Extensive structure‐activity relationship study of albicidin’s C‐terminal dipeptidic p‐aminobenzoic acid moiety

Albicidin is a recently described natural product that strongly inhibits bacterial DNA gyrase. The pronounced activity, particularly against Gram‐negative bacteria, turns it into a promising lead structure for an antibacterial drug. Hence, structure–activity relationship studies are key for the in‐depth understanding of structural features/moieties affecting gyrase inhibition, antibacterial activity and overcoming resistance. The 27 newly synthesized albicidins give profound insights into possibilities for variations of the C‐terminus. Furthermore, in the present study, a novel derivative has been identified as overcoming resistance posed by the Klebsiella‐protease AlbD. Structural modifications include, for example, azahistidine replacing the previous instable cyanoalanine as the central amino acid, as well as a triazole amide bond isostere between building blocks D and E.BMBF, 03VP00030, Validierung einer neuen antibakteriellen Wirkstoffklasse - AlbiPharmTU Berlin, Open-Access-Mittel - 201

Structure activity relationship study of [1,2,3]thiadiazole necroptosis inhibitors

Necroptosis is a regulated caspase-independent cell death mechanism that results in morphological features resembling non-regulated necrosis. This form of cell death can be induced in an array of cell types in apoptotic deficient conditions with death receptor family ligands. A series of [1,2,3]thiadiazole benzylamides was found to be potent necroptosis inhibitors (called necrostatins). A structure activity relationship study revealed that small cyclic alkyl groups (i.e. cyclopropyl) and 2,6-dihalobenzylamides at the 4- and 5-positions of the [1,2,3]thiadiazole, respectively, were optimal. In addition, when a small alkyl group (i.e. methyl) was present on the benzylic position all the necroptosis inhibitory activity resided with the (S)-enantiomer. Finally, replacement of the [1,2,3]thiadiazole with a variety of thiophene derivatives was tolerated, although some erosion of potency was observed

Structure–activity relationship study of EphB3 receptor tyrosine kinase inhibitors

A structure–activity relationship study for a 2-chloroanilide derivative of pyrazolo[1,5-a]pyridine revealed that increased EphB3 kinase inhibitory activity could be accomplished by retaining the 2-chloroanilide and introducing a phenyl or small electron donating substituents to the 5-position of the pyrazolo[1,5-a]pyridine. In addition, replacement of the pyrazolo[1,5-a]pyridine with imidazo[1,2-a]pyridine was well tolerated and resulted in enhanced mouse liver microsome stability. The structure–activity relationship for EphB3 inhibition of both heterocyclic series was similar. Kinase inhibitory activity was also demonstrated for representative analogs in cell culture. An analog (32, LDN-211904) was also profiled for inhibitory activity against a panel of 288 kinases and found to be quite selective for tyrosine kinases. Overall, these studies provide useful molecular probes for examining the in vitro, cellular and potentially in vivo kinase-dependent function of EphB3 receptor

Synthesis and Structure-Activity Relationship Study of Novel Nitrodiphenylurea Antibiotics

According to the World Health Organization, tuberculosis (TB) is the leading cause of death by infectious disease. Tuberculosis is caused by the bacteria Mycobacterium tuberculosis and occurs globally. Additionally, in 2017, TB was reported in all 50 states. Due to the scope of TB, strict observation of patients is required to ensure adherence to the current drug regimen. However, most reported cases are in developing countries where proper care is difficult. With the emergence of multidrug-resistant TB exhibiting resistance to current treatments, novel antibiotics are needed. Recently, our lab discovered a family of diphenyl ureas that exhibit antimicrobial activity against several bacterial strains, including Mycobacterium. Based on our lab’s previous results, we have synthesized several diphenyl urea derivatives to examine their structure-activity relationship. Herein, we report the synthesis of the diphenyl ureas with varying nitro positions, chain-lengths, and sites of variation

Structure–activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors

A structure–activity relationship study of dorsomorphin, a previously identified inhibitor of SMAD 1/5/8 phosphorylation by bone morphogenetic protein (BMP) type 1 receptors ALK2, 3, and 6, revealed that increased inhibitory activity could be accomplished by replacing the pendent 4-pyridine ring with 4-quinoline. The activity contributions of various nitrogen atoms in the core pyrazolo[1,5-a]pyrimidine ring were also examined by preparing and evaluating pyrrolo[1,2-a]pyrimidine and pyrazolo[1,5-a]pyridine derivatives. In addition, increased mouse liver microsome stability was achieved by replacing the ether substituent on the pendent phenyl ring with piperazine. Finally, an optimized compound 13 (LDN-193189 or DM-3189) demonstrated moderate pharmacokinetic characteristics (e.g., plasma t1/2 = 1.6 h) following intraperitoneal administration in mice. These studies provide useful molecular probes for examining the in vivo pharmacology of BMP signaling inhibition

A Structure-Activity Relationship Study of Dihydroajoenes as Anti-Cancer Agents

Includes bibliographical references.Ajoene (( E-/Z )-4,5,9-trithiadodeca-1,6,11-triene-9-oxide), a constituent of garlic is known to possess in vitro and in vivo anticancer activity based on the presence of a vinyl disulfide as its pharmacophore. This thesis reports on the synthesis of dihydroajoenes, a novel set of ajoene analogues, containing a saturated double bond, in which the intention was to study the influence of removing the double bond on biological activity and metabolic stability, since ajoenes are unstable in blood. A divergent synthetic route to 6 new dihydroajoene analogues has been developed in which a phenolic hydroxyl group at the disulfide end served as a platform for modulating aqueous solubility. The dihydroajoene analogues synthesized retained good in vitro anti-proliferation activity against a WHCO1 oesophageal cancer cell line, with the phenol derivative showing the greatest activity, with an IC 50 of 4.1 μM as about 7-times more active than the parent ajoene. In addition the dihydroajoenes were found to be significantly more stable in the red blood cell fraction of mouse blood, when compared with ajoene analogues retaining the double bond. This opens up the possibility of exploring them as anti-cancer agents in an in vivo setting. This thesis also describes a preliminary study towards the synthesis of an ajoene-drug (fludarabine) conjugate for chemosensitization studies, in which an advanced synthetic intermediate was secured

A Structure-Activity Relationship Study of Bimodal BODIPY-Labeled PSMA-Targeting Bioconjugates

The aim of this study was to identify a high-affinity BODIPY peptidomimetic that targets the prostate-specific membrane antigen (PSMA) as a potential bimodal imaging probe for prostate cancer. For the structure-activity study, several BODIPY (difluoroboron dipyrromethene) derivatives with varying spacers between the BODIPY dye and the PSMA Glu-CO-Lys binding motif were prepared. Corresponding affinities were determined by competitive binding assays in PSMA-positive LNCaP cells. One compound was identified with comparable affinity (IC50=21.5±0.1 nM) to Glu-CO-Lys-Ahx-HBED-CC (PSMA-11) (IC50=18.4±0.2 nM). Radiolabeling was achieved by Lewis-acid-mediated 19F/18F exchange in moderate molar activities (∼0.7 MBq nmol−1) and high radiochemical purities (>99 %) with mean radiochemical yields of 20–30 %. Cell internalization of the 18F-labeled high-affinity conjugate was demonstrated in LNCaP cells showing gradual increasing PSMA-mediated internalization over time. By fluorescence microscopy, localization of the high-affinity BODIPY-PSMA conjugate was found in the cell membrane at early time points and also in subcellular compartments at later time points. In summary, a high-affinity BODIPY-PSMA conjugate has been identified as a suitable candidate for the development of PSMA-specific dual-imaging agents

Structure–activity relationship study of pyridazine derivatives as glutamate transporter EAAT2 activators

Excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter and functions to remove glutamate from synapses. A thiopyridazine derivative has been found to increase EAAT2 protein levels in astrocytes. A structure–activity relationship study revealed that several components of the molecule were required for activity, such as the thioether and pyridazine. Modification of the benzylthioether resulted in several derivatives (7-13, 7-15 and 7-17) that enhanced EAAT2 levels by >6-fold at concentrations <5 ?M after 24 h. In addition, one of the derivatives (7-22) enhanced EAAT2 levels 3.5–3.9-fold after 24 h with an EC50 of 0.5 ?M

Structure–activity relationship study of 2,4-diaminothiazoles as Cdk5/p25 kinase inhibitors

Cdk5/p25 has emerged as a principle therapeutic target for numerous acute and chronic neurodegenerative diseases, including Alzheimer’s disease. A structure–activity relationship study of 2,4-diaminothiazole inhibitors revealed that increased Cdk5/p25 inhibitory activity could be accomplished by incorporating pyridines on the 2-amino group and addition of substituents to the 2- or 3-position of the phenyl ketone moiety. Interpretation of the SAR results for many of the analogs was aided through in silico docking with Cdk5/p25 and calculating protein hydrations sites using WaterMap. Finally, improved in vitro mouse microsomal stability was also achieved

Toward Novel Antioxidant Drugs: Quantitative Structure-Activity Relationship Study of Eugenol Derivatives

The study of the Quantitative Structure-Activity Relationship (QSAR) of eugenol compound and its derivatives towards antioxidant activities was conducted using electronic and molecular descriptors. These descriptors were generated from semi-empirical chemical computation with PM3 level of theory. The QSAR model in this research could be used to predict novel antioxidant compounds which are more potent. The activity of the compound determined based on the IC50 value (Inhibition Concentration 50%) was linked with the descriptor results that had been calculated in a QSAR equation. The data showed that the descriptors that had a significant effect were a net charge of C-6, C-7, O-12, and HOMO energy and hydration energy. The best QSAR equations obtained with these descriptors and their parameters are shown as follows.log1/IC50 = - 3,3026 (± 0,4066) qC6 - 4,7450 (± 0,7224) qC7 + 3,2746 (± 0,6752) qO12 + 0,6326 (± 0,0645) HOMO - 0,0086 (± 0,0011) hydration energy + 4,8053 (± 0,6336)(n = 8 ; R = 1,000 ; s = 0,004 ; F = 3655,537 ; p = 0,0003 ; Q2 = 0,988 ; SPress = 0,039 ; SDEP = 0,021