Biological Screening Research Articles

Structure-guided discovery of adenosine triphosphate-competitive casein kinase 2 inhibitors.

Casein kinase 2 (CK2) is a ubiquitous, highly pleiotropic serine-threonine kinase. CK2 has been identified as a potential drug target for the treatment of cancer and related disorders. Several adenosine triphosphate-competitive CK2 inhibitors have been identified and have progressed at different levels of clinical trials. This review presents details of CK2 protein, structural insights into adenosine triphosphate binding pocket, current clinical trial candidates and their analogues. Further, it includes the emerging structure-based drug design approaches, chemistry, structure-activity relationship and biological screening of potent and selective CK2 inhibitors. The authors tabulated the details of CK2 co-crystal structures because these co-crystal structures facilitated the structure-guided discovery of CK2 inhibitors. The narrow hinge pocket compared with related kinases provides useful insights into the discovery of CK2 inhibitors.

Biological screening of divalent transition metal decanoates owning powerful antimicrobial and cytotoxic properties

Biological screening of divalent transition metal decanoates owning powerful antimicrobial and cytotoxic properties

High-Throughput Purification in Drug Discovery: Scaling New Heights of Productivity.

With the "low hanging fruit" of early drug discovery gone, pharmaceutical companies are increasingly turning to developing high-throughput synthetic platforms capable of greatly shortening the design-make-test cycle of new drugs. Purification has long been considered the bottleneck of this procedure; however, new technologies and systems are now being integrated into these high-throughput synthetic workflows, providing compounds of high purity capable of being used directly in biological screening.

N-Aryl Amino Acids as Potential Antibacterial Agents

The resistance of bacteria to current antibiotic drugs and the re-occurrence of different ailments after several therapeutic protocols continue to be a cause for concern. Arylated amino acids are vital synthons to many compounds; they serve as essential building blocks in the synthesis of nitrogen heterocycles with various biological activities. This research reports on the synthesis of some N-aryl amino acids and evaluates their antibacterial activities. The N-aryl amino acids 3a–3j were obtained by reacting different 4-substituted fluorobenzene 1a–1d with different amino acids 2a–2g via a metal-free base-induced aryl amination reaction of aryl halides. The antibacterial activities of the synthesized compounds were evaluated against eight bacterial strains (Four Gram-positive, Bacillus subtilis (ATCC 6633), Streptococcus pneumonia (ATCC 33400), Staphylococcus aureus (ATCC 25923), and Staphylococcus epidermidis (ATCC 14990), and four Gram-negative, Enterobacter cloacae (ATCC 43560), Escherichia coli (ATCC 25922), Proteus mirabilis (ATCC 43071), and Klebsiella oxytoca (ATCC 13182) using the agar well diffusion method with streptomycin as a reference drug. The biological screening indicates that the synthesized compounds 3a, 3e, and 3j have promising broad-spectrum antibacterial potential, as the N-aryl amino acid displayed activity that was comparable to the standard drug against Streptococcus pneumonia, Escherichia coli, and Proteus mirabilis.

Frequency of hepatitis and HIV co-infection markers in blood donors at the Hospital Professor Bocar Sidy Sall of Kati-Mali

The transmission of infectious agents such as human immunodeficiency virus (HIV), hepatitis B (HBV), and hepatitis C (HCV) represents the greatest threat to the safety of blood transfusion to the recipient. The association of HIV infection with HBV and/or HCV is common worldwide, due to shared modes of transmission. The prevalence of HIV-HBV co-infection is estimated to be 5-10% in the United States and 20-30% in Asia and parts of sub-Saharan Africa. Other studies report HCV co-infection in 9-25% of HIV-infected patients. The aim of this study was to determine the frequency of markers of co-infection between hepatitis (B,C) and human immunodeficiency virus in blood donations collected at the CHU Kati blood transfusion center. It was a retrospective study conducted from October 1 to December 31, 2018. Data were collected from blood donors aged 18 to 60 years. The Pre-donation medical interview was the first barrier for the selection of subjects at risk. The sample was composed of 92% males and 8% females out of a total of 507 individuals sampled. Biological screening was performed by ELISA (Enzyme Linked Immuno Sorbent Assay). The results revealed a prevalence of 0.86% of HIV-HBV co-infection only in rhesus negative donors. No co-infection between HIV and HCV was found. This study showed that at the Kati University Hospital, only rhesus-negative donors presented cases of HIV-HBV co-infection.

Phytochemical and Biological Screening of Catholic Vegetable (Jatropha Tanjorensis) Aqueous Extract in Bali, Taraba State, Nigeria

Jatropha tanjorensis has been used as a medicinal herb in treatment and management of disease because they are relatively safer, more affordable and sometimes offers better therapeutic value than synthetic drugs. The study investigated the phytochemical and biological screening of catholic vegetable (Jatropha tanjorensis) aqueous extract with the objectives of evaluating some secondary metabolites in the plant using standard qualitative methods and ascertaining the antimicrobial effect of Jatropha tanjorensis aqueous leave extract on bacteria of medical importance such as Pseudomonas aeruginosa, Klebsiella pneumonia, Staphylococcus aureus, Salmonella typhi and Escherichia coli using the agar well diffusion method. The results revealed that the extract of the leaf of J. tanjorensis contain some important bioactive components (phytochemicals) in a high amount such as saponins followed by flavonoids, alkaloid and tannins in moderate amount whereas phenol, phlobatannins and glycosides are in low amount. It also shows that the extract was active against E. coli, P. aeruginosa, S. aureus, K. pneumonia and S. typhi measuring clear zones of inhibition 30.0mm, 22.0mm, 19.0mm, 18.0mm and 17.0mm respectively. Thus, the exhibition of strong antibacterial activity and phytochemical profiles obtained from the analyses of J. tanjorensis leaf indicated that it might be recommended for human consumption and adequate amount of consumption could contribute greatly towards meeting human nutritional needs for normal body growth and adequate protection and curative measures to common diseases related to the test organisms.

Studies on the synthesis, spectroscopy, thermal properties, docking, and biology of new Schiff base and its mono- and binuclear complexes.

A novel Schiff base has been synthesized from the condensation of the 3-formyl-2-hydroxybenzoic acid and 4-nitrobenzene-1,2-diamine. The new ligand was found to have two coordination sites. So, it has the capability to form mono- and binuclear complexes with different metal ions. The free ligand and its mono- and binuclear cobalt(II) complexes have been characterized by UV-Visible spectra, IR, elemental analyzes, H1 NMR, conductimetric, thermal, and magnetic measurements. Results indicated that the cobalt(II) ion is attached to the inside coordination site and the second metal ion attached to the outside coordination site. The complexes are all non-electrolytes, as demonstrated by the molar conductance tests. The thermodynamic parameters of the metal complexes are calculated using Horowitz Metzger and Coats-Redfern methods. The complexes' bonding properties have also been estimated. Molecular docking was employed to forecast the interaction of the prepared with the Candida-albicans receptor (1zap). The biological activities of these metal complexes were tested against some bacteria and fungi. It is evident from the biological screening data that the prepared Co(II) binuclear complexes exhibit predominant activity against Candida albicans, Penicillium oxalicum and Escherichia coli, while they have no activity against Micrococcus roseus and Micrococcus luteus.

Isonimesulide and Its Carborane Analogues as Isoform‐Selective COX Inhibitors and Antitumor Agents

AbstractNonsteroidal anti‐inflammatory drugs (NSAIDs) are the most widely used therapeutics against pain, fever, and inflammation; additionally, antitumor properties are reported. NSAIDs reduce the synthesis of prostaglandins by inhibiting the cyclooxygenase (COX) isoforms COX‐1 and COX‐2. As nonselective inhibition is associated with off‐target effects, strategies to achieve selectivity for the clinically preferred isoform COX‐2 are of high interest. The modification of NSAIDs using carborane clusters as phenyl mimetics is reported to alter the selectivity profile through size exclusion. Inspired by these findings, isonimesulide and its carborane derivatives are prepared. The biological screening shows that the carborane containing compounds exhibit a stronger antitumor potential compared to nimesulide and isonimesulide. Furthermore, the replacement of the phenyl ring of isonimesulide with a carborane moiety resulted in a shift of the COX activity from nonactive to COX‐active compounds.

Antiviral activity of some benzo[g]quinazolines against coxsackievirus B4: biological screening and docking study.

Serotype coxsackievirus B (CVB) infection has been linked to viral myocarditis, dilated cardiomyopathy, meningitis, and pancreatitis in children and young adults. As of yet, no antiviral drug has been authorized for the treatment of coxsackievirus infection. Therefore, there is perpetual demand for new therapeutic agents and the improvement of existing ones. Benzo[g]quinazolines, the subject of several well-known heterocyclic systems, have risen to prominence and played a significant role in the development of antiviral agents, particularly those for anti-coxsackievirus B4 infection. This study investigated the cytotoxicity of the target benzo[g]quinazolines (1-16) in the BGM cells line as well as their anti-coxsackievirus B4 activity. Determination of CVB4 titers using a plaque assay. Most of the target benzoquinazolines exhibited antiviral activity, however, compounds 1-3 appeared to be the most effective (reduction percentages of 66.7, 70, and 83.3%, respectively). The binding mechanisms and interactions of the three most active 1-3 with the constitutive amino acids in the active site of the multi-target of coxsackievirus B4 (3Clpro and RdRp) targets were also investigated using molecular docking. The anti coxsackievirus B4 activity has resulted, and the top three active benzoquinazolines (1-3) have bonded to and interacted with the constitutive amino acids in the active region of the multi-target coxsackievirus B4 (RdRp and 3Clpro). Further research is required in the lab. to determine the exact benzoquinazolines mechanism of action.

A case report of unilateral cerebral vasculitis in adults: keep in mind Lyme neuroborreliosis

BackgroundLyme neuroborreliosis (LNB), due to infection of the nervous system by the spirochete Borrelia burgdorferi, occurs in 15% of Lyme disease cases. However, neurovascular involvement is uncommon, especially recurrent stroke related to cerebral vasculitis in the absence of CSF pleocytosis.Case presentationWe report the case of a 58-year-old man without any medical history who exhibited recurrent strokes in the same vascular territory (left internal carotid). Multiple biological screening, neuroimaging methods, and cardiovascular examinations failed to provide a diagnosis and treatment that could have prevented recurrences. Finally, B. burgdorferi sensu lato serology testing in blood and cerebrospinal fluid enabled diagnosis of LNB, in relation to a cerebral vasculitis. The patient experienced no further stroke after four weeks of doxycycline treatment.ConclusionB. burgdorferi central nervous system infection must be considered in case of unexplained recurrent and/or multiple strokes, especially if cerebral vasculitis is suspected or demonstrated on neuroimaging.

Fungal plant pathogen "mutagenomics" reveals tagged and untagged mutations in Zymoseptoria tritici and identifies SSK2 as key morphogenesis and stress-responsive virulence factor.

"Mutagenomics" is the combination of random mutagenesis, phenotypic screening, and whole-genome re-sequencing to uncover all tagged and untagged mutations linked with phenotypic changes in an organism. In this study, we performed a mutagenomics screen on the wheat pathogenic fungus Zymoseptoria tritici for altered morphogenetic switching and stress sensitivity phenotypes using Agrobacterium-mediated "random" T-DNA mutagenesis (ATMT). Biological screening identified four mutants which were strongly reduced in virulence on wheat. Whole genome re-sequencing defined the positions of the T-DNA insertion events and revealed several unlinked mutations potentially affecting gene functions. Remarkably, two independent reduced virulence mutant strains, with similarly altered stress sensitivities and aberrant hyphal growth phenotypes, were found to have a distinct loss of function mutations in the ZtSSK2 MAPKKK gene. One mutant strain had a direct T-DNA insertion affecting the predicted protein's N-terminus, while the other possessed an unlinked frameshift mutation towards the C-terminus. We used genetic complementation to restore both strains' wild-type (WT) function (virulence, morphogenesis, and stress response). We demonstrated that ZtSSK2 has a non-redundant function with ZtSTE11 in virulence through the biochemical activation of the stress-activated HOG1 MAPK pathway. Moreover, we present data suggesting that SSK2 has a unique role in activating this pathway in response to specific stresses. Finally, dual RNAseq-based transcriptome profiling of WT and SSK2 mutant strains revealed many HOG1-dependent transcriptional changes in the fungus during early infection and suggested that the host response does not discriminate between WT and mutant strains during this early phase. Together these data define new genes implicated in the virulence of the pathogen and emphasise the importance of a whole genome sequencing step in mutagenomic discovery pipelines.

Multicolor flow cytometry in clinical samples for platelet signaling assessment

BackgroundAvailability of multichannel cytometers and specific commercial antibodies makes flow cytometry a new option to simultaneously assess multiple intracellular platelet signaling pathways for clinical purposes, in small volume of blood or low platelet count. ObjectivesTo describe a multicolor flow cytometry with fluorescent barcoding technique for screening signaling pathways downstream membrane receptors of major platelet agonists (adenosine diphosphate, thrombin, thromboxane, and collagen). MethodsBy comparison with immunoblotting, we first selected the target phosphoproteins, AKT, P38MAPK, LIMK, and SPL76; the times of stimulation; and phosphoflow barcoding conditions. We then performed a clinical study on whole blood of patients without evidence of blood platelet disorder on standard biological screening, consulting for trivial or occasionally provoked bleeds without familial antecedent (bleeding of unknown origin, n = 23) or type-1 von Willebrand disease (n = 9). In addition, we included a small group of patients with definite platelet disorders (Glanzmann thrombasthenia, δ-storage pool deficiency, and immune glycoprotein VI–related disease with granule secretion defect). ResultsThe range, kinetics, and distribution of fluorescence intensity were established for each agonist-target protein combination. Principal component analysis indicates a correlation in response to a target phosphoprotein (AKT and P38MAPK) to different agonists but no correlation in the response of different target phosphoproteins to the same agonist. The heterogeneity of individual responses in the whole population displayed was analyzed using clustering algorithm. Patients with platelet storage pool deficiency were positioned as lowest responders on the heatmap. ConclusionIn complement of functional tests, this study introduces a new approach for rapid platelet signaling profiling in clinical practice.

Synthesis and Biological Screening of Novel Derivatives of Benzothiazol as Anticonvulsant Agents

The Benzothiazole ring system belongs to a much studied class of compound. In the last few decades, the chemistry of benzothiazole and their fused heterocyclic derivatives have received considerable attention owing to their significant and effective biological activity. The present study aimed to design and synthesize novel derivatives of bezothiazole obtained from 3-chloro-4-flouro aniline treated with potassium thiocynide with chloro acetyl chloride gives (7-chloro-6-fluro-1,3-benzothiazol-2-yl) acetyl chloride which is converted into hydrazide and yields the resultant compound derivatives of 2-(7-chloro-6-fluro-1,3-benzothiazol-2-yl) –N’-[(Z)-phenyl methylidene] acetohydrazide (SMVB-IIIA-IIIG).Title compound were synthesized and the structures of newly synthesized compounds were confirmed by IR, Mass and 1H-NMR spectroscopy All the compounds synthesized were confirmed by spectral data and evaluated for their anticonvulsant activity. The Compounds SMVB-IIIC, SMVB-IIIEand SMVB-IIIF showed maximal activity whereas remaining compounds showed good activity.

Endogenous Protease-Activatable Nanosensor Based on PNA–Peptide–DNA Engineering for AND-Gated and Dual-Model Detection of MicroRNA in Single Living Tumor Cells

The in situ detection of low-content cancer biomarkers by an endogenous activator instead of an exogenous initiator in vitro remains a great challenge, leaving a gap in the development of a tumor-specific nanosensor with an endogenous protease-activatable manner. Herein, we proposed an endogenous protease-activatable nanosensor (PA-NS) guided by peptide nucleic acid-peptide-DNA copolymers to realize AND-gated and dual-model sensing of miRNA-21 (miR-21) by combining electrochemical detection with optical imaging in living tumor cells, without an additional introduction of an exogenous activator or nanomaterials. Moreover, the PA-NS can only be activated by "dual keys" (overexpressed miR-21 and cathepsin B protease in tumor cells) simultaneously, which enables effective improvement of the tumor-to-healthy cells ratio. The fluorescence intensity measured in single tumor cells was ∼3.5-fold higher than that in single healthy cells, and the electrochemical response decreased ∼30% in the presence of target miRNA. Furthermore, studies on regulation of the protease activity and miR-21 fluctuation under external stimulation have contributed to our understanding of the biological processes and drug screenings underlying disease development. This specific endogenous protease-mediated manner for dual-model detection of miRNA guarantees excellent tumor-selective capability, which offers new opportunities to study cell heterogeneity and provides more reliable fundamentals for the diagnosis and treatment of cancer down to the single-cell level.

Synthesis, Characterization and Biological Screening Study of Some New Mixed Ligand Complexes with Pt(II) Complex

The Aim: The purpose of our study to synthesis of [6-(((Z)-1,5-dimethyl-2-phenyl-4-(((E)-4-(pyridin-2-yl)benzylidene)amino)-1,2-dihydro-3H-pyrazol-3-ylidene)amino)-3,3-dimethyl-7-oxo-4-thia-1azabicyclo[3.2.0]hept-5-ene-2-carboxylic acid] (L1) was new Schiff base and (E)-1-(2-((5-amino-2-hydroxyphenyl) diazenyl) phenyl)ethan-1-one (HL2) was azo ligand were mused to synthesize mixed ligand complexes of ions Co(II), Ni(II), Cu(II), Zn(II), Cd(II) Hg(II)and Pt(II).
 Study Design: Preparation of new ligands and study of their biological activity on Cancer Cells.
 Place and Duration of Study: The experimental Part carried out in Chemistry department- Lab of Inorganic chemistry.
 Methodology: The spectroscopic data of the complexes suggest that their (1:1:1) (L1:M:HL2) is mole ratio. Also, the analytical studies for all new complexes have shown octahedral geometries, except for Pt (II) complex which suggested square planar geometry also its conductivity measurements show electrical properties
 Results: All new compounds were analyzed The structure of these compounds has been investigated by using elemental analysis, FT-IR, UV-Vis spectrometric methods, 1H-NMR, mass spectra, atomic absorption, molar conductivity and magnetic susceptibility of metal complexes, and computational techniques to elucidate their chemical formulae.
 Conclusion: The biological activity results showed the inhibitory effect for platinum(II) the complex. In this study the cytotoxicity of Pt(II) complex on human colon cancer cell line LS 174 T CRC was investigated and African green monkey kidney cells normal cells were MTT assay. The metal complexes showed selective High cytotoxicity against colorectal, this metal Complex excelled in halting proliferation of LS174T CRC cancer cells line with median inhibitory concentration (IC50) values of Pt(II) complex. The outcomes unquestionably point to the feasibility of utilizing them as antitumor drugs in the field of pharmacy colon cancer.

Study on Azo-aldehyde Part-X: Synthesis, Characterization, Liquid Chromatography and Biological screening of Azo-salicylaldehyde from Nitro and Methyl-anilines

Study on Azo-aldehyde Part-X: Synthesis, Characterization, Liquid Chromatography and Biological screening of Azo-salicylaldehyde from Nitro and Methyl-anilines

Some novel peptides containing a modified pyrazolopyrimidine moiety: design, synthesis, and in vitro antibacterial screening

Numerous peptide drugs are currently undergoing advanced phases of clinical testing to determine their efficacy in combating antibiotic-resistant bacterial pathogens. Our aim was to prepare some novel peptides containing a modified pyrazolopyrimidine moiety and assess their activity against a set of selected bacteria in comparison to a widely used antibiotic, ciprofloxacin. In this study, eight new peptide compounds incorporating a modified pyrazolopyrimidine moiety were synthesized. Our results revealed that compounds 4 and 5, which contained only the pyrazolopyrimidine scaffold were less active than the peptide-conjugated pyrazolopyrimidines 10, 11, 13, 14, 15, and 17. The antibacterial activities of the eight novel compounds 4, 5, 10, 11, 13, 14, 15, and 17 were evaluated against a panel of bacterial strains. All the novel compounds exhibited potent antibacterial activity against Staphylococcus aureus, Enterococcus faecalis, and Pseudomonas aeruginosa strains compared to the reference antibiotic ciprofloxacin. The tested Escherichia coli strain displayed resistance against the newly synthesized compounds. Moreover, P. aeruginosa strain displayed resistance against ciprofloxacin and six of the newly synthesized compounds. Compounds 15 and 17 effectively inhibited the growth of the P. aeruginosa strain at MIC ≥ 1 μg/mL. Our results are encouraging and urge additional biological and pharmacological screening of the most active compounds against drug-resistant microbial strains.

Biological Screening and Crystallographic Studies of Hydroxy γ-Lactone Derivatives to Investigate PPARγ Phosphorylation Inhibition.

PPARγ represents a key target for the treatment of type 2 diabetes and metabolic syndrome. To avoid serious adverse effects related to the PPARγ agonism profile of traditional antidiabetic drugs, a new opportunity is represented by the development of molecules acting as inhibitors of PPARγ phosphorylation by the cyclin-dependent kinase 5 (CDK5). Their mechanism of action is mediated by the stabilization of the PPARγ β-sheet containing Ser273 (Ser245 in PPARγ isoform 1 nomenclature). In this paper, we report the identification of new γ-hydroxy-lactone-based PPARγ binders from the screening of an in-house library. These compounds exhibit a non-agonist profile towards PPARγ, and one of them prevents Ser245 PPARγ phosphorylation by acting mainly on PPARγ stabilization and exerting a weak CDK5 inhibitory effect.

Fourteen immunomodulatory alkaloids and two prenylated phenylpropanoids with dual therapeutic approach for COVID-19: molecular docking and dynamics studies

The pandemic outbreak of COVID-19 caused by the new severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a global health burden. To date, there is no highly effective antiviral therapy to eradicate the virus; as a result, researchers are racing to introduce new potential therapeutic agents. Alternatively, traditional immunity boosters and symptomatic treatment based on natural bioactive compounds are also an option. The 3-chymotrypsin-like protease (3CLpro) crystal structure, the main proteolytic enzyme of SARS-CoV-2, has been unraveled, allowing the development of effective protease inhibitors via in silico and biological studies. In COVID-19 infected patients, the loss of lung function, and mortality are reported to be linked to several inflammatory mediators and cytokines. In this context, the approach of introducing immunomodulatory agents may be considered a dual lifesaving strategy in combination with antiviral drugs. This study aims to provide immunomodulatory natural products exhibiting potential protease inhibitory activities. Selected groups of alkaloids of different classes and two prenylated phenylpropanoids from the Brazilian green propolis were in silico screened for their ability to inhibit COVID-19 3CLpro protease. Results showed that compounds exhibited binding energy scores with values ranging from −6.96 to −3.70 compared to the reference synthetic protease inhibitor O6K with a binding energy score of −7.57. O6K binding energy was found comparable with lead phytochemicals in our study, while their toxicity and drug-likeness criteria are better than that of O6K. The activities of these molecules are mainly ascribed to their ability to form hydrogen bonding with 3CLpro crucial amino acid residues of the catalytic site. In addition, the molecular dynamics simulations further showed that some of these compounds formed stable complexes as evidenced by the occupancy fraction measurements. The study suggested that the major immunomodulators 3β, 20α-diacetamido-5α-pregnane, (20S)-(benzamido)-3β-(N,N-dimethyamino)-pregnane, and baccharin are 3CLpro inhibitors. Biological screenings of these phytochemicals will be valuable to experimentally validate and consolidate the results of this study before a rigid conclusion is reached, which may pave the way for the development of efficient modulatory bioactive compounds with dual bioactions in COVID-19 intervention. Communicated by Ramaswamy H. Sarma

Synthesis of the Indole-Based Inhibitors of Bacterial Cystathionine γ-Lyase NL1-NL3.

Bacterial cystathionine γ-lyase (bCSE) is the main producer of H2S in pathogenic bacteria such as Staphylococcus aureus, Pseudomonas aeruginosa, etc. The suppression of bCSE activity considerably enhances the sensitivity of bacteria to antibiotics. Convenient methods for the efficient synthesis of gram quantities of two selective indole-based bCSE inhibitors, namely (2-(6-bromo-1H-indol-1-yl)acetyl)glycine (NL1), 5-((6-bromo-1H-indol-1-yl)methyl)- 2-methylfuran-3-carboxylic acid (NL2), as well as a synthetic method for preparation 3-((6-(7-chlorobenzo[b]thiophen-2-yl)-1H-indol-1-yl)methyl)- 1H-pyrazole-5-carboxylic acid (NL3), have been developed. The syntheses are based on the use of 6-bromoindole as the main building block for all three inhibitors (NL1, NL2, and NL3), and the designed residues are assembled at the nitrogen atom of the 6-bromoindole core or by the substitution of the bromine atom in the case of NL3 using Pd-catalyzed cross-coupling. The developed and refined synthetic methods would be significant for the further biological screening of NL-series bCSE inhibitors and their derivatives.