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The concept of polypharmacology embraces multiple drugs combined in a therapeutic regimen (drug combination or cocktail), fixed dose combinations (FDCs), and a single drug that binds to different targets (multi-target drug). A polypharmacology approach is widely applied in the treatment of acquired immunodeficiency syndrome (AIDS), providing life-s...
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... purpose of this was to better highlight "their ability to interact with the multiple targets thought to be responsible for the disease pathogenesis" and to clearly differentiate them from so-called "promiscuous drugs" [1]. On this basis, in this review the term MTDLs will be used to refer to these compounds ( Figure 1). As mentioned, the polypharmacology approach is currently applied in the treatment of AIDS, which remains a worldwide public health problem. ...
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... fact, triazole derivatives can act by inhibiting different HIV-1 enzymes, such as RT, integrase, and protease [50]. As an example, compound 14 (Figure 11), featuring a 1,2,3-triazole as a spacer between AZT and the C-28 position of betulinic acid, exhibited an EC50 value of 0.10 µM, which corresponds to that of AZT (EC50 = 0.10 µM) and is higher than that of bevirimat (EC50 = 0.077 µM) [37]. Compound 14 also displayed toxicity comparable to bevirimat (CC50 of 11.2 and 13.2 µM, respectively) and greater than AZT. ...
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... and co-workers synthesized novel AZT-betulinic/betulonic acid hybrids using a 1,2,3-triazole as a linker between the C-2 of the triterpenoid acid and the 3′-azido group of AZT [51]. However, none of the three hybrids conjugated with AZT (15, 16, and 17) displayed significant anti-HIV activity ( Figure 12). A successful attempt at clicking AZT into 1,2,3-triazoles carrying a bulky aromatic group at the C-4 or C-5 position provided potent antivirals [52]. ...
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... successful attempt at clicking AZT into 1,2,3-triazoles carrying a bulky aromatic group at the C-4 or C-5 position provided potent antivirals [52]. SAR studies pointed out that hybrid 18 (Figure 13), substituted at the C-5 position of the 1,2,3-triazole ring, was more potent (83% inhibition of HIV-1 in CEM-SS cells at 10 µM) than the corresponding C-4 substituted compound 19 (33% inhibition of HIV-1 in CEM-SS cells at 10 µM) [52]. ...
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... 18 and 19 showed a reduced anti-viral activity in a single replication cycle WT HIV assay (EC50 = 1 µM and 7.2 µM, respectively) compared to AZT (EC50 = 0.14 µM). The authors further characterized the antiviral profile of 18 and 19 against a NNRTI-resistant (NNRTIr) HIV strain ( Figure 13). Notably, 18 (EC50 = 0.6 µM) had 3.5-fold higher efficacy than 19 (EC50 = 2.1 µM) against the resistant strain, but 5-fold lower than AZT (EC50 = 0.12 µM). ...
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... 18 (EC50 = 0.6 µM) had 3.5-fold higher efficacy than 19 (EC50 = 2.1 µM) against the resistant strain, but 5-fold lower than AZT (EC50 = 0.12 µM). In a subsequent study, the same authors showed that when the naphthyl group is replaced by a tetrazole as for 20 (Figure 13), a significant loss of activity occurred [53]. Additionally, the substitution of the hydroxyl functionality with the silyl group of compound 21 was detrimental to the anti-HIV activity [54]. ...
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... substitution at the C-4′ position of the sugar moiety with a 1,2,3-triazole ring (rather than at the C-3′ position) was evaluated and provided derivative 22 (Figure 14). Although 22 had the best anti-HIV profile within the series, it had a moderate anti-HIV-1 activity (18-62% inhibition at 10 µM), indicating that the substitution at C-4 negatively affected the antiviral profile [55]. ...
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... is because the second Inactive against HIV-1 moiety linked to AZT was not deliberately chosen as carrier of a second pharmacological activity. Olomola and co-workers developed triazole-based anti-HIV hybrids 23 and 24 (Fig- ure 15) by linking a coumarin-based HIV-1 protease inhibitor (PI) and AZT as RT inhibitor. Hybrids 23 and 24 are able to inhibit the selected HIV targets in a similar manner as dual-acting inhibitors with a balanced activity [56]. ...
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... 23 and 24 are able to inhibit the selected HIV targets in a similar manner as dual-acting inhibitors with a balanced activity [56]. Our research group has been developing several compounds with potential anti-HIV activity, including hybrids, which bear the AZT core ( Figure 16) [57][58][59]. Knowing the importance of maintaining the terminal hydroxyl group (5′-OH) to provide the active compound, we explored the C-3′ position of the sugar ring to generate potential drug candidates. ...
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... on a molecular hybridization strategy, AZT was combined with isatin via a 1,2,3-triazole ring leading to hybrid 25 ( Figure 16). Remarkably, 25 turned out to be 2-fold more potent (IC50 = 0.6 µM) than the anti-HIV drug tenofovir (IC50 = 1.2 µM) [57]. ...
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... 25 turned out to be 2-fold more potent (IC50 = 0.6 µM) than the anti-HIV drug tenofovir (IC50 = 1.2 µM) [57]. This result inspired the development of compound 26 [58] (Figure 16), designed to act against HIV-1 and Mycobacterium tuberculosis (Mtb), which is a clinically relevant co-infection. Assays in TMZ cells demonstrated the potential for decreasing the HIV-1 infection by 91% (Figure 16). ...
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... result inspired the development of compound 26 [58] (Figure 16), designed to act against HIV-1 and Mycobacterium tuberculosis (Mtb), which is a clinically relevant co-infection. Assays in TMZ cells demonstrated the potential for decreasing the HIV-1 infection by 91% (Figure 16). In 2018, we decided to replace the isatin core with that of efavirenz, a RT inhibitor of the NNRTI class. ...
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... 2018, we decided to replace the isatin core with that of efavirenz, a RT inhibitor of the NNRTI class. The novel hybrid 27 showed the lowest IC50 value (0.9 µM) and the ability to inhibit HIV-1 RT comparably to tenofovir (Figure 16) [59]. ...
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... the search for multi-target compounds against HIV-malaria co-infection, Aminake and co-workers [60] synthesized hybrids carrying AZT and dihydroartemisinin (DHA) or chloroquine (CQ), which are effective anti-malaria scaffolds. Taking into consideration only the HIV-inhibitory activity, compound 28, featuring a protected C-5′ OH-AZT linked to CQ through a succinyl spacer, was the most potent antiviral hybrid with an IC50 of 0.9 µM (Figure 17). This was partially expected since additive in vitro anti-HIV effects were observed with AZT-CQ combination. ...
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... important co-infection in which the multi-target approach might be particularly suitable is HIV-tuberculosis. Senthilkumar and colleagues combined the C-5′ hydroxyl group of AZT with antimycobacterial fluoroquinolones to afford hybrids 29 and 30 ( Figure 18) [61]. As reported in Figure 18, compound 29 proved to be the best HIV-1 replication inhibitor in acutely infected C8166 cells (inhibition of syncytium formation, Syn form) with an EC50 of 0.00098 µM, being 15-fold more active than the parent drug AZT. ...
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... and colleagues combined the C-5′ hydroxyl group of AZT with antimycobacterial fluoroquinolones to afford hybrids 29 and 30 ( Figure 18) [61]. As reported in Figure 18, compound 29 proved to be the best HIV-1 replication inhibitor in acutely infected C8166 cells (inhibition of syncytium formation, Syn form) with an EC50 of 0.00098 µM, being 15-fold more active than the parent drug AZT. Hybrid 29 showed low toxicity and an SI (CC50 /EC50) > 6000. ...
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... 1988, Busso and co-workers employed this strategy, seeking to obtain a superior pharmacological effect with nucleotides possessing a dimeric structure [65]. For this purpose, a series of nucleotide homo-and heterodimers were synthesized and their in vitro antiviral and cytotoxicity properties compared to their parent monomers (31-34, Figure 19). The authors reported that nucleotide dimers linked via a phosphate bridge have enhanced in vitro anti-HIV potency in comparison with the monomers, as presented in Figure 19. ...
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... this purpose, a series of nucleotide homo-and heterodimers were synthesized and their in vitro antiviral and cytotoxicity properties compared to their parent monomers (31-34, Figure 19). The authors reported that nucleotide dimers linked via a phosphate bridge have enhanced in vitro anti-HIV potency in comparison with the monomers, as presented in Figure 19. The anti-HIV activity demonstrated by the dimers was quantified through 50% effective dose (ED50) values. ...
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... compounds were more potent HIV inhibitors when compared with the reference molecules as well as AZT + 2′,3′-dideoxyadenosine (ddA) combination, which exhibited the highest inhibitory activity. The dimer 31 stood out as it demonstrated an ED50 of 0.7 µM (Figure 19). According to the value of 50% inhibitory dose (ID50), which is indicative of cell viability, 32 showed the highest toxicity with an ID50 of 60 µM (Figure 19). ...
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... dimer 31 stood out as it demonstrated an ED50 of 0.7 µM (Figure 19). According to the value of 50% inhibitory dose (ID50), which is indicative of cell viability, 32 showed the highest toxicity with an ID50 of 60 µM (Figure 19). While exploring the synthesis and biological evaluation of novel symmetrical nucleotide-(5′,5′)-dimer phosphotriester derivatives of AZT, McGuigan and co-workers [67] developed compounds 38 and 39 ( Figure 21). ...
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... to the value of 50% inhibitory dose (ID50), which is indicative of cell viability, 32 showed the highest toxicity with an ID50 of 60 µM (Figure 19). While exploring the synthesis and biological evaluation of novel symmetrical nucleotide-(5′,5′)-dimer phosphotriester derivatives of AZT, McGuigan and co-workers [67] developed compounds 38 and 39 ( Figure 21). Both the AZT derivatives showed anti-HIV-1 activity, and compound 39, which has 2,2,2-trifluoroethyl, had the best inhibitory HIV-1 potential (ED50 of 0.4 µM) with high cell protection (CC50 = 600 µM). ...
Citations
... 50 The azido group is also an active moiety in some biologically active compounds such as anti-TB 51 (compound I; Fig. 1) and zidovudine, a clinically used antiviral drug. 52 Moreover, the antibacterial and antiprotozoal properties of the broadspectrum antibiotic metronidazole were significantly enhanced by converting its hydroxyl group into azide (compound II; Fig. 1). 53 Currently, the azido group is most frequently used in the field of click cycloaddition reactions to introduce the 1,4-disubstituted-1,2,3-triazole moiety (compound III; Fig. 1) in order to enhance the solubility and/or biological activities of antimicrobial agents, 54-57 particularly, antiTB compounds. ...
A new series inspired by combining fragments from nitazoxanide (NTZ) and 4-aminosalicylic acid (4-ASA) was synthesized and screened for in vitro antibacterial and antimycobacterial activities. The majority showed higher antibacterial potency than NTZ against all the screened strains, notably, 5f, 5j, 5n and 5o with MICs 0.87-9.00 μM. Compounds 5c, 5n and 5o revealed higher potency than ciprofloxacin against K. pneumoniae, while 5i was equipotent. For E. faecalis, 3b, 5j, 5k showed higher potency than ciprofloxacin. 5j Was more potent against P. aeruginosa than ciprofloxacin, while 5n was more potent against S. aureus with MIC 0.87 μM. 5f showed equipotency to ciprofloxacin against H. pylori with MIC 1.74 μM. Compounds 3a and 3b (4-azidoNTZ, MIC 4.47 μM)) are 2 and 5-fold more potent against Mycobacterium tuberculosis (Mtb H37Rv) than NTZ (MIC 20.23 μM) and safer. 4-Azidaion and/or acetylation of NTZ improve both activities, while introducing 1,2,3-triazoles improves the antibacterial activity. Molecular docking studies within pyruvate ferredoxin oxidoreductase (PFOR), glucosamine-6-phosphate synthase (G6PS) and dihydrofolate reductase (DHFR) active sites were performed to explore the possible molecular mechanisms of actions. Acceptable drug-likeness properties were found. This study may in light of further rational design of substituted NTZ as broad-spectrum more potent antimicrobial candidates.
... 3-Azido-2,3-dideoxythymidine (AZT) is a thymine analog commonly used to treat various virus-related human cancers [110]. Now, however, in clinical trials, AZT has been used alone or in combination to treat various types of non-viral tumors, including breast cancer, ovarian cancer, hepatocarcinoma, hepatocellular carcinoma and other advanced malignancies [111][112][113][114]. ...
Telomeres are unique structures located at the ends of linear chromosomes, responsible for stabilizing chromosomal structures. They are synthesized by telomerase, a reverse transcriptase ribonucleoprotein complex. Telomerase activity is generally absent in human somatic cells, except in stem cells and germ cells. Every time a cell divides, the telomere sequence is shortened, eventually leading to replicative senescence and cell apoptosis when the telomeres reach a critical limit. However, most human cancer cells exhibit increased telomerase activity, allowing them to divide continuously. The importance of telomerase in cancer and aging has made developing drugs targeting telomerase a focus of research. Such drugs can inhibit cancer cell growth and delay aging by enhancing telomerase activity in telomere-related syndromes or diseases. This review provides an overview of telomeres, telomerase, and their regulation in cancer and aging, and highlights small-molecule drugs targeting telomerase in these fields.
... The first step is the synthesis of proviral DNA through RNA by the action of the enzyme reverse transcriptase (RT) (Figure 1; step 3). Once synthesized, this pro-viral DNA becomes incorporated into the host genome by the enzyme integrase (IN) (Figure 1; step 4) [7]. (Figure 1; step 6). ...
... (Figure 1; step 6). Finally, translation of the mRNA into proteins occurs, which will undergo the action of the protease (PR) to give rise to individual functional proteins ( Figure 1; step 7) [7]. ...
... Studies show that the use of dolutegravir (DTG) as an INSTI is preferred because of (Figure 1; step 6). Finally, translation of the mRNA into proteins occurs, which will undergo the action of the protease (PR) to give rise to individual functional proteins ( Figure 1; step 7) [7]. ...
The human immunodeficiency virus (HIV) produces the pathologic basis of acquired immunodeficiency syndrome (AIDS). An increase in the viral load in the body leads to a decline in the number of T lymphocytes, compromising the patient’s immune system. Some opportunistic diseases may result, such as tuberculosis (TB), which is the most common in seropositive patients. Long-term treatment is required for HIV-TB coinfection, and cocktails of drugs for both diseases are used concomitantly. The most challenging aspects of treatment are the occurrence of drug interactions, overlapping toxicity, no adherence to treatment and cases of resistance. Recent approaches have involved using molecules that can act synergistically on two or more distinct targets. The development of multitarget molecules could overcome the disadvantages of the therapies used to treat HIV-TB coinfection. This report is the first review on using molecules with activities against HIV and Mycobacterium tuberculosis (MTB) for molecular hybridization and multitarget strategies. Here, we discuss the importance and development of multiple targets as a means of improving adherence to therapy in cases of the coexistence of these pathologies. In this context, several studies on the development of structural entities to treat HIV-TB simultaneously are discussed.
Acquired immunodeficiency syndrome (AIDS) is an enormous global health threat stemming from human immunodeficiency virus (HIV-1) infection. Up to now, the tremendous advances in combination antiretroviral therapy (cART) have shifted HIV-1 infection from a fatal illness into a manageable chronic disorder. However, the presence of latent reservoirs, the multifaceted nature of HIV-1, drug resistance, severe off-target effects, poor adherence, and high cost restrict the efficacy of current cART targeting the distinct stages of the virus life cycle. Therefore, there is an unmet need for the discovery of new therapeutics that not only bypass the limitations of the current therapy but also protect the body’s health at the same time. The main goal for complete HIV-1 eradication is purging latently infected cells from patients’ bodies. A potential strategy called “lock-in and apoptosis” targets the budding phase of the life cycle of the virus and leads to susceptibility to apoptosis of HIV-1 infected cells for the elimination of HIV-1 reservoirs and, ultimately, for complete eradication. The current work intends to present the main advantages and disadvantages of United States Food and Drug Administration (FDA)-approved anti-HIV-1 drugs as well as plausible strategies for the design and development of more anti-HIV-1 compounds with better potency, favorable pharmacokinetic profiles, and improved safety issues.
Monkeypox is a zoonotic viral disease and remains endemic in tropical regions of Central and West Africa. Since May of 2022, cases of monkeypox have soared and spread worldwide. Confirmed cases have shown no travel history to the endemic regions as seen in the past. The World Health Organization declared monkeypox a global public health emergency in July 2022, and the United States government followed suit one month later. The current outbreak, in contrast to traditional epidemics, has high coinfection rates, particularly with HIV (human immunodeficiency virus), and to a lesser extent with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the pathogen of COVID-19. No drugs have been approved specifically for monkeypox. However, there are therapeutic agents authorized to treat monkeypox under the Investigational New Drug protocol, including brincidofovir, cidofovir, and tecovirimat. In contrast to limited options for monkeypox treatment, there are available drugs specifically for HIV or SARS-CoV-2 infection. Interestingly, these HIV and COVID-19 medicines share metabolism pathways with those authorized to treat monkeypox, par¬ticu¬larly of hydrolysis, phospho¬rylation, and active membrane transport. This review discusses how these pathways shared by these medicines should be considered to gain therapeutic synergy and maximize safety for treating monkeypox coinfections.
