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SAR Based Optimization of a 4-Quinoline Carboxylic Acid Analog with Potent Anti-Viral Activity.

ABSTRACT: It is established that drugs targeting viral proteins are at risk of generating resistant strains. However, drugs targeting host factors can potentially avoid this problem. Herein we report structure-activity relationship studies leading to the discovery of a very potent lead compound 6-fluoro-2-(5-isopropyl-2-methyl-4-phenoxyphenyl)quinoline-4-carboxylic acid (C44) that inhibits human dihydroorotate dehydrogenase (DHODH) with an IC₅₀ of 1 nM, and viral replication of VSV and WSN-Influenza with an EC₅₀ of 2 nM and 41 nM. We also solved the X-ray structure of human DHODH bound to C44, providing structural insight into the potent inhibition of biaryl ether analogs of brequinar.

SUBMITTER: Das P

PROVIDER: S-EPMC3733392 | biostudies-literature |

REPOSITORIES: biostudies-literature

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2-Chloro-quinoline-3-carboxylic acid.

Project description:The crystal structure of the title compound, C(10)H(6)ClNO(2), can be described by two types of crossed layers which are parallel to (110) and (10). The crystal packing is stabilized by inter-molecular C-H?O and O-H?N hydrogen bonds, resulting in the formation of a two-dimensional network and reinforcing the cohesion of the structure.

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| S-EPMC6301076 | biostudies-literature

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| S-EPMC2960518 | biostudies-other

A new steroidal 5,7-diene derivative, 3beta-hydroxyandrosta-5,7-diene-17beta-carboxylic acid, shows potent anti-proliferative activity.

Project description:The new steroidal 5,7-diene, 3beta-hydroxyandrosta-5,7-diene-17beta-carboxylic acid (17-COOH-7DA), was synthesized from 21-acetoxypregnenolone, with the oxidative cleavage of the side chain being dependent on the presence of oxygen. In human epidermal (HaCaT) keratinocytes, 17-COOH-7DA inhibited proliferation in a dose-dependent manner, starting at a dose as low as 10(-11) M. This inhibition was accompanied by decreased expression of epidermal growth factor receptor, bcl2 and cyclin E2 mRNAs and by increased expression of involucrin mRNA. Inhibition of proliferation was associated with slowing of the cell cycle in G1/G0 phases but not with cell death. 17-COOH-7DA was significantly more potent than pregnenolone, 17-COOH-pregnenolone, 17-COOCH(3)-7DA and calcitriol. 17-COOH-7DA also inhibited proliferation of normal human epidermal melanocytes and human and hamster melanoma lines, however, with lower potency than for keratinocytes. In normal human dermal fibroblasts 17-COOH-7DA stimulated proliferation in serum-free media but inhibited it in the presence of 5% serum. 17-COOH-7DA inhibited cell colony formation of human and hamster melanoma cells, and induced monocyte-like differentiation of human HL60 leukemia cells. Thus, the new steroidal 5,7-diene, 17-COOH-7DA, can serve as an inhibitor of proliferation of normal keratinocytes and normal and malignant melanocytes, as a condition-dependent regulator of fibroblast proliferation and a stimulator of leukemia cell differentiation.

| S-EPMC2846116 | biostudies-literature

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| S-EPMC7687077 | biostudies-literature

Potent Quinoline-Containing Combretastatin A-4 Analogues: Design, Synthesis, Antiproliferative, and Anti-Tubulin Activity.

Project description:A novel series of quinoline derivatives of combretastatin A-4 incorporating rigid hydrazone and a cyclic oxadiazole linkers were synthesized and have demonstrated potent tubulin polymerization inhibitory properties. Many of these novel derivatives have shown significant antiproliferative activities in the submicromolar range. The most potent compound, 19h, demonstrated superior IC50 values ranging from 0.02 to 0.04 µM against four cancer cell lines while maintaining low cytotoxicity in MCF-10A non-cancer cells, thereby suggesting 19h's selectivity towards proliferating cancer cells. In addition to tubulin polymerization inhibition, 19h caused cell cycle arrest in MCF-7 cells at the G2/M phase and induced apoptosis. Collectively, these findings indicate that 19h holds potential for further investigation as a potent chemotherapeutic agent targeting tubulin.

| S-EPMC7698209 | biostudies-literature

(Benzoato-?O,O')(quinoline-2-carboxyl-ato-?N,O)(quinoline-2-carboxylic acid-?N,O)manganese(II).

Project description:The crystal structure of the title compound, [Mn(C(7)H(5)O(2))(C(10)H(6)NO(2))(C(10)H(7)NO(2))], contains manganese(II) ions six-coordinated in a distorted octa-hedral environment. The equatorial plane is occupied by four O atoms, two from the carboxyl-ate group of the benzoate ion, the other two from carboxyl-ate/carboxyl groups of the quinaldate/quinaldic acid mol-ecules. The axial positions are occupied by the N atoms of the quinoline ring systems. The metal ion lies on a twofold rotation axis that bisects the benzoate ligand; the quinaldate and quinaldic acid ligands are therefore equivalent by symmetry, and the carboxylate/carboxyl groups are disordered. The complexes are joined together by hydrogen bonds between the carboxyl-ate/carboxyl groups of adjacent quinaldate/quinaldic acid mol-ecules, forming zigzag chains that run along the c axis.

| S-EPMC2915171 | biostudies-literature

(Benzoato-?O,O')(quinoline-2-carboxyl-ato-?N,O)(quinoline-2-carboxylic acid-?N,O)copper(II).

Project description:The crystal structure of the title compound, [Cu(C(10)H(6)NO(2))(C(7)H(5)O(2))(C(10)H(7)NO(2))], contains copper(II) ions five-coordinated in a distorted trigonal-bipyramidal environment. The equatorial plane is occupied by three O atoms, one from the carboxyl-ate group of the benzoate ion considered as occupying a single coordination site, the other two from two carboxyl-ate groups of the quinaldic acid and quinaldate ligands. The axial positions are occupied by the N atoms of the quinoline ring system. The metal ion lies on a twofold axis that bisects the benzoate ion. The quinaldate and quinaldic acid ligands are equivalent by symmetry, and the carboxyl-ate/carboxyl groups are disordered. The disordered H atom is shared between the carboxyl-ate groups of adjacent quinaldic acid mol-ecules. Such hydrogen bonds delineate zigzag chains that run along the c axis. The structure is very similar to that of the Mn(II) analog.

| S-EPMC2961369 | biostudies-literature

Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids.

Project description:BackgroundBecause Plasmodium falciparum displays increase tolerance against the recommended artemisinin combination therapies (ACT), new classes of anti-malarial drugs are urgently required. Previously synthesized artemisinin-aminoquinoline hybrids were evaluated to ascertain whether the potent low nanomolar in vitro anti-plasmodial activity would carry over in vivo against Plasmodium vinckei. A snapshot pharmacokinetic analysis was carried out on one of the hybrids to obtain an indication of the pharmacokinetic properties of this class of anti-malarial drugs.MethodsIn vitro activity of hybrids 2 and 3 were determined against the 3D7 strain of P. falciparum. Plasmodium vinckei-infected mice were treated with hybrids 1 - 3 for four days at a dosage of 0.8 mg/kg, 2.5 mg/kg, 7.5 mg/kg or 15 mg/kg intraperitoneally (ip), or orally (per os) with 2.7 mg/kg, 8.3 mg/kg, 25 mg/kg or 50 mg/kg. Artesunate was used as reference drug. A snapshot oral and IV pharmacokinetic study was performed on hybrid 2.ResultsHybrids 1 - 3 displayed potent in vivo anti-malarial activity with ED50 of 1.1, 1.4 and <0.8 mg/kg by the ip route and 12, 16 and 13 mg/kg per os, respectively. Long-term monitoring of parasitaemia showed a complete cure of mice (without recrudescence) at 15 mg/kg via ip route and at 50 mg/kg by oral route for hybrid 1 and 2, whereas artesunate was only able to provide a complete cure at 30 mg/kg ip and 80 mg/kg per os.ConclusionsThese compounds provide a new class of desperately needed anti-malarial drug. Despite a short half-life and moderate oral bioavailability, this class of compounds was able to cure malaria in mice at very low dosages. The optimum linker length for anti-malarial activity was found to be a diaminoalkyl chain consisting of two carbon atoms either methylated or unmethylated.

| S-EPMC3598976 | biostudies-literature

Synthesis and SAR of Lehualide B: a marine-derived natural product with potent anti-multiple myeloma activity.

Project description:We report a concise and convergent laboratory synthesis of the rare marine natural product lehualide B that has led to the discovery that (1) this compound has low nanomolar activity against human multiple myeloma cells and (2) the anticancer effects of lehualide B and its analogues are selective (i.e., they are approximately 2-3 orders of magnitude less toxic to human breast cancer cells). Synthetic lehualide B is shown to be an effective inhibitor of complex I of the mitochondrial electron transport chain, with potency similar to that observed for the terrestrial natural products piericidin A1 and rotenone, an observation that led to the discovery that piericidin A1 is also selectively cytotoxic toward human multiple myeloma cells. Interestingly, synthetic derivatives of lehualide B that resemble verticipyrone (an established complex I inhibitor composed of a ?-pyrone and a simple monounsaturated hydrophobic chain) lack the potent antimyeloma activity of the natural product. Finally, the synthesis and evaluation of a collection of lehualide-inspired analogues led to the elucidation of structure-activity relationships for this rare natural product that established important roles for the substituted ?-pyrone headgroup and the skipped polyene side chain.

| S-EPMC3758376 | biostudies-literature

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