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Antimetabolites
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
5-FU is initially metabolized to its 2′-deoxyribonucleotide form, 5-fluoro-2′-deoxyuridylic acid (FUdRP), which is a potent inhibitor of thymidylate synthase. This enzyme works by transferring a methyl group from the coenzyme methylenetetrahydrofolic acid to deoxyuridylic acid, which is converted to thymidylic acid and then incorporated into DNA. 5-FU has been shown to bind to thymidylate synthetase with an affinity several thousand times greater than that of the natural substrate. This remarkable property is associated with the bioisosteric fluorine atom, whose van der Waals radius compares favorably with that of hydrogen, although the bond strength is significantly greater. Additionally, the high electronegativity of fluorine affects the electron distribution, conferring a lower pKa on the molecule compared to uracil. These two features combine to enable FUdRP to fit into the active site of the enzyme extremely well, although the fluorine cannot be removed, thus inhibiting the enzyme. Further studies have suggested that a nucleophilic sulphydryl group at the active site forms a covalent bond to FUdRP, leading to a “dead end” adduct of the enzyme, coenzyme, and 5-FU. Structure-activity studies have shown that the increased size but lower electronegativity of other types of halogen atoms leads to reduced activity. Overall, the inhibition of TS causes depletion of dTTP, resulting in an imbalance of the dATP:dTTP ratio, and thus disrupt DNA synthesis and repair, leading to a thymine-deficient death.
Biochemical and Pharmacological Rationales in Radiotracer Design
Published in Lelio G. Colombetti, Principles of Radiopharmacology, 2019
Raymond E. Counsell, Nancy Korn
Nuclides popular for use in foreign labeling of organic compounds include selenium-75, and the halogens — fluorine-18, and bromine and iodine in several isotopic forms. Selenium-75 and fluorine-18 have been considered as bioisosteric replacements for sulfur and hydroxyl (or hydrogen), respectively.25 The many useful isotopic forms of iodine make this element especially versatile and widely used in nuclear medicine. Io-dine-125 is useful in preliminary animal studies due to its relatively long half-life (60 days) and low radiation energy (35 keV), which simplify synthesis, storage, and safety procedures. Replacement of iodine-125 with other more energetic isotopes of iodine (iodine-131 or iodine-123) can be done with relative ease. Bromine has been suggested as a substitution for methyl groups in organic molecules.25 While there are many nuclides of bromine with characteristics suitable for incorporation into radiotracers, only bromine-82 has been used to any extent clinically. It has not received much use, however, because of the high energy gammas associated with its decay. Recently, however, bromine-76 (T1/2 = 17 hr, positron emission) and bromine-77 (T½ = 57 hr, 30% 242 keV gamma) have become available and have considerable clinical promise.26,27
HIV Integrase Inhibitors
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
A review of SAR data has shown that research efforts from different groups have resulted in the development of several second-generation inhibitors with nanomolar potency. Most of these inhibitors are the result of bioisosteric replacement of the carboxylic group (e.g., tetrazole and triazole), rearrangement of the keto-enol moiety for metal chelation, modification of the fluorobenzyl hydrophobic group, and other suitable modifications to improve their pharmacokinetic profile. Select examples of these secondgeneration inhibitors include benzylamide and benzylindole DKA, 1,6-naphthyridine carboxamides, dihydropyrimidine 4-carboxamides, N-methylpyrimidinones, pyrrolinones, and quinolone 3-carboxylic acids. Optimization of these inhibitors may lead to new drugs active against IN drug-resistant and mutant viruses.
Novel chalcone/aryl carboximidamide hybrids as potent anti-inflammatory via inhibition of prostaglandin E2 and inducible NO synthase activities: design, synthesis, molecular docking studies and ADMET prediction
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Tarek S. Ibrahim, Amr H. Moustafa, Ahmad J. Almalki, Rasha M. Allam, Abdulhamid Althagafi, Shadab Md, Mamdouh F. A. Mohamed
On the other hand, amidoxime derivatives exhibited notable biological activities as anti-inflammatory, antihyperglycemic, antimycobacterial, serotonergic inhibitory, muscarinic agonist and peptide inhibitory activities12,41–45. It has been used as bioisostere for carboxylic and ester groups for the design of drugs having improved pharmacokinetic (PK) and pharmacodynamic (PD) properties45. Recently, we have investigated the effects of a series of aryl carboximidamides appended Naproxen derivatives as dual acting COX-2/15-LOX inhibitors12 (Figure 1). Among these estimated derivatives, IV and V were the targets having remarkable inhibitory potencies; furthermore, compound V is the most potent as COX-2 inhibitor with approximately 6.6-folds higher than the reference drug, celecoxib and compound V has bestowed with the strongest 15-LOX inhibitory activity. Moreover, and very recently we have studied the effects of aryl carboximidamides appended indomethacin as dual iNOS/PGE2 inhibitors10. Most of the target indomethacin/aryl carboximidamides displayed powerful inhibitory action against LPS-prompted NO production. Compounds VI and VII (Figure 1), showed significant in vivo anti-inflammatory activity. Notably, compound VI demonstrated inhibition to LPS-induced NO production, iNOS activity and PGE2 with IC50 of 10.70 nM, 2.31 nM and 29 nM, respectively.
An overview of spirooxindole as a promising scaffold for novel drug discovery
Published in Expert Opinion on Drug Discovery, 2020
Li-Ming Zhou, Ren-Yu Qu, Guang-Fu Yang
It is well established that oriented or synergic biological property can be achieved through the splicing of active pharmacophore and the replacement of bioisostere. In this review, there are two apparent cases verifying the effectiveness of this strategy, i.e. compounds 39 and 64. As another optimization direction, simplifying the structure of natural products is also regarded as a practical approach to obtain active molecules in view of the creation cost, the difficulty of synthesis, and molecular modifiability [213]. Compound 98 is a successful example through simplifying natural products because it displays stronger antiplasmodial activity than initial speciophylline. These molecule optimization strategies provide a valuable reference for developing new spirooxindole derivatives with more potent and broader biological properties.
The 1,2,3-triazole ‘all-in-one’ ring system in drug discovery: a good bioisostere, a good pharmacophore, a good linker, and a versatile synthetic tool
Published in Expert Opinion on Drug Discovery, 2022
Deniz Lengerli, Kübra Ibis, Yahya Nural, Erden Banoglu
The past and present advances show that the 1,2,3-triazole moiety has been widely explored as an amide bioisoster despite some subtle differences in terms of topological and electronic properties. However, most of these studies do not maintain satisfactory evidence supporting the position of the 1,2,3-triazole group as a true amide bioisoster. As one can imagine, any successful bioisosteric restoration should preserve the related properties between two counterparts such as physical, chemical, electronic, and conformational, and complementing all these parameters may not be realized. And a few recent experimental studies comparing the similarities and differences between the two groups suggest that the use of the 1,2,3-triazole group as an amide surrogate could be dependent on the compound class as well as on the conformity with the biological target and should be taken cautiously. In addition, early research incentives mostly focused on the synthetic utility of the 1,2,3-triazole core as a connective unit between two pharmacophoric groups or as a platform for suitable placement of pharmacophoric functions for a complementary binding interaction at the active site. On the other hand, exploration of the 1,2,3-triazole ring as a pharmacophore have recently become more prominent toward many biological targets and disease states as reviewed herein. However, the potential pharmacophoric contribution through interacting power of the 1,2,3-triazole ring requires more experimental evidence in different compound classes toward different biological targets to determine the true nature of the 1,2,3-triazole nucleus in molecular recognition process.