Chemical studies of selected chromone derivatives

This investigation has been geared towards several aspects of chromone chemistry. Selected 2-(N,N-dimethylarnino)chromones have been synthesized via 2-hydroxyacetophenone boron difluoride complex intermediates, and potentiometric analysis of these compounds in ethanolwater has been used to determine the influence of substituents on their basicity. The pKa values have been found to lie within a narrow range (1.92 - 2.52), and the observed substituent effects have been rationalized with the aid of semi-empirical and ab initio molecular orbital calculations. An efficient route has been developed for the synthesis of the naturally-occurring chromone, "granulosin" [7,8-(methylenedioxy)-2-propylchromone], and several C-2 side chain analogues in good yields, by condensing 2'-hydroxy-3',4'-(methylenedioxy)acetophenone with a range of ethyl carboxylate esters. These compounds show significant cytotoxic activity against the brine shrimp, Artemia salina, and two of them, the 2-ethyl and 2-benzyl derivatives also show 100% activity as pesticides on Beet army worms (BAW). Another naturally-occurring chromone derivative, 5-hydroxy-2-isopropyl-7-methoxychromone, and four C-2 side chain analogues have been prepared in moderate yields. These compounds also show significant cytotoxic activity against the brine shrimp, Artemia salina, and it is apparent that the presence of the hydroxyl group at C-5 is critical for such activity. The electronimpact mass spectra of both series of chromone derivatives have been investigated, permitting the elucidation of characteristic fragmentation patterns. In work directed towards the synthesis of potential HIV -1 protease inhibitors, five novel chromone-containing analogues of the clinically useful drug, ritonavir, have been synthesized. The design strategy has involved the coupling of substituted chromone-2- carboxylic acids with a specially prepared, hydroxyethylene dipeptide isostere to afford ritonavir analogues containing chromone termini. An interactive docking procedure has been used to explore the docking of ritonavir and the novel chromone-containing analogues into ' the active site of the enzyme, and has indicated the capacity of the ritonavir analogues to form hydrogen-bonds with the HJV-l enzyme receptor. Various substituted cbromone-3-carbaldehydes, which have been synthesized from the corresponding o-hyclroxyacetophenones using Vilsmeier-Haack methodology, have been examined as substrates for Morita-Baylis-Hillman reactions, using 3-hyclroxyquinuclidine as the catalyst and arcylonitrile and methyl acrylate as the activated alkenes. Optimization of the reaction conditions has permitted efficient conversion of the cbromone-3-carbaldehydes to the Morita-Baylis-Hillman products and, in some cases, dimeric products, within 24 h. Heating of the Morita-Baylis-Hillman products, arising from reactions with methyl acrylate, at 80 ºC for 3 h in the presence of DABCO as catalyst, has been shown to effect transformation to the corresponding dimers in good yield

UCT943, a next generation Plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of malaria

The 2-aminopyridine MMV048 was the first drug candidate inhibiting; Plasmodium; phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant; Plasmodium falciparum; and; Plasmodium vivax; clinical isolates. Excellent; in vitro; antiplasmodial activity translated into high efficacy in; Plasmodium berghei; and humanized; P. falciparum; NOD-; scid IL-2R; γ; null; mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate; in vivo; intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generation; Plasmodium; PI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria

Crystal structure of the N domain of human somatic angiotensin I-converting enzyme provides a structural basis for domain-specific inhibitor design

Human somatic angiotensin I-converting enzyme (sACE) is a key regulator of blood pressure and an important drug target for combating cardiovascular and renal disease. sACE comprises two homologous metallopeptidase domains, N and C, joined by an inter-domain linker. Both domains are capable of cleaving the two hemoregulatory peptides angiotensin I and bradykinin, but differ in their affinities for a range of other substrates and inhibitors. Previously we determined the structure of testis ACE (C domain); here we present the crystal structure of the N domain of sACE (both in the presence and absence of the antihypertensive drug lisinopril) in order to aid the understanding of how these two domains differ in specificity and function. In addition, the structure of most of the inter-domain linker allows us to propose relative domain positions for sACE that may contribute to the domain cooperativity. The structure now provides a platform for the design of “domain-specific” second-generation ACE inhibitors

Lerisetron Analogues with Antimalarial properties - Synthesis, Structure-Activity Relationship (SAR) studies and Biological Assessment

A phenotypic whole cell high throughput screen against asexual blood and liver stages of the malaria parasite identified a benzimidazole chemical series. Among the hits were the antiemetic benzimidazole drug Lerisetron 1 (IC50 NF54 = 0.81 µM) and its methyl substituted analogue 2 (IC50 NF54 = 0.098 µM). A medicinal chemistry hit to lead effort led to the identification of chloro substituted analogue 3 with high potency against the drug sensitive NF54 (IC50 NF54 = 0.062 µM) and multidrug-resistant K1 (IC50 K1= 0.054 µM) strains of the human malaria parasite Plasmodium falciparum. Cardiotoxicity risks as expressed in strong inhibition of the hERG potassium channel was identified as major liability to address. This led to the synthesis and biological assessment of around sixty (60) analogues from which several compounds with more potent anti-plasmodium activity, relative to the lead compound 3, were identified

Characterization of angiotensin I-converting enzyme N-domain selectivity using positional-scanning combinatorial libraries of fluorescence resonance energy transfer peptides

Somatic angiotensin I-converting enzyme (ACE) has two homologous active sites (N and C domains) that show differences in various biochemical properties. in a previous study, we described the use of positional-scanning synthetic combinatorial (PS-SC) libraries of fluorescence resonance energy transfer (FRET) peptides to define the ACE C-domain versus N-domain substrate specificity and developed selective substrates for the C-domain (Bersanetti et al., 2004). in the present work, we used the results from the PS-SC libraries to define the N-domain preferences and designed selective substrates for this domain. the peptide Abz-GDDVAK(Dnp)-OH presented the most favorable residues for N-domain selectivity in the P-3 to P-1' positions. the fluorogenic analog Abz-DVAK(Dnp)-OH (Abz=ortho-aminobenzoic acid; Dnp=2,4-dinitrophenyl) showed the highest selectivity for ACE N-domain (k(cat)/K-m = 1.76 mu M-1.s(-1)). Systematic reduction of the peptide length resulted in a tripeptide that was preferentially hydrolyzed by the C-domain. the binding of Abz-DVAK(Dnp)-OH to the active site of ACE N-domain was examined using a combination of conformational analysis and molecular docking. Our results indicated that the binding energies for the N-domain-substrate complexes were lower than those for the C-domain-substrate, suggesting that the former complexes are more stable.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)National Research FoundationUCTUniversidade Federal de São Paulo, Dept Biophys, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Hlth Informat Dept, BR-04023062 São Paulo, BrazilUCT Fac Hlth Sci, Div Med Biochem, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South AfricaUniv Cape Town, Dept Chem, ZA-7700 Cape Town, South AfricaUniversidade Federal de São Paulo, Dept Biophys, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Hlth Informat Dept, BR-04023062 São Paulo, BrazilWeb of Scienc

Antimalarial lead-optimization studies on a 2,6-imidazopyridine series within a constrained chemical space to circumvent atypical dose-response curves against multidrug resistant parasite strains

A lead-optimization program around a 2,6-imidazopyridine scaffold was initiated based on the two early lead compounds, 1 and 2, that were shown to be efficacious in an in vivo humanized Plasmodium falciparum NODscidIL2Rγnull mouse malaria infection model. The observation of atypical dose-response curves when some compounds were tested against multidrug resistant malaria parasite strains guided the optimization process to define a chemical space that led to typical sigmoidal dose-response and complete kill of multidrug resistant parasites. After a structure and property analysis identified such a chemical space, compounds were prepared that displayed suitable activity, ADME, and safety profiles with respect to cytotoxicity and hERG inhibition

Structure-activity-relationship studies around the 2-amino group and pyridine core of antimalarial 3,5-diarylaminopyridines lead to a novel series of pyrazine analogues with oral in vivo activity

Replacement of the pyridine core of antimalarial 3,5-diaryl-2-aminopyridines led to the identification of a novel series of pyrazine analogues with potent oral antimalarial activity. However, other changes to the pyridine core and replacement or substitution of the 2-amino group led to loss of antimalarial activity. The 3,5-diaryl-2-aminopyrazine series showed impressive in vitro antiplasmodial activity against the K1 (multidrug resistant) and NF54 (sensitive) strains of Plasmodium falciparum in the nanomolar IC50 range of 6-94 nM while also demonstrating good in vitro metabolic stability in human liver microsomes. In the Plasmodium berghei mouse model, this series generally exhibited good efficacy at low oral doses. One of the frontrunner compounds, 4, displayed potent in vitro antiplasmodial activity with IC50 values of 8.4 and 10 nM against the K1 and NF54 strains, respectively. When evaluated in P. berghei -infected mice, compound 4 was completely curative at an oral dose of 4 × 10 mg/kg