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Tetrahydropyran derivative 1 was discovered in a high-throughput screening campaign to find new inhibitors of mycobacterial InhA. Following initial in-vitro profiling, a structure-activity relationship study was initiated and a focused library of analogs was synthesized and evaluated. This yielded compound 42 with improved antimycobacterial activity and low cytotoxicity. Additionally, the crystal structure of InhA in complex with inhibitor 1 was resolved, to reveal the binding mode and provide hints for further optimization.

Isoniazid (INH) remains one of the cornerstones of antitubercular chemotherapy for drug-sensitive strains of M. tuberculosis bacteria. However, the increasing prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains containing mutations in the KatG enzyme, which is responsible for the activation of INH into its antitubercular form, have rendered this drug of little or no use in many cases of drug-resistant tuberculosis. Presented herein is a novel family of antitubercular direct NADH-dependent 2-trans enoyl-acyl carrier protein reductase (InhA) inhibitors based on an N-benzyl-4-((heteroaryl)methyl)benzamide template; unlike INH, these do not require prior activation by KatG. Given their direct InhA target engagement, these compounds should be able to circumvent KatG-related resistance in the clinic. The lead molecules were shown to be potent inhibitors of InhA and showed activity against M. tuberculosis bacteria. This new family of inhibitors was found to be chemically tractable, as exemplified by the facile synthesis of analogues and the establishment of structure-activity relationships. Furthermore, a co-crystal structure of the initial hit with the enzyme is disclosed, providing valuable information toward the design of new InhA inhibitors for the treatment of MDR/XDR tuberculosis.

A set of triterpenoids with different grades of oxidation in the lupane skeleton were prepared and evaluated as cholinesterase inhibitors. Allylic oxidation with selenium oxide and Jones’s oxidation were employed to obtain mono-, di- and tri-oxolupanes, starting from calenduladiol (1) and lupeol (3). All the derivatives showed a selective inhibition of butyrylcholinesterase over acetylcholinesterase (BChE vs. AChE). A kinetic study proved that compounds 2 and 9, the more potent inhibitors of the series, act as competitive inhibitors. Molecular modeling was used to understand their interaction with BChE, the role of carbonyl at C-16 and the selectivity towards this enzyme over AChE. These results indicate that oxidation at C-16 of the lupane skeleton is a key transformation in order to improve the cholinesterase inhibition of these compounds. Fil: Castro, Maria Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina Fil: Richmond, Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Faraoni, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina Fil: Murray, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina

One way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series of Mycobacterium tuberculosis gyrase inhibitors, which stem from the long-term efforts GSK has dedicated to the discovery and development of novel bacterial topoisomerase inhibitors (NBTIs). The compounds identified were found to be devoid of fluoroquinolone (FQ) cross-resistance and seem to operate through a mechanism similar to that of the previously described NBTI GSK antibacterial drug candidate. The remarkable in vitro and in vivo antitubercular profiles showed by the hits has prompted us to further advance the MGI project to full lead optimization.

A novel and efficient synthesis of dibenzo[b,e]oxepin-11(6H)-ones by direct intramolecular ortho-acylation from readily available 2-(phenoxymethyl)benzoic acids was developed. The method takes advantage of a newly developed cooperative system consisting of sustainable FeCl2 and Cl2CHOCH3 as the key components. This methodology is compatible with a wide variety of functional groups in good to excellent yields and high regioselectivity. The synthetic application of new protocol was extended to the synthesis of known tricyclic drug doxepin as well as a small library of oxepin based derivatives. For the first time, the obtained dibenzo[b,e]oxepinone derivatives were evaluated for their biological activities on the free-living nematode Caenorhabditis elegans as an effective and cost-efficient model system for anthelmintic discovery. Fil: Scoccia, Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina Fil: Castro, Maria Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina Fil: Faraoni, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina Fil: Martín García, Victor Sotero. Universidad de La Laguna; España Fil: Gerbino, Darío César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina

A set of twenty one lupane derivatives (2–22) was prepared from the natural triterpenoid calenduladiol (1) by transformations on the hydroxyl groups at C-3 and C-16, and also on the isopropenyl moiety. The derivatives were tested for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and some structure–activity relationships were outlined with the aid of enzyme kinetic studies and docking modelization. The most active compound resulted to be 3,16,30-trioxolup-20(29)-ene (22), with an IC50 value of 21.5 μM for butyrylcholinesterase, which revealed a selective inhibitor profile towards this enzyme. Fil: Castro, Maria Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina Fil: Richmond, Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Romero, Carmen. Universidad de la Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-Orgánica "Antonio González"; España Fil: Maier, Marta Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Estevez Braun, Ana. Universidad de la Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-Orgánica "Antonio González"; España Fil: Ravelo, Angel G.. Universidad de la Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-Orgánica "Antonio González"; España Fil: Faraoni, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina Fil: Murray, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina

Two new families of closely related selective, non-cytotoxic, and potent antitubercular agents were discovered: thioquinolines and thiazoloquinolines. The compounds were found to possess potent antitubercular properties in vitro, an activity that is dependent on experimental conditions of MIC determination (resazurin test and the presence or absence of Tween-80). To clarify the therapeutic potential of these compound families, a medicinal chemistry effort was undertaken to generate a lead-like structure that would enable murine efficacy studies and help elucidate the in vivo implications of the in vitro observations. Although the final compounds showed only limited levels of systemic exposure in mice, modest levels of efficacy in vivo at nontoxic doses were observed.

In 2010, GlaxoSmithKline published the structures of 13533 chemical starting points for antimalarial lead identification. By using an agglomerative structural clustering technique followed by computational filters such as antimalarial activity, physicochemical properties, and dissimilarity to known antimalarial structures, we have identified 47 starting points for lead optimization. Their structures are provided. We invite potential collaborators to work with us to discover new clinical candidates.

Falcipain-2 and falcipain-3 are papain-family cysteine proteases of the malaria parasite Plasmodium falciparum that are responsible for host hemoglobin hydrolysis to provide amino acids for parasite protein synthesis. Different heteroarylnitrile derivatives were studied as potential falcipain inhibitors and therefore potential antiparasitic lead compounds, with the 5-substituted-2-cyanopyrimidine chemical class emerging as the most potent and promising lead series. Through a sequential lead optimization process considering the different positions present in the initial scaffold, nanomolar and subnanomolar inhibitors at falcipains 2 and 3 were identified, with activity against cultured parasites in the micromolar range. Introduction of protonable amines within lead molecules led to marked improvements of up to 1000 times in activity against cultured parasites without noteworthy alterations in other SAR tendencies. Optimized compounds presented enzymatic activities in the picomolar to low nanomolar range and antiparasitic activities in the low nanomolar range.

Starting from a 3,5-dihydroxyheptanoic acid derivative, a new synthesis of pyrrole statins that contain a double bond on the dihydroxyacid chain has been developed. Key steps are N-acylamino acid enamide formation through enamine trapping with aromatic acyl chlorides and subsequent munchnone cycloaddition with activated acetylenes.

A number of novel 3'-O-acyl and alkyl sordarins were synthesised for structure-activity relationship studies. Many of these derivatives exhibit high activity against Candida albicans, Candida pseudotropicalis, Candida tropicalis and Cryptococcus neoformans.

Rapid triaging of three series of related hits selected from the Tres Cantos Anti-Malarial Set (TCAMS) are described. A triazolopyrimidine series was deprioritized due to delayed inhibition of parasite growth. A lactic acid series has derivatives with IC50 < 500 nM in a standard Plasmodium falciparumin vitro whole cell assay (Pf assay) but shows half-lives of < 30 min in both human and murine microsomes. Compound 19, from a series of cyclopropyl carboxamides, is a highly potent in vitro inhibitor of P. falciparum (IC50 = 3 nM) and has an oral bioavailability of 55% in CD-1 mice and an ED90 of 20 mg/kg after oral dosing in a nonmyelo-depleted P. falciparum murine model.

The synthesis of (6R,5S,2RS)-6-amino-5-hydroxy-2-isobutyl-4-oxo-7- phenylheptanoic acid (9), a carbaanalogue of the aminopeptidase (AP) inhibitor bestatin (1) is described. This synthesis was carried out by a malonic ester alkylation with the suitably protected halomethyl ketone of (2S,3R)-AHPBA*), followed by a second alkylation with isobutyl bromide of the resulting 4-ketodiester, and subsequent decarboxylation and deprotection. The inhibitory potencies of the 1:1 diastereomeric mixture 9 against AP-B, AP-M and Leu-AP were approximately 10-fold lower than those of bestatin.

A bioactivity-guided approach was taken to identify the acetylcholinesterase (AChE) inhibitory agents in the ethanolic extract of CHUQUIRAGA ERINACEA D. Don. subsp. ERINACEA leaves using a bioautographic method. This permitted the isolation of the pentacyclic triterpenes calenduladiol ( 1), faradiol ( 2), heliantriol B2 ( 3), lupeol ( 4), and a mixture of α-and β-amyrin ( 5A and 5B) as active constituents. Pseudotaraxasterol ( 6) and taraxasterol ( 7) were also isolated from this extract and showed no activity at the same analytical conditions. Compound 1 showed the highest AChE inhibitory activity with 31.2 % of inhibition at 0.5 mM. Looking forward to improve the water solubility of the active compounds, the sodium sulfate ester of 1 was prepared by reaction with the (CH 3 ) 3 N.SO 3 complex. The semisynthetic derivative disodium calenduladiol disulfate ( 8) elicited higher AChE inhibition than 1 with 94.1 % of inhibition at 0.5 mM (IC 50 = 0.190 ± 0.003 mM). Compounds 1, 2, 3, 5, 6, and 7 are reported here for the first time in C. ERINACEA. This is the first report of AChE inhibition from calenduladiol ( 1) as well as from a sulfate derived from a natural product.

A number of new 2′,3′-fused oxirane derivatives were synthesized for structure–activity relationship study. Many of these derivatives exhibit high potency against Candida spp. In addition, sordarin manno epoxide derivative 6 presents in vivo therapeutic effect in mice and is considered a promising antifungal lead within this series.

4 pages, 1 figure, 1 table, 2 schemes.-- Printed version published Sep 17, 2001., The use of polymer-bound guanidine 6b or polymer-bound phosphazene 6c significantly improve the yield of the Hofmann elimination step in the preparation of tertiary amines using REM resin, providing products with superior purities and free from contamination with trialkylammonium salts.

5′-N-(α-Amino-β-mercaptoacyl)amino-5′-deoxynucleosides have been synthesized by coupling of N-formylthiazolidines derived from D- and L-penicillamine, and D- and L-cysteine to 5′-amino-5′-deoxynucleosides using the DCC/HOSu method, followed by deprotection in N HCL in MeOH under argon. Although these compounds were designed as potential anti-HIV-1 agents, none of them showed anti-HIV-1 activity in MT-4 cells or antiviral effect against some other viruses, at concentrations below the cytotoxicity threshold. 5′-N-(α-Amino-β-mercaptoacyl)amino-5′-desoxynucleoside als potentiell antivirale Verbindungen 5′-N-(α-Amino-β-mercaptoacyl)amino-5′-desoxynucleoside wurden durch Kopplung von N-Formylthiazolidinen (aus D- und L-Penicillamin bzw. D-und L-Cystein) mit den entspr. 5′-Amino-5′-desoxynucleosiden mittels DCC/HOSu Methode und anschliesender Entfemung der Schutzgruppe mit N HCL in MeOH unter Argon hergestellt. Diese Verbindungen wurden als potentielle anti-HIV-1 Agentien entwickelt, zeigen aber unter der Cytotoxizitats-Schwelle keine anti-HIV-1 Wirkung gegenuber MT-4-Zellen oder anderen Viren.

The nucleoside antibiotic ascamycin [2-chloro-5'- O -[ N -( L-alanyl )sulfamoyl] adenosine 1 ] has been synthesized by an improved procedure involving the direct condensation of 2-chloro-2',3'- O -isopropylidene-5'- O -sulfamoyladenosine ( 3 ) with Boc- L -Ala-OSu in DMF and in the presence of DBU, followed by removal of the protecting groups. A similar condensation of 3 with Boc- D -Ala-OSu and Boc-Gly-OSu, and subsequent deprotection, yielded the D -Ala and Gly analogues of 1 , namely 2-chloro-5'- O -[ N -( D -alanyl)sulfamoyl] and 2-chloro-5'- O -[ N -(glycyl)sulfamoyl]adenosine [ D -ascamycin ( 14 ) and (18)]. Similar reactions of 2',3'- O -isopropylidene-5'- O -sulfamoyladenosine, 6 with the three amino acid derivatives above mentioned provided the corresponding adenosine analogues 12 , 16 and 20 . Several studies directed to demonstrate that the previous protection of the 6-NH2 group of the adenosine derivatives 3 and 6 is not necessary for the selective aminoacylation of the SO2NH2 group are also reported.