemical out of the 70 anticonvulsant phytocompounds that can be used to treat epilepsy. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03948-1.

Inhibition of Uridine 5'-diphospho-glucuronosyltransferases A10 and B7 by vitamins: insights from in silico and in vitro studies.

Uridine 5'-diphospho-glucuronosyltransferases (UGTs) have been considered as a family of enzymes responsible for the glucuronidation process, a crucial phase II detoxification reaction. Among the various UGT isoforms, UGTs A10 and B7 have garnered significant attention due to their broad substrate specificity and involvement in the metabolism of numerous compounds. Recent studies have suggested that certain vitamins may exert inhibitory effects on UGT activity, thereby influencing the metabolism of drugs, environmental toxins, and endogenous substances, ultimately impacting their biological activities. In the present study, the inhibition potential of vitamins (A, B1, B2, B3, B5, B6, B7, B9, D3, E, and C) on UGT1A10 and UGT2B7 was determined using in silico and in vitro approaches. A 3-dimensional model of UGT1A10 and UGT2B7 enzymes was built using Swiss Model, ITASSER, and ROSETTA and verified using Ramachandran plot and SAVES tools. Molecular docking studies revealed that vitamins interact with UGT1A10 and UGT2B7 enzymes by binding within the active site pocket and interacting with residues. Among all vitamins, the highest binding affinity predicted by molecular docking was - 8.61 kcal/mol with vitamin B1. The in vitro studies results demonstrated the inhibition of the glucuronidation activity of UGTs by vitamins A, B1, B2, B6, B9, C, D, and E, with IC50 values of 3.28 ± 1.07 µg/mL, 24.21 ± 1.11 µg/mL, 3.69 ± 1.02 µg/mL, 23.60 ± 1.08 µg/mL, 6.77 ± 1.08 µg/mL, 83.95 ± 1.09 µg/ml, 3.27 ± 1.13 µg/mL and 3.89 ± 1.12 µg/mL, respectively. These studies provided the valuable insights into the mechanisms underlying drug-vitamins interactions and have the potential to guide personalized medicine approaches, optimizing therapeutic outcomes, and ensuring patient safety. Indeed, further research in the area of UGT (UDP-glucuronosyltransferase) inhibition by vitamins is essential to fully understand the clinical relevance and implications of these interactions. UGTs play a crucial role in the metabolism and elimination of various drugs, toxins, and endogenous compounds in the body. Therefore, any factors that can modulate UGT activity, including vitamins, can have implications for drug metabolism, drug-drug interactions, and overall health. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00182-0.

Comprehensive coverage on anti-mycobacterial endeavour reported during 2022.

TB being one of the deadliest diseases and second most common infectious cause of deaths, poses the severe threat to global health. The extended duration of therapy owing to resistance and its upsurge in immune-compromised patients have been the driving force for the development of novel of anti-TB scaffolds. Recently, we have compiled the account of anti-mycobacterial scaffolds published during 2015-2020 and updated them in 2021. The present work involves the insights on the anti-mycobacterial scaffolds reported in 2022 with their mechanism of action, structure activity relationships, along with the key perceptions for the design of newer anti-TB agents for the broader interests of medicinal chemists.

Unveiling the modulation of Nogo receptor in neuroregeneration and plasticity: Novel aspects and future horizon in a new frontier.

Neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, Multiple Sclerosis, Hereditary Spastic Paraplegia, and Amyotrophic Lateral Sclerosis have emerged as the most dreaded diseases due to a lack of precise diagnostic tools and efficient therapies. Despite the fact that the contributing factors of NDs are still unidentified, mounting evidence indicates the possibility that genetic and cellular changes may lead to the significant production of abnormally misfolded proteins. These misfolded proteins lead to damaging effects thereby causing neurodegeneration. The association between Neurite outgrowth factor (Nogo) with neurological diseases and other peripheral diseases is coming into play. Three isoforms of Nogo have been identified Nogo-A, Nogo-B and Nogo-C. Among these, Nogo-A is mainly responsible for neurological diseases as it is localized in the CNS (Central Nervous System), whereas Nogo-B and Nogo-C are responsible for other diseases such as colitis, lung, intestinal injury, etc. Nogo-A, a membrane protein, had first been described as a CNS-specific inhibitor of axonal regeneration. Several recent studies have revealed the role of Nogo-A proteins and their receptors in modulating neurite outgrowth, branching, and precursor migration during nervous system development. It may also modulate or affect the inhibition of growth during the developmental processes of the CNS. Information about the effects of other ligands of Nogo protein on the CNS are yet to be discovered however several pieces of evidence have suggested that it may also influence the neuronal maturation of CNS and targeting Nogo-A could prove to be beneficial in several neurodegenerative diseases.

A Quinquennial Review on Recent Advancements and Developments in Search of Anti-malarial Agents.

Malaria has been a major parasitic disease in tropical and subtropical regions and is estimated to kill between one and two million people (mainly children) every year. Novel anti-malarial agents are urgently needed to combat the malarial parasites enduring resistance to the current medications, leading to increased morbidity and mortality. The heterocycles, holding a prominent position in chemistry and found in both natural and synthetic sources, have shown several biological activities including anti-malarial activity. Towards this goal, several research groups have reported the design and development of novel and potential anti-malarial agents like artemisinin, benzimidazole, benzothiazole, chalcone, cyclopeptide, fosmidomycin, furan, indole oxadiazole, 2-oxindoles, peroxides, pyrazole, pyrazolines, pyridines, pyrimidine, pyrrolidine, quinazoline, quinazolinone, quinolone, quinoline, thiazole, triazole and other scaffolds acting against newly emerging anti-malarial targets. The present work reports the complete quinquennial coverage of anti-malarial agents reported during 2016-2020 with a view of providing the merits and demerits of reported anti-malarial scaffolds, structure-activity relationship, along with their in vitro/ in vivo/ in silico profiles to the medicinal chemists working in the field of design and discovery of novel anti-malarial agents.

In silico screening, ADMET analysis and MD simulations of phytochemicals of Onosma bracteata Wall. as SARS CoV-2 inhibitors.

Being attracted with their cardiotonic, antidiabetic, cough relieving activity, treatment of fever, absorbent, anti-asthmatic, etc. activities reported in ancient Ayurvedic literature, phytochemicals of Onosma bracteata wall should be evaluated for their activity against SARS-CoV-2 virus. The main objective of this study is to identify a hit molecule for the inhibition of entry, replication, and protein synthesis of SARS CoV-2 virus into the host. To achieve given objective, computational virtual screening of phytochemicals of Onosma bracteata wall has been performed against three main viral targets: spike, RdRp, and Mpro. Further, the analysis of Lipinski's Ro5 and their estimation of ADMET profiles were performed using computational tools. The MD simulations studies of top hits against each viral target have also been performed for 20 ns to ensure their stability. The analysis of results revealed that Pulmonarioside C (9) and other plant compounds showed better binding affinity towards targets than existing antiviral compounds, making them probable lead compounds against SARS-CoV-2. Structural modifications and studies through in silico analysis provided the founding stone for the establishment of SARS CoV-2 inhibitory potential of phytoconstitutents of Onosma bracteata wall.

Benzo[d]thiazole-2-carboxamides as new antituberculosis chemotypes inhibiting mycobacterial ATP phosphoribosyl transferase.

Aims: The screening of antimycobacterial benzo[d]thiazole-2-carboxamides against ATP-phosphoribosyl transferase (ATP-PRTase) was conducted. Materials & methods: The antitubercular potential of compounds 1 and 2 against ATP-PRTase was assessed through the determination of half maximal effective concentration (EC50) and binding constant (Kd), as well as competitive inhibitory studies and studies of perturbation of secondary structure, molecular modeling and L-histidine complementation assay. Results & conclusion: Compounds 1n and 2a significantly inhibited ATP-PRTase as evidenced by their EC50 and Kd values and the perturbation of the secondary structure study. Compound 1n exhibited stronger competitive inhibition toward ATP compared with 2a. The inhibition of the growth of Mycobacterium tuberculosis by targeting the L-histidine biosynthesis pathway and molecular modeling studies further supported the inhibition of ATP-PRTase.

In-silico Computational Investigations of AntiViral Lignan Derivatives as Potent Inhibitors of SARS CoV-2.

Due to alarming outbreak of pandemic COVID-19 in recent times, there is a strong need to discover and identify new antiviral agents acting against SARS CoV-2. Among natural products, lignan derivatives have been found effective against several viral strains including SARS CoV-2. Total of twenty-seven reported antiviral lignan derivatives of plant origin have been selected for computational studies to identify the potent inhibitors of SARS CoV-2. Molecular docking study has been carried out in order to predict and describe molecular interaction between active site of enzyme and lignan derivatives. Out of identified hits, clemastatin B and erythro-strebluslignanol G demonstrated stronger binding and high affinity with all selected proteins. Molecular dynamics simulation studies of clemastin B and savinin against promising targets of SARS CoV-2 have revealed their inhibitory potential against SARS CoV-2. In fine, in-silico computational studies have provided initial breakthrough in design and discovery of potential SARS CoV-2 inhibitors.

Bacterial FtsZ inhibition by benzo[d]imidazole-2-carboxamide derivative with anti-TB activity.

Aims: The present study aimed to assess the mode of action of previously reported anti-Mycobacterium tuberculosis benzo[d]imidazole-2-carboxamides against FtsZ along with their antibacterial potential. Materials & methods: The anti-mycobacterial action of benzo[d]imidazole-2-carboxamides against FtsZ was evaluated using inhibition of Bacillus subtilis 168, light scattering assay, circular dichroism spectroscopy, in silico molecular docking and molecular dynamics simulations. Results & conclusion: Three compounds (1k, 1o and 1e) were active against isoniazid-resistant strains. Four compounds (1h, 1i, 1o and 4h) showed >70% inhibition against B. subtilis 168. Compound 1o was the most potent inhibitor (91 ± 5% inhibition) of B. subtilis 168 FtsZ and perturbed its secondary structure. Molecular docking and molecular dynamics simulation of complexed 1o suggested M. tuberculosis FtsZ as a possible target for antitubercular activity.

Simultaneous Estimation of Six Nitrosamine Impurities in Valsartan Using Liquid Chromatographic Method.

BACKGROUND: Nitrosamine impurities are potent carcinogens in animals and probable carcinogens in humans. There is a need for effective analytical methods to detect and identify various nitrosamine impurities, and to develop rapid solutions to ensure the safety and quality of the drugs. OBJECTIVE: A liquid chromatographic method was developed for estimation of six nitrosamine impurities in valsartan. METHODS: The developed method employed: a C18 (250 × 4.6 mm, 5 µm) column as a stationary phase; a combination of acetonitrile, water (pH 3.2 adjusted with formic acid), and methanol with gradient elution as mobile phase; and 228 nm as the detection wavelength. The developed method was validated as per International Conference on Harmonization Q2(R1) guidelines. The method was successfully applied to estimate six nitrosamine impurities in valsartan API (active pharmaceutical ingradient) and formulation (tablets). RESULTS: The method was able to separate each impurity and valsartan with resolved and sharp peaks. Results indicated that the developed method is linear in selected ranges (coefficient of regressions >0.9996), precise (RSD <2%), accurate (recovery in a range of 99.02-100.16%), sensitive (low detection and quantitation limits), and specific for estimation of each impurity in valsartan. Assay results were in agreement with the spiked amount of each impurity. CONCLUSION: The developed method can be applied for simultaneous estimation of six nitrosamine impurities in valsartan raw material, tablets, and fixed dose combination at very low levels. HIGHLIGHTS: Development, validation, and application of a HPLC method for the estimation of six nitrosamine impurities in valsartan API and formulation samples.

Polyamide/Poly(Amino Acid) Polymers for Drug Delivery.

Polymers have always played a critical role in the development of novel drug delivery systems by providing the sustained, controlled and targeted release of both hydrophobic and hydrophilic drugs. Among the different polymers, polyamides or poly(amino acid)s exhibit distinct features such as good biocompatibility, slow degradability and flexible physicochemical modification. The degradation rates of poly(amino acid)s are influenced by the hydrophilicity of the amino acids that make up the polymer. Poly(amino acid)s are extensively used in the formulation of chemotherapeutics to achieve selective delivery for an appropriate duration of time in order to lessen the drug-related side effects and increase the anti-tumor efficacy. This review highlights various poly(amino acid) polymers used in drug delivery along with new developments in their utility. A thorough discussion on anticancer agents incorporated into poly(amino acid) micellar systems that are under clinical evaluation is included.