2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis:Structure-Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization

<i>Mycobacterium tuberculosis</i> (<i>MTb</i>) possesses two nonproton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing for the structure-based design of small-molecule inhibitors. Herein, we disclose <i>MTb</i> whole-cell structure–activity relationships (SARs) for a series of 2-mercapto-quinazolinones which target the <i>ndh</i> encoded NDH-2 with nanomolar potencies. The compounds were inactivated by glutathione-dependent adduct formation as well as quinazolinone oxidation in microsomes. Pharmacokinetic studies demonstrated modest bioavailability and compound exposures. Resistance to the compounds in <i>MTb</i> was conferred by promoter mutations in the alternative nonessential NDH-2 encoded by <i>ndhA</i> in <i>MTb</i>. Bioenergetic analyses revealed a decrease in oxygen consumption rates in response to inhibitor in cells in which membrane potential was uncoupled from ATP production, while inverted membrane vesicles showed mercapto-quinazolinone-dependent inhibition of ATP production when NADH was the electron donor to the respiratory chain. Enzyme kinetic studies further demonstrated noncompetitive inhibition, suggesting binding of this scaffold to an allosteric site. In summary, while the initial <i>MTb</i> SAR showed limited improvement in potency, these results, combined with structural information on the bacterial protein, will aid in the future discovery of new and improved NDH-2 inhibitors

Defining the clinical and cognitive phenotype of child savants with autism spectrum disorder

Objective: Whilst savant syndrome is most commonly observed in individuals with Autism Spectrum Disorder (ASD), it has historically been associated with intellectual impairment, and little is known about the clinical and cognitive characteristics of intellectually able individuals with ASD and savant skills. Methods: Participants with ASD and validated savant skills were compared with age and intelligence matched non-savants with ASD using a range of diagnostic and standardised tests. Results: Although the analysis of the clinical data revealed few differences between the groups, striking differences emerged during cognitive testing. Children with savant skills exhibited highly superior working memory and their scores on tests of analytic skills were also superior to those of non-savants. Conclusion: We propose that obsessionality, focused attention, superior working memory and analytic skills facilitate veridical mapping and pattern perception abilities characteristic in savant syndrome

3D-QSAR Modeling and Synthesis of New Fusidic Acid Derivatives as Antiplasmodial Agents

Wide spread Plasmodium falciparum (P. falciparum) resistance has compromised existing antimalarial therapies to varying degrees. Novel agents, able to circumvent antimalarial drug resistance, are therefore needed. Fusidic acid is a unique antibiotic with a unique mode of action, which has shown weak <i>in vitro</i> antiplasmodial activity. Toward identifying new fusidic acid derivatives with superior antiplasmodial activity, a 3D-QSAR model was developed based on the antiplasmodial activity of previously synthesized fusidic acid derivatives. The validated Hypo 2 model was used as the 3D-structural search query to screen a fusidic acid-based combinatorial library. On the basis of the predicted activity and pharmacophore fit value, eight virtual hit compounds were selected and synthesized, including C-21 amide and C-3 ether derivatives. All synthesized hit compounds showed superior antiplasmodial activity compared to fusidic acid. Two C-21 amide derivatives displayed significant activity against the drug-sensitive NF54 strain with IC₅₀ values of 0.3 μM and 0.7 μM, respectively. These two derivatives also displayed activity against the multidrug-resistant K1 strain, with an IC₅₀ value of 0.2 μM and were found to be relatively noncytotoxic

Design, Synthesis, and Antiplasmodial Activity of Hybrid Compounds Based on (2<i>R</i>,3<i>S</i>)‑<i>N</i>‑Benzoyl-3-phenylisoserine

A series of hybrid compounds based on (2<i>R</i>,3<i>S</i>)-<i>N</i>-benzoyl-3-phenylisoserine, artemisinin, and quinoline moieties was synthesized and tested for in vitro antiplasmodial activity against erythrocytic stages of K1 and W2 strains of <i>Plasmodium falciparum.</i> Two hybrid compounds incorporating (2<i>R</i>,3<i>S</i>)-<i>N</i>-benzoyl-3-phenylisoserine and artemisinin scaffolds were 3- to 4-fold more active than dihydroartemisinin, with nanomolar IC₅₀ values against <i>Plasmodium falciparum</i> K1 strain

Synthesis and Evaluation of a Carbosilane Congener of Ferroquine and Its Corresponding Half-Sandwich Ruthenium and Rhodium Complexes for Antiplasmodial and β‑Hematin Inhibition Activity

A silicon-containing congener of ferroquine (<b>1</b>) was synthesized by incorporating an organosilicon motif in the lateral side chain of ferroquine. Compound <b>1</b> was then further reacted with dinuclear half-sandwich transition-metal precursors [Ru­(Ar)­(μ-Cl)­Cl]₂ (Ar = η⁶-<i>p</i>-ⁱPrC₆H₄Me, η⁶-C₆H₆, η⁶-C₆H₅OCH₂CH₂OH), [Rh­(COD)­(μ-Cl)]₂, and [RhCp*­(μ-Cl)­Cl]₂, to yield a series of heterometallic organometallic complexes (<b>2</b>–<b>6</b>). Compound <b>1</b> coordinates selectively in a monodentate manner to the transition metals via the quinoline nitrogen of the aminoquinoline scaffold. All of the compounds were characterized using various analytical and spectroscopic techniques, and the molecular structure of compound <b>1</b> was elucidated by single-crystal X-ray diffraction analysis. Furthermore, the <i>in vitro</i> antiplasmodial activity of compounds <b>1</b>–<b>6</b> was established against the chloroquine-sensitive (NF54) and chloroquine-resistant (Dd2) strains of the malaria parasite Plasmodium falciparum

In silico Comparison of Antimycobacterial Natural Products with Known Antituberculosis Drugs

The chemical space based on physicochemical properties and structural features of a diverse group of natural products with reported in vitro activity against different Mycobacterium tuberculosis strains is investigated using in silico tools. This is compared to the chemical space occupied by drugs currently recommended for the treatment of various forms of tuberculosis as well as compounds in preclinical and clinical development. Docking studies exploring possible binding affinities and modes of two main clusters of natural products on two different mycobacterial targets are also reported. Our docking results suggest that scytoscalarol, an antibacterial and antifungal guanidine-bearing sesterterpene, can inhibit arabinosyltransferase Mtb EmbC, and the β-carboline alkaloids 8-hydroxymanzamine A and manzamine A can bind to the oxidoreductase of Mtb INHA. On this basis, these products showing high binding affinities to the two targets in silico could be rationally selected for in vitro testing against these targets and/or semisynthetic modification

Synthesis, Antiplasmodial Activity, and β‑Hematin Inhibition of Hydroxypyridone–Chloroquine Hybrids

A series of noncytotoxic 4-aminoquinoline-3-hydroxypyridin-4-one hybrids were synthesized on the basis of a synergistic in vitro combination of a precursor <i>N</i>-alkyl-3-hydroxypyridin-4-one with chloroquine (CQ) and tested in vitro against CQ resistant (K1 and W2) and sensitive (3D7) strains of <i>Plasmodium falciparum</i>. In vitro antiplasmodial activity of the precursors was negated by blocking the chelator moiety via complexation with gallium­(III) or benzyl protection. None of the precursors inhibited β-hematin formation. Most hybrids were more potent inhibitors of β-hematin formation than CQ, and a correlation between antiplasmodial activity and inhibition of β-hematin formation was observed. Potent hybrids against K1, 3D7, and W2, respectively, were <b>8c</b> (0.13, 0.004, and 0.1 μM); <b>8d</b> (0.08, 0.01, and 0.02 μM); and <b>7g</b> (0.07, 0.03, and 0.08 μM)

Synthesis and Evaluation of a Carbosilane Congener of Ferroquine and Its Corresponding Half-Sandwich Ruthenium and Rhodium Complexes for Antiplasmodial and β‑Hematin Inhibition Activity

A silicon-containing congener of ferroquine (<b>1</b>) was synthesized by incorporating an organosilicon motif in the lateral side chain of ferroquine. Compound <b>1</b> was then further reacted with dinuclear half-sandwich transition-metal precursors [Ru­(Ar)­(μ-Cl)­Cl]₂ (Ar = η⁶-<i>p</i>-ⁱPrC₆H₄Me, η⁶-C₆H₆, η⁶-C₆H₅OCH₂CH₂OH), [Rh­(COD)­(μ-Cl)]₂, and [RhCp*­(μ-Cl)­Cl]₂, to yield a series of heterometallic organometallic complexes (<b>2</b>–<b>6</b>). Compound <b>1</b> coordinates selectively in a monodentate manner to the transition metals via the quinoline nitrogen of the aminoquinoline scaffold. All of the compounds were characterized using various analytical and spectroscopic techniques, and the molecular structure of compound <b>1</b> was elucidated by single-crystal X-ray diffraction analysis. Furthermore, the <i>in vitro</i> antiplasmodial activity of compounds <b>1</b>–<b>6</b> was established against the chloroquine-sensitive (NF54) and chloroquine-resistant (Dd2) strains of the malaria parasite Plasmodium falciparum

Identification of New Human Malaria Parasite Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors by Pharmacophore and Structure-Based Virtual Screening

Plasmodium falciparum dihydroorotate dehydrogenase (<i>Pf</i>DHODH), a key enzyme in the de novo pyrimidine biosynthesis pathway, which the Plasmodium falciparum relies on exclusively for survival, has emerged as a promising target for antimalarial drugs. In an effort to discover new and potent <i>Pf</i>DHODH inhibitors, 3D-QSAR pharmacophore models were developed based on the structures of known <i>Pf</i>DHODH inhibitors and the validated Hypo1 model was used as a 3D search query for virtual screening of the National Cancer Institute database. The virtual hit compounds were further filtered based on molecular docking and Molecular Mechanics/Generalized Born Surface Area binding energy calculations. The combination of the pharmacophore and structure-based virtual screening resulted in the identification of nine new compounds that showed >25% inhibition of <i>Pf</i>DHODH at a concentration of 10 μM, three of which exhibited IC₅₀ values in the range of 0.38–20 μM. The most active compound, NSC336047, displayed species-selectivity for <i>Pf</i>DHODH over human DHODH and inhibited parasite growth with an IC₅₀ of 26 μM. In addition to this, 13 compounds inhibited parasite growth with IC₅₀ values of ≤50 μM, 4 of which showed IC₅₀ values in the range of 5–12 μM. These compounds could be further explored in the identification and development of more potent <i>Pf</i>DHODH and parasite growth inhibitors

The Dynamic Nonprime Binding of Sampatrilat to the C‑Domain of Angiotensin-Converting Enzyme

Sampatrilat is a vasopeptidase inhibitor that inhibits both angiotensin I-converting enzyme (ACE) and neutral endopeptidase. ACE is a zinc dipeptidyl carboxypeptidase that contains two extracellular domains (nACE and cACE). In this study the molecular basis for the selectivity of sampatrilat for nACE and cACE was investigated. Enzyme inhibition assays were performed to evaluate the in vitro ACE domain selectivity of sampatrilat. The inhibition of the C-domain (<i>K</i>_i = 13.8 nM) by sampatrilat was 12.4-fold more potent than that for the N-domain (171.9 nM), indicating differences in affinities for the respective ACE domain binding sites. Interestingly, replacement of the P₂ group of sampatrilat with an aspartate abrogated its C-selectivity and lowered the potency of the inhibitor to activities in the micromolar range. The molecular basis for this selective profile was evaluated using molecular modeling methods. We found that the C-domain selectivity of sampatrilat is due to occupation of the lysine side chain in the S₁ and S₂ subsites and interactions with Glu748 and Glu1008, respectively. This study provides new insights into ligand interactions with the nonprime binding site that can be exploited for the design of domain-selective ACE inhibitors