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A Pharmacological Appraisal of Antimalarial Plant Species
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Mahwahwatse J. Bapela, Precious B. Ramontja, Mcebisi J. Mabuza
Antifolates include two classes of antimalarial drugs that interfere with folate metabolism, a pathway essential for DNA replication and protein synthesis of malaria parasites. They specifically target two enzymes involved in the biosynthesis of tetrahydrofolate, the dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) (Rudrapal, 2011). Sulphonamides, sulphadoxine (Figure 18.3), sulphones, dapsone and sulphalene act as competitive inhibitors against DHPS, thereby preventing the formation of dihydropteroate. The second class includes proguanil, chloroproguanil, cycloguanil and pyrimethamine, which inhibit DHFR, consequently preventing the reduction of dihydrofolate (DHF) to tetrahydrofolic acid (THF). The combination of both classes of antifolates proved to have a synergistic effect against malaria, though clinical resistance developed quickly, compromising their use in many malaria-endemic areas (Heinberg and Kirkman, 2015). Atovaquone (Figure 18.3) is a hydroxynaphthoquinone that is used in combination with proguanil for prophylaxis and therapy of asymptomatic malaria. It is active against all Plasmodium species, inhibiting the exoerythrocytic stage in humans and the oocyst development in the mosquitoes. It acts by inhibiting the mitochondrial electron transport chain, thereby leading to a breakdown of the mitochondrial membrane potential (Barton et al., 2010). The prevalence of mutations of the cytochrome b gene has resulted in therapy failure of atovaquone (Siregar et al., 2015).
Neoplasia in pregnancy
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Combination chemotherapy has become the therapeutic management of choice in patients with acute leukemia. Children who were exposed to chemotherapeutic agents in utero showed normal growth and development from 1 to 17 years of age (235). If given after the second trimester, chemotherapy is not associated with an increased rate of fetal malformations (240). Remission rates of pregnant women treated with combination chemotherapy compare favorably with those in comparable nonpregnant women. Standard anti-leukemic agents, such as cytarabine and anthracyclines, can be safely administered during the second and third trimesters. However, antifolates should be avoided during the first trimester, owing to a 10% to 20% risk of congenital anomalies (245). Use of L-asparaginase during pregnancy should always been done with caution as it has been shown to decrease the levels of certain thrombosis inhibitors and is associated with a significantly increased risk of thromboembolism (246–249). It is important to note that evidence shows that delaying appropriate chemotherapy for more than a few weeks at any time other than the latter part of the third trimester is associated with excessive fetal mortality (235,250,251).
Introduction to Cancer
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Chemotherapy involves the use of low-molecular-weight drugs (also known as “small molecules”) to selectively shrink or destroy a tumor, or at least limit its growth. The nitrogen mustards were one of the first agents to be introduced clinically in the 1940s. Their activity was discovered accidentally (i.e., serendipitously) through the observation that the mustard gas used in World War II had antileukemic properties (see Chapter 5). This was followed later in the decade by the introduction of antifolates such as methotrexate (see Chapter 3). Since then, important advances have been made in the development of new anticancer drugs. For example, cisplatin, which was also discovered serendipitously and developed in the 1970s, provided a major advance in the treatment of testicular and ovarian carcinomas. Antitubulin agents such as vinblastine and taxol are described in Chapter 4.
Novel Glu-based pyrazolo[3,4-d]pyrimidine analogues: design, synthesis and biological evaluation as DHFR and TS dual inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Mater Mahnashi, Mohammed Merae Alshahrani, Amer Al Ali, Abdulaziz Asiri, Mahrous A. Abou-Salim
The next generation of antifolates, as plevitrexed, revealed similar pharmacophoric properties of classical ones in which the free γ-carboxylic group was replaced with bioisosteric tetrazole moiety which, in turn, either improved the drug absorption or did not need to be polyglutamylated by FPGS and hence allows more decrease in drug resistance. In this context, the nonclassical antifolates such as nolatrexed and piritrexim (PTX) were designed as they are more lipophilic and non-polyglutamatable agents11,12. Modifications in the antifolates structures have helped delineate the structural influence on the interaction with DHFR, TS, and FPGS utilisation. Therefore, intense interest has been in developing a new class of antifolate agents with these crucial structural pharmacophoric properties.
Design, synthesis and antitumor evaluation of novel pyrazolo[3,4-d]pyrimidines incorporating different amino acid conjugates as potential DHFR inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Ibrahim M. Salem, Samia M. Mostafa, Ismail Salama, Osama I. El-Sabbagh, Wael A. H. Hegazy, Tarek S. Ibrahim
Dihydrofolate reductase (DHFR) is a critical enzyme in folic acid metabolism; it promotes catalysis for conversion of dihydrofolate (DHF) to tetrahydrofolate (THF), which is essential for purine de novo synthesis and thymidylate synthesis in cell proliferation1, therefore inhibition of DHFR enzyme exhibits great antitumor activity as it suppresses de novo nucleotide biosynthesis leading to an imbalance of purine and pyrimidine precursors and rendering cells incapable of undergoing a proper DNA replication2. The most common dihydrofolate reductase inhibitors (DHFRIs) are the classical antifolates such as methotrexate (MTX), aminopterine, pralatrexate and pemetrexed (PMX)3. The chemical structure of MTX prototype is composed of 3 main important pharmacophores: pteridine nucleus, 4-amino benzoic acid and glutamic acid4 (Figure 1). With mismatch, pemetrexed (PMX) elucidates ascendant DHFR inhibition effect although it accommodates pyrrolo[2,3-d]pyrimidine nucleus instead of pteridine5 as well the furo[2,3-d]pyrimidine in analogue I was also reported as potential DHFR inhibitor6 as shown in Figure 1.
Are long-chain methotrexate polyglutamate levels the reason for LD-MTX related adverse events in inflammatory arthritis?
Published in Expert Review of Clinical Pharmacology, 2021
Amit Sandhu, Paramvir Kaur, Varun Dhir, Owais Mohmad Bhat
MTX is actively transported inside blood cells with the help of solute carrier family 19 member 1 (SLC19A1, also known as reduced folate carrier 1) and forms its metabolites by the addition of glutamic acid residue with the help of folylpolyglutamate synthase (FPGS) enzyme [2]. These sequential additions of glutamate residue create methotrexate polyglutamates (MTXPG2-n). This γ-linkage process leads to modification in its properties and also enhances its retention. This transport and intracellular glutamation process is also responsible for the disappearance of MTX from the circulation within 24 h of its administration [3]. This property allows MTX to be given weekly unlike newer antifolates (e.g. CH-1504) that are not polyglutamated and are given daily [4]. Apart from increasing retention, polyglutamation also enhances the inhibitory effects against amino-imidazole carboxamide ribonucleotide (AICAR) transformylase and dihydrofolate reductase, enzymes thought to be crucial to its anti-inflammatory and immunosuppressive effect. These glutamate moieties can be further divided into short-chain (MTXPG1 and MTXPG2) and long-chain polyglutamates (MTXPG3-n). Gamma glutamyal hydrolase (GGH) can remove these residues and convert back MTX polyglutamate to MTX monoglutamate form, which can be easily effluxes out of cell by the ATP transporter family protein. Hence the pharmacokinetics of MTX depends on the mutual action of these four enzymes (FPGS, GGH, RFC1 and ABCB1).