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Leprosy continues to be the belligerent public health hazard for the causation of high disability and eventual morbidity cases with stable prevalence rates, even with treatment by the on-going multidrug therapy (MDT). Today, dapsone (DDS) resistance has led to fear of leprosy in more unfortunate people of certain developing countries. Herein, DDS was chemically conjugated with five phytochemicals independently as dapsone-phytochemical conjugates (DPCs) based on azo-coupling reaction. Possible biological activities were verified with computational chemistry and quantum mechanics by molecular dynamics simulation program before chemical synthesis and spectral characterizations viz., proton-HNMR, FTIR, UV and LC-MS. The in vivo antileprosy activity was monitored using the ‘mouse-foot-pad propagation method’, with WHO recommended concentration 0.01% mg/kg each DPC for 12 weeks, and the host-toxicity testing of the active DPC4 was seen in cultured-human-lymphocytes in vitro . One-log bacilli cells in DDS-resistant infected mice footpads decreased by the DPC4, and no bacilli were found in the DDS-sensitive mice hind pads. Additionally, the in vitro host toxicity study also confirmed that the DCP4 up to 5,000 mg/L level was safety for oral administration, since a minor number of dead cells were found in red color under a fluorescent microscope. Several advanced bioinformatics tools could help locate the potential chemical entity, thereby reducing the time and resources required for in vitro and in vitro tests. DPC4 could be used in place of DDS in MDT, evidenced from in vivo antileprosy activity and in vitro host toxicity study.

Dapsone (DDS), Rifampicin (RIF) and Ofloxacin (OFL) are drugs recommended by the World Health Organization (WHO) for the treatment of leprosy. In the context of leprosy, resistance to these drugs occurs mainly due to mutations in the target genes (Folp1, RpoB and GyrA). It is important to monitor antimicrobial resistance in patients with leprosy. Therefore, we performed a meta-analysis of drug resistance in Mycobacterium leprae and the mutational profile of the target genes. In this paper, we limited the study period to May 2022 and searched PubMed, Web of Science (WOS), Scopus, and Embase databases for identified studies. Two independent reviewers extracted the study data. Mutation and drug-resistance rates were estimated in Stata 16.0. The results demonstrated that the drug-resistance rate was 10.18% (95% CI: 7.85–12.51). Subgroup analysis showed the highest resistance rate was in the Western Pacific region (17.05%, 95% CI:1.80 to 13.78), and it was higher after 2009 than before [(11.39%, 7.46–15.33) vs. 6.59% (3.66–9.53)]. We can conclude that the rate among new cases (7.25%, 95% CI: 4.65–9.84) was lower than the relapsed (14.26%, 95 CI%: 9.82–18.71). Mutation rates of Folp1, RpoB and GyrA were 4.40% (95% CI: 3.02–5.77), 3.66% (95% CI: 2.41–4.90) and 1.28% (95% CI: 0.87–1.71) respectively, while the rate for polygenes mutation was 1.73% (0.83–2.63). For further analysis, we used 368 drug-resistant strains as research subjects and found that codons (Ser, Pro, Ala) on RpoB, Folp1 and GyrA are the most common mutation sites in the determining region (DRDR). In addition, the most common substitution patterns of Folp1, RpoB, and GyrA are Pro→Leu, Ser→Leu, and Ala→Val. This study found that a higher proportion of patients has developed resistance to these drugs, and the rate has increased since 2009, which continue to pose a challenge to clinicians. In addition, the amino acid alterations in the sequence of the DRDR regions and the substitution patterns mentioned in the study also provide new ideas for clinical treatment options.

The 4,4′-diaminodiphenyl sulfone (DDS), also known as dapsone, is traditionally used as a potent anti-bacterial agent in clinical management of leprosy. For decades, dapsone has been among the first-line medications used in multidrug treatment of leprosy recommended by the World Health Organization (WHO). Shortly after dapsone’s discovery as an antibiotic in 1937, the dual function of dapsone (anti-microbial and anti-inflammatory) was elucidated. Dapsone exerts its anti-bacterial effects by inhibiting dihydrofolic acid synthesis, leading to inhibition of bacterial growth, while its anti-inflammatory properties are triggered by inhibiting reactive oxygen species (ROS) production, reducing the effect of eosinophil peroxidase on mast cells and downregulating neutrophil-mediated inflammatory responses. Among the leading mechanisms associated with its anti-microbial/anti-protozoal effects, dapsone clearly has multiple antioxidant, anti-inflammatory, and anti-apoptotic functions. In this regard, it has been described in treating a wide variety of inflammatory and infectious skin conditions. Previous reports have explored different molecular targets for dapsone and provided insight into the anti-inflammatory mechanism of dapsone. This article reviews several basic, experimental, and clinical approaches on anti-inflammatory effect of dapsone. Graphical abstract

Sepsis is a life-threatening condition caused by the body’s response to an infection. Dapsone is a sulfone with antibiotic properties, and experimental evidence suggests it has significant anti-inflammatory and anti-oxidative stress effects. The objective of this study was to investigate the efficacy of dapsone in mice after CLP (cecal ligation and puncture) surgery, which is a model for inducing sepsis. The study divided animals into five groups: CLP, sham, and three groups receiving different doses of dapsone (0.5, 1, 2 mg/kg). Sepsis was induced through CLP surgery, followed by dapsone administration. In each group, half of the mice were used to evaluate levels of various markers and pathological changes at 24 h post-CLP, while the other half was used to record the mortality rates within 96 h. The results showed that single-dose administration of dapsone at (0.5, 1, 2 mg/kg) after CLP surgery improved survival compared to the CLP group. Dapsone was also associated with a significant reduction in pro-inflammatory cytokines TNF-α, IL-1β, IL-6, NO, and MPO, as well as lactate and creatinine serum levels. However, dapsone did not have a significant effect on urea serum levels. In conclusion, the data suggest that dapsone treatment leads to increased survival in septic mice after CLP, and due to its ability to reduce TNF-α, IL-1β, IL-6, MPO, and lactate levels, it has anti-inflammatory effects in sepsis. The sepsis treatment with dapsone in mice protects against inflammation and oxidative stress.

PurposeIt has been supposed that cardiac toxicity of doxorubicin is due to its production of free radicals and inflammatory cytokines. Dapsone, an antibiotic drug which is the principal in a multidrug regimen for the treatment of leprosy, is a sulfone with anti-inflammatory and antioxidant immunosuppressive properties. Therefore, we designed this study to investigate the possible effects of dapsone on doxorubicin-induced cardiotoxicity.MethodsMale rats were administrated doxorubicin (2.5 mg/kg) and dapsone (1, 3, 10 mg/kg) intraperitoneally six times in 2 weeks. Then electrocardiographic (ECG) parameters (QRS complexes, RR and QT intervals) alternation, papillary muscle contraction and excitation, and histopathological changes were assessed. Also, the heart tissue levels of malondialdehyde (MDA) as oxidant factor and superoxide dismutase (SOD) as antioxidant enzyme, tumor necrosis factor-alpha (TNF-α) and serum level of CK-MB were analyzed.ResultsAdministration of dapsone with doxorubicin significantly reversed alterations induced by doxorubicin in serum levels of CK-MB, ECG parameters, papillary muscle contractility and excitation. Furthermore, the measurement of MDA, SOD and TNF-α tissue level indicated that dapsone significantly reduced oxidative stress and inflammation. These findings were consistent with histopathological analysis.ConclusionDapsone exerts cardioprotective effects on doxorubicin-induced cardiotoxicity through its anti-inflammatory and antioxidant mechanism.

Dapsone (DDS) therapy can frequently lead to hematological side effects, such as methemoglobinemia and DNA damage. In this study, we aim to evaluate the protective effect of racemic alpha lipoic acid (ALA) and its enantiomers on methemoglobin induction. The pre- and post-treatment of erythrocytes with ALA, ALA isomers, or MB (methylene blue), and treatment with DDS-NOH (apsone hydroxylamine) was performed to assess the protective and inhibiting effect on methemoglobin (MetHb) formation. Methemoglobin percentage and DNA damage caused by dapsone and its metabolites were also determined by the comet assay. We also evaluated oxidative parameters such as SOD, GSH, TEAC (Trolox equivalent antioxidant capacity) and MDA (malondialdehyde). In pretreatment, ALA showed the best protector effect in 2.5 µg/mL of DDS-NOH. ALA (1000 µM) was able to inhibit the induced MetHb formation even at the highest concentrations of DDS-NOH. All ALA tested concentrations (100 and 1000 µM) were able to inhibit ROS and CAT activity, and induced increases in GSH production. ALA also showed an effect on DNA damage induced by DDS-NOH (2.5 µg/mL). Both isomers were able to inhibit MetHb formation and the S-ALA was able to elevate GSH levels by stimulating the production of this antioxidant. In post-treatment with the R-ALA, this enantiomer inhibited MetHb formation and increased GSH levels. The pretreatment with R-ALA or S-ALA prevented the increase in SOD and decrease in TEAC, while R-ALA decreased the levels of MDA; and this pretreatment with R-ALA or S-ALA showed the effect of ALA enantiomers on DNA damage. These data show that ALA can be used in future therapies in patients who use dapsone chronically, including leprosy patients.

Dapsone is a sulfone used in treating inflammatory skin conditions. Despite its widespread dermatological use, the pharmacological actions of dapsone remain poorly understood. Here, we examined how different aspects of neutrophil functions are affected by dapsone. Peripheral blood neutrophils from healthy donors were stimulated with phorbol-12-myristate-13-acetate (PMA), N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), or calcium ionophore (CaI) or primed with cytokines prior to stimulation, in the presence of different concentrations of dapsone (from 10 to 50 µg/mL), followed by analyses of their survival, phenotype, and functional properties. We found that dapsone at the concentration of 50 μg/mL induced a significant neutrophil apoptotic rate during 6 h and 18 h, while other concentrations were well tolerated compared to control non-treated cells. However, dapsone significantly decreased the induced oxidative burst of neutrophils at all non-cytotoxic concentrations. Additionally, dapsone showed a dose-dependent suppression of NETosis in activated neutrophils. The production of IL-8 by dapsone-treated neutrophils was decreased under both stimulated (fMLP) and primed (TNF-α/fMLP) conditions. Moreover, dapsone inhibited the expression of CD11b/CD18, CD66, and CD89 and reversed or significantly mitigated the downregulation of CD16, CD32, CD181, CD88, and CD62L on neutrophils after priming and fMLP stimulation. In conclusion, our results indicate the complexity of dapsone actions on neutrophil functions, extending previous knowledge on the suppression of oxidative burst and IL-8 production upon neutrophils’ activation. Suppressed NETosis and modulation of marker expression associated with different neutrophil functions under inflammatory conditions are new findings, not recognized previously.

The aim of this study is to examine the use of an inflammasome competitor as a preventative agent. Coronaviruses have zoonotic potential due to the adaptability of their S protein to bind receptors of other species, most notably demonstrated by SARS-CoV. The binding of SARS-CoV-2 to TLR (Toll-like receptor) causes the release of pro-IL-1β, which is cleaved by caspase-1, followed by the formation and activation of the inflammasome, which is a mediator of lung inflammation, fever, and fibrosis. The NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome is implicated in a variety of human diseases including Alzheimer’s disease (AD), prion diseases, type 2 diabetes, and numerous infectious diseases. By examining the use of 4,4′-diaminodiphenyl sulfone (DDS) in the treatment of patients with Hansen’s disease, also diagnosed as Alzheimer’s disease, this study demonstrates the diverse mechanisms involved in the activation of inflammasomes. TLRs, due to genetic polymorphisms, can alter the immune response to a wide variety of microbial ligands, including viruses. In particular, TLR2Arg677Trp was reported to be exclusively present in Korean patients with lepromatous leprosy (LL). Previously, mutation of the intracellular domain of TLR2 has demonstrated its role in determining the susceptibility to LL, though LL was successfully treated using a combination of DDS with rifampicin and clofazimine. Of the three tested antibiotics, DDS was effective in the molecular regulation of NLRP3 inflammasome activators that are important in mild cognitive impairment (MCI), Parkinson’s disease (PD), and AD. The specific targeting of NLRP3 itself or up-/downstream factors of the NLRP3 inflammasome by DDS may be responsible for its observed preventive effects, functioning as a competitor.

Dapsone (DDS) hydroxylamine metabolites cause oxidative stress- linked adverse effects in patients, such as methemoglobin formation and DNA damage. This study evaluated the ameliorating effect of the antioxidant resveratrol (RSV) on DDS hydroxylamine (DDS-NHOH) mediated toxicity in vitro using human erythrocytes and lymphocytes. The antioxidant mechanism was also studied using in-silico methods. In addition, RSV provided intracellular protection by inhibiting DNA damage in human lymphocytes induced by DDS-NHOH. However, whilst pretreatment with RSV (10-1000 μM significantly attenuated DDS-NHOH-induced methemoglobinemia, but it was not only significantly less effective than methylene blue (MET), but also post-treatment with RSV did not reverse methemoglobin formation, contrarily to that observed with MET. DDS-NHOH inhibited catalase (CAT) activity and reactive oxygen species (ROS) generation, but did not alter superoxide dismutase (SOD) activity in erythrocytes. Pretreatment with RSV did not alter these antioxidant enzymes activities in erythrocytes treated with DDS-NHOH. Theoretical calculations using density functional theory methods showed that DDS-NHOH has a pro-oxidant effect, whereas RSV and MET have antioxidant effect on ROS. The effect on methemoglobinemia reversion for MET was significantly higher than that of RSV. These data suggest that the pretreatment with resveratrol may decrease heme-iron oxidation and DNA damage through reduction of ROS generated in cells during DDS therapy.

The sulfone dapsone is an old antibiotic used for the treatment of mycobacterial and protozoal infections. We postulated before that dapsone might possess biological activity exceeding its anti-infectious properties and that it could potentially be repurposed for the treatment of glioma. To test this hypothesis, we treated established and primary cultured glioma cells with dapsone or several dapsone analogues which we previously synthesized (D2–D5) and determined effects on proliferation, anchorage-independent growth and migration. While dapsone and its synthetic analogues D2–D5 displayed only modest anti-proliferative activity, important neoplastic features such as anchorage-independent growth, clonogenic survival and directed migration were significantly inhibited by dapsone treatment. Moreover, dapsone analogues D3, D4 and D5 yielded even enhanced anti-glioma activity against different pro-neoplastic features. Overall these data suggest that dapsone provides activity against glioma which can be further enhanced by molecular modifications. These compounds could potentially serve as a therapeutic adjunct to the treatment of gliomas in a repurposing approach.