Medicinal Chemistry - Volume 15, Issue 6, 2019

Background: The Angiotensin-I converting enzyme (ACE) is one of the most important components of the renin-angiotensin-aldosterone system controlling blood pressure and renal functions. Inhibitors of ACE are first line therapeutics used in the treatment of hypertension and related cardiovascular diseases. Somatic ACE consists of two homologous catalytic domains, the C- and N-domains. Recent findings have shown that although both domains are highly homologous in structure, they may have different physiological functions. The C-domain is primarily involved in the control of blood pressure, in contrast to the N-domain that is engaged in the regulation of hematopoietic stem cell proliferation. The currently available ACE inhibitors have some adverse effects that can be attributed to the non-selective inhibition of both domains. In addition, specific Ndomain inhibitors have emerged as potential antifibrotic drugs. Therefore, ACE is still an important drug target for the development of novel domain-selective drugs not only for the cardiovascular system but also for other systems. Objective: Detailed structural information about interactions in the protein-ligand complex is crucial for rational drug design. This review highlights the structural information available from crystallographic data which is essential for the development of domain selective inhibitors of ACE. Methods: Over eighty crystal complexes of ACE are placed into the Protein Database. An overview of X-ray ACE complexes with various inhibitors in C- and N-domains and an analysis of their binding mode have given mechanistic explanation of the structural determinants of selective ligand binding. In addition, ACE domain selective inhibitors with dual modes of action in complexes with ACE are also discussed. Conclusion: Selectivity of ACE inhibitors for the N- and C-domain is controlled by subtle differences in the amino-acids forming the active site. Reported studies of crystal complexes of inhibitors in the C- and N-domains revealed that most selective inhibitors interact with non-conserved amino-acids between domains and have distinct interactions with the residues in the S2 and S2’ subsites of the ACE catalytic site. Moreover, unusual binding of the second molecule of inhibitors in the binding cavity opens new possibilities of exploiting more distant regions of the catalytic center in structure-based design of novel drugs.

Background: PI3Kδ is predominantly expressed in hematopoietic cells and participates in the activation of leukocytes. PI3Kδ inhibition is a promising approach for treating inflammatory diseases and leukocyte malignancies. Accordingly, we decided to model PI3Kδ binding. Methods: Seventeen PI3Kδ crystallographic complexes were used to extract 94 pharmacophore models. QSAR modelling was subsequently used to select the superior pharmacophore(s) that best explain bioactivity variation within a list of 79 diverse inhibitors (i.e., upon combination with other physicochemical descriptors). Results: The best QSAR model (r2 = 0.71, r2 LOO = 0.70, r2 press against external testing list of 15 compounds = 0.80) included a single crystallographic pharmacophore of optimal explanatory qualities. The resulting pharmacophore and QSAR model were used to screen the National Cancer Institute (NCI) database for new PI3Kδ inhibitors. Two hits showed low micromolar IC50 values. Conclusion: Crystallography-based pharmacophores were successfully combined with QSAR analysis for the identification of novel PI3Kδ inhibitors.

Background: Aberrant expression of eukaryotic translation initiation factor 4E (eIF4E) is common in many types of cancer including acute myeloid leukaemia (AML). Phosphorylation of eIF4E by MAPK-interacting kinases (Mnks) is essential for the eIF4E-mediated oncogenic activity. As such, the pharmacological inhibition of Mnks can be an effective strategy for the treatment of cancer. Methods: A series of N-phenyl-4-(1H-pyrrol-3-yl)pyrimidin-2-amine derivatives was designed and synthesised. The Mnk inhibitory activity of these derivatives as well as their anti-proliferative activity against MV4-11 AML cells was determined. Results: These compounds were identified as potent Mnk2 inhibitors. Most of them demonstrated potent anti-proliferative activity against MV4-11 AML cells. The cellular mechanistic studies of the representative inhibitors revealed that they reduced the level of phosphorylated eIF4E and induced apoptosis by down-regulating the anti-apoptotic protein myeloid cell leukaemia 1 (Mcl-1) and by cleaving poly(ADP-ribose)polymerase (PARP). The lead compound 7k possessed desirable pharmacokinetic properties and oral bioavailability. Conclusion: This work proposes that exploration of the structural diversity in the context of Nphenyl- 4-(1H-pyrrol-3-yl)pyrimidin-2-amine would offer potent and selective Mnk inhibitors.

Background: The development of new classes of blood glucose–lowering medications has increased the number of treatment opportunities available for type 2 diabetes. Nevertheless, long term complicated treatments and side effects of available antidiabetic therapies have urged huge demands for effective affordable anti-diabetic agents that can lessen negative health consequences. In this sense, the exploration of alternative medicinal remedies associated with new significant antidiabetic efficiencies with minimized adverse effects is an active domain of research. Objective: The aim of this study was to synthesize a series of benzothiazole-pyrazolidinedione hybrids and evaluate their antidiabetic activity along with molecular docking and in silico analysis. Methods: The hybrids were synthesized by a multi-step synthesis and were further subjected for in vivo anti-hyperglycemic assessment on rat models of type II diabetes. Molecular modelling study was undertaken against peroxisome proliferator-activated receptor γ (PPARγ) to highlight possible key interactions. Results: Docking studies revealed that appropriate substituents on benzothiazole ring interacted favorably with the hydrophobic Ω-pocket of PPARγ binding site resulting in improving their antihyperglycemic activity. All the synthesized hybrids manifested promising anti-hyperglycemic potency. Excitingly, 5a, 5b and 5c were even more potent than the standard drug. Conclusion: The newly synthesized hybrids can be considered as a new class of antidiabetic agents and this study provided useful information on further optimization.

Background: Sulphonylureas are the oldest and commonly used to treat diabetic patients, but its efficacy declines by time. It was reported that quinazoline nucleus exhibits a potent hypoglycemic effect in diabetic animal models. Objective: The current study aimed to synthesize new quinazoline-sulfonylurea conjugates and evaluate their hypoglycemic effects in alloxan-induced diabetic rats. Methods: The conjugates were synthesized by bioisosteric replacement of 5-chloro-2-methoxybenzamide moiety in glibenclamide or 1,3-dioxo-3,4-dihydroisoquinoline moiety in gliquidone with 6,7-dimethoxy-4-oxoquinazoline moiety (compounds 4a-4d, 9b-9c and 10b-10d). Diabetes was induced in rats by a single i.p. administration of alloxan, followed by treatment with the synthesized conjugates (5mg/kg Body weight). Results: All conjugates showed hypoglycemic effects with different efficacy indicated by the reduction in blood glucose and elevation of insulin levels. Moreover, these conjugates up-regulated the expression of pancreatic glucose transporter 2, muscle glucose transporter 4, and insulin receptor substrate-1 genes, compared to the diabetic group. A normal pancreatic tissue pattern was noticed in diabetic rats treated with compounds 9b, 9c, and 10c. Conclusion: Conjugation of sulfonylurea with quinazoline (especially 9b, 9c, 10c) possessed a significant hypoglycemic effect through improving blood insulin level and insulin action and consequently increased the glucose uptake by the skeletal muscles.

Background: The increasing incidence of fungal infections, especially caused by Candida albicans, and their increasing drug resistance has drastically increased in recent years. Therefore, not only new drugs but also alternative treatment strategies are promptly required. Methods: We previously reported on the synergistic interaction of some azole and non-azole compounds with fluconazole for combination antifungal therapy. In this study, we synthesized some non-azole Schiff-base derivatives and evaluated their antifungal activity profile alone and in combination with the most commonly used antifungal drugs- fluconazole (FLC) and amphotericin B (AmB) against four drug susceptible, three FLC resistant and three AmB resistant clinically isolated Candida albicans strains. To further analyze the mechanism of antifungal action of these compounds, we quantified total sterol contents in FLC-susceptible and resistant C. albicans isolates. Results: A pyrimidine ring-containing derivative SB5 showed the most potent antifungal activity against all the tested strains. After combining these compounds with FLC and AmB, 76% combinations were either synergistic or additive while as the rest of the combinations were indifferent. Interestingly, none of the combinations was antagonistic, either with FLC or AmB. Results interpreted from fractional inhibitory concentration index (FICI) and isobolograms revealed 4-10-fold reduction in MIC values for synergistic combinations. These compounds also inhibit ergosterol biosynthesis in a concentration-dependent manner, supported by the results from docking studies. Conclusion: The results of the studies conducted advocate the potential of these compounds as new antifungal drugs. However, further studies are required to understand the other mechanisms and in vivo efficacy and toxicity of these compounds.

Background: Quinazolines and quinazolinones derivatives are well known for their important range of therapeutic activities. Objective: The study aims to carry out the synthesis of some derivatives of substituted fluoroquinazolinones based on structure-based design and evaluation of their antibacterial, antifungal, and anti-biofilm activities. Methods: Compounds were chemically synthesized by conventional methods. Structures were established on the basis of spectral and elemental analyses. The antimicrobial potential was tested against various microorganisms using the agar disc-diffusion method. MIC and MBC as well as anti-biofilm activity for the highly active compounds were assessed. Moreover, the computational studies were performed using Auto dock free software package (version 4.0) to explain the predicted mode of binding. Results: All derivatives (5-8), (10a-g), and (A-H) were biologically tested and showed significant antimicrobial activity comparable to the reference compounds. Compounds 10b, 10c, and 10d had a good MIC and MBC against Gram-positive bacteria, whereas 10b and 10d showed significant MIC and MBC against Gram-negative bacteria. However, compounds E and F exhibited good MIC and MBC against fungi. Compound 10c and 8 exhibited significant anti-biofilm activity towards S. aureus and M. luteus. Molecular docking study revealed a strong binding of these derivatives with their receptor-site and detected their predicted mode of binding. Conclusion: The synthesized derivatives showed promising antibacterial, antifungal, and antibiofilm activities. Modeling study explained their binding mode and showed strong binding affinity with their receptor-site. The highly active compounds 5 and 10c could be subjected to future optimization and investigation to be effective antimicrobial agents.

Background: Despite a massive industry endeavor to develop RORγ-modulators for autoimmune disorders, there has been no indication of efforts to target the close family member RORα for similar indications. This may be due to the misconception that RORα is redundant to RORγ, or the inherent difficulty in cultivating tractable starting points for RORα. RORα-selective modulators would be useful tools to interrogate the biology of this understudied orphan nuclear receptor. Objective: The goal of this research effort was to identify and optimize synthetic ligands for RORα starting from the known LXR agonist T0901317. Methods: Fourty-five analogs of the sulfonamide lead (1) were synthesized and evaluated for their ability to suppress the transcriptional activity of RORα, RORγ, and LXRα in cell-based assays. Analogs were characterized by 1H-NMR, 13C-NMR, and LC-MS analysis. The pharmacokinetic profile of the most selective RORα inverse agonist was evaluated in rats with intraperitoneal (i.p.) and per oral (p.o.)dosing. Results: Structure-activity relationship studies led to potent dual RORα/RORγ inverse agonists as well as RORα-selective inverse agonists (20, 28). LXR activity could be reduced by removing the sulfonamide nitrogen substituent. Attempts to improve the potency of these selective leads by varying substitution patterns throughout the molecule proved challenging. Conclusion: The synthetic RORα-selective inverse agonists identified (20, 28) can be utilized as chemical tools to probe the function of RORα in vitro and in vivo.

Background: Malaria, caused by the deadly Plasmodium falciparum strain, claims the lives of millions of people annually. The emergence of drug-resistant strains of P. falciparum to the artemisinin-based combination therapy (ACT), the last line of defense against malaria, is worrisome and urges for the development of new chemo-types with a new mode of action. In the search of new antimalarial agents, hybrids of triazoles and other known antimalarial drugs have been reported to possess better activity than either of the parent compounds administered individually. Despite their better activity, no hybrid antimalarial drugs have been developed so far. Objective: In the hope of developing new antimalarial prototypes, we propose the design, synthesis and antimalarial evaluation of novel sulfoximine-triazole hybrids owing to their interesting biological and physiological properties. Methods: The sulfoximine part of the hybrid will be synthesized via imidation of the corresponding sulfoxide. Propargylation of the NH moiety of the sulfoximine followed by copper-catalyzed click chemistry with benzyl azide was envisaged to provide the target sulfoximine-triazole hybrids. Results: Five novel sulfoximine-triazole hybrids possessing various substituents on the sulfoximine moiety have been successfully synthesized and evaluated for their antiplasmodial and cytotoxicity activities. The results revealed that the co-presence of the sulfoximine and triazole moieties along with a lipophilic alkyl substituent on the sulfur atom impart significant activity. Conclusion: Sulfoximine-triazole hybrids could be used as a prototype for the synthesis of new derivatives with better antiplasmodial activities.

Background: Despite the development of extensive control strategies and treatment options, approximately 200 million malaria cases, leading to approximately 450,000 deaths, were reported in 2015. Due to issue of disease resistance, additional drug development efforts are needed to produce new, more effective treatments. Quinazoline-2,4-diamines were identified as antiparasitic compounds over three decades ago and have remained of interest to date in industry and academia. Objective: An anti-malarial SAR evaluation of previously unreported N2 ,N4 -disubstituted quinazoline- 2,4-diamines have been undertaken in this study. We have synthesized and evaluated new derivatives against P. falciparum in our attempt to better characterize their biological activity and overall physical properties. Methods: The synthesis of N2 ,N4 -disubstituted quinazoline-2,4-diamines inhibitors is reported along with activities in a radioactive labeled hypoxanthine incorporation assay against the f Plasmodium falciparum (Pf.) K1 strain. In addition, cytotoxicity was determined in the A549 and Vero cell lines using an MTT based. The aqueous solubility of key compounds was assessed at pH 7.4 using a shake flask-based approach. Results: We identified compounds 1 and 6p as sub μM inhibitors of P. falciparum, having equivalent anti-malarial activity to Chloroquine. Compounds 1 and 6m are low μM inhibitors of P. falciparum with improved cytotoxicity profiles. Compound 6m displayed the best balance between P. falciparum Inhibitory activity (2 μM) and cytotoxicity, displaying >49 fold selectivity over A549 and Vero cell lines. Conclusion: Twenty one N2 ,N4 -Disubstituted Quinazoline-2,4-diamines have been prepared in our group and characterized in terms of their antimalarial activity, cytotoxicity and physical properties. Compounds with good activity and reasonable selectivity over mammalian cell lines have been identified. SAR analyses suggest further exploration is are necessary to improve the balance of P. falciparum Inhibitory activity, cytotoxicity and solubility.

Background: L-asparaginase (L-ASN) is an anti-cancer enzyme therapeutic drug that exerts cytotoxicity via inhibition of protein synthesis through depletion of L-asparagine in the tumor microenvironment. The therapeutic performance of the native drug is partial due to the associated instability, reduced half-life and immunogenic complications. Objective: In this study, we attempted the modification of recombinant L-asparaginase with PEG and an integrated computational strategy to probe the PEGylation in the protein to understand the biological stability/activity imparted by PEG. Methods: In vitro PEGylation of recombinant L-ASN was carried out and further evaluated in silico. Results: PEGylation enhanced thermal and pH activities with extended serum half-life and resistance to proteases compared to the native enzyme. The molecular dynamics analysis revealed intricate interactions required in the coupling of PEG to L-asparaginase to bestow stronger binding affinity of L-asparagine moiety towards L-asparaginase. PEG-asparagine complex ensured stable conformation over both the native protein and asparagine-protein complex thus elucidating the PEG-induced stable conformation in the protein. PEG mechanistically stabilized L-asparaginase through inducing pocket modification at the receptor to adapt to the cavity. Conclusion: The study provides the rationale of PEGylation in imparting the stability towards Lasparaginase which would expand the potential application of L-asparaginase enzyme for the effective treatment of cancer.