Novel thiazolotriazole and triazolothiadiazine scaffolds as selective tumor associated carbonic anhydrase inhibitors endowed with cathepsin B inhibition.

The present research focused on the tail-approach synthesis of novel extended thiazolotriazoles (8a-8j) and triazolothiadiazines (11a-11j) including aminotriazole intermediate 10. After successful synthesis, all the compounds were evaluated for their inhibition potential against cytosolic isoforms of human carbonic anhydrase (hCA I, II), tumor-linked transmembrane isoforms (hCA IX, XII), and cathepsin B. As per the inhibition data, the newly synthesized compounds showed poor inhibition against hCA I. Many of the compounds showed effective inhibition toward hCA IX and/or XII in low nanomolar concentration. Despite the strong to moderate inhibition of hCA II by these compounds, more than half of them demonstrated better inhibition against hCA IX and/or XII, comparatively. Further, insights of CA inhibition data of these extended analogs and their comparison with earlier reported thiazolotriazole and triazolothiadiazine derivatives might help in the rational design of novel potent and selective hCA IX and XII inhibitors. The novel compounds were also found to possess anti-cathepsin B potential at a low concentration of 10-7 M. Broadly, compounds of series 11a-11j presented more effective inhibition against cathepsin B than their counterparts in series 8a-8j. Moreover, these in vitro results with respect to cathepsin B inhibition were also supported by the in silico insights obtained via molecular modeling studies.

Benzenesulfonamides functionalized with triazolyl-linked pyrazoles possess dual cathepsin B and carbonic anhydrase inhibitory action.

The design and synthesis of a library of 21 novel benzenesulfonamide-bearing 3-functionalized pyrazole-linked 1,2,3-triazole derivatives as dual inhibitors of cathepsin B and carbonic anhydrase enzymes are reported. The target 1,2,3-triazole-linked pyrazolic esters (16) were synthesized by the condensation of 1,2,3-triazolic diketo esters with 4-hydrazinobenzenesulfonamide hydrochloride, and these were further converted into the corresponding carboxylic acid (17) and carboxamide (18) analogs. The synthesized compounds were assayed in vitro for their inhibition potential against human carbonic anhydrase (hCA) isoforms I, II, IX, and XII. They were found to be potent inhibitors at the low nanomolar level against the cancer-related hCA IX and XII and to be selective towards the cytosolic isoform hCA I. The physiologically important isoform hCA II was potently inhibited by all the newly synthesized compounds showing KI values ranging between 0.8 and 561.5 nM. The ester derivative 16c having 4-fluorophenyl (KI = 5.2 nM) was the most potent inhibitor of hCA IX, and carboxamide derivative 18b (KI = 2.2 nM) having 4-methyl substituted phenyl was the most potent inhibitor of hCA XII. The newly synthesized compounds exhibited potent cathepsin B inhibition at 10-7 M concentration. In general, the carboxamide derivatives (18) showed higher % inhibition as compared with the corresponding ester derivatives (16) and carboxylic acid derivatives (17) for cathepsin B. The interactions of the target compounds with the active sites of cathepsin B and CA were studied through molecular docking studies. Further, the in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of the target compounds were also studied.

Spinal Cord Transcutaneous Stimulation in Cervical Spinal Cord Injury: A Review Examining Upper Extremity Neuromotor Control, Recovery Mechanisms, and Future Directions.

Cervical spinal cord injury (SCI) results in significant sensorimotor impairments below the injury level, notably in the upper extremities (UEs), impacting daily activities and quality of life. Regaining UE function remains the top priority for individuals post-cervical SCI. Recent advances in understanding adaptive plasticity within the sensorimotor system have led to the development of novel non-invasive neurostimulation strategies, such as spinal cord transcutaneous stimulation (scTS), to facilitate UE motor recovery after SCI. This comprehensive review investigates the neuromotor control of UE, the typical recovery trajectories following SCI, and the therapeutic potential of scTS to enhance UE motor function in individuals with cervical SCI. Although limited in number with smaller sample sizes, the included research articles consistently suggest that scTS, when combined with task-specific training, improves voluntary control of arm and hand function and sensation. Further, the reported improvements translate to the recovery of various UE functional tasks and positively impact the quality of life in individuals with cervical SCI. Several methodological limitations, including stimulation site selection and parameters, training strategies, and sensitive outcome measures, require further advancements to allow successful translation of scTS from research to clinical settings. This review also summarizes the current literature and proposes future directions to support establishing approaches for scTS as a viable neuro-rehabilitative tool.

In-vitro and in-silico investigations of SLC-0111 hydrazinyl analogs as human carbonic anhydrase I, II, IX, and XII inhibitors.

Two novel series of hydrazinyl-based benzenesulfonamides 9a-j and 10a-j were designed and synthesized using SLC-0111 as the lead molecule. The newly synthesized compounds were evaluated for their inhibitory activity against four different human carbonic anhydrase (hCA) isoforms I, II, IX, and XII. Both the series reported here were practically inactive against the off-target isozyme hCA I. Notably, derivative 10a exhibited superior potency (Ki of 10.2 nM) than acetazolamide (AAZ) against the cytosolic isoform hCA II. The hCA IX and XII isoforms implicated in tumor progression were effectively inhibited with Kis in the low nanomolar range of 20.5-176.6 nM and 6.0-127.5 nM, respectively. Compound 9g emerged as the most potent and selective hCA IX and XII inhibitor with Ki of 20.5 nM and SI of 200.1, and Ki of 6.0 nM and SI of 683.7, respectively, over hCA I. Furthermore, six compounds (9a, 9h, 10a, 10g, 10i, and 10j) exhibited significant inhibition toward hCA IX (Kis = 27.0, 41.1, 27.4, 25.9, 40.7, and 30.8 nM) relative to AAZ and SLC-0111 (Kis = 25.0 and 45.0 nM, respectively). These findings underscore the potential of these derivatives as potent and selective inhibitors of hCA IX and XII over the off-target hCA I and II.

Differences in autophagy marker levels at birth in preterm vs. term infants.

BACKGROUND: Preterm infants are susceptible to oxidative stress and prone to respiratory diseases. Autophagy is an important defense mechanism against oxidative-stress-induced cell damage and involved in lung development and respiratory morbidity. We hypothesized that autophagy marker levels differ between preterm and term infants. METHODS: In the prospective Basel-Bern Infant Lung Development (BILD) birth cohort we compared cord blood levels of macroautophagy (Beclin-1, LC3B), selective autophagy (p62) and regulation of autophagy (SIRT1) in 64 preterm and 453 term infants. RESULTS: Beclin-1 and LC3B did not differ between preterm and term infants. However, p62 was higher (0.37, 95% confidence interval (CI) 0.05;0.69 in log2-transformed level, p = 0.025, padj = 0.050) and SIRT1 lower in preterm infants (-0.55, 95% CI -0.78;-0.31 in log2-transformed level, padj < 0.001). Furthermore, p62 decreased (padj-value for smoothing function was 0.018) and SIRT1 increased (0.10, 95% CI 0.07;0.13 in log2-transformed level, padj < 0.001) with increasing gestational age. CONCLUSION: Our findings suggest differential levels of key autophagy markers between preterm and term infants. This adds to the knowledge of the sparsely studied field of autophagy mechanisms in preterm infants and might be linked to impaired oxidative stress response, preterm birth, impaired lung development and higher susceptibility to respiratory morbidity in preterm infants. IMPACT: To the best of our knowledge, this is the first study to investigate autophagy marker levels between human preterm and term infants in a large population-based sample in cord blood plasma This study demonstrates differential levels of key autophagy markers in preterm compared to term infants and an association with gestational age This may be linked to impaired oxidative stress response or developmental aspects and provide bases for future studies investigating the association with respiratory morbidity.

Novel 1,2,4-triazoles as selective carbonic anhydrase inhibitors showing ancillary anticathepsin B activity.

Background: Exploration of the multi-target approach considering both human carbonic anhydrase (hCA) IX and XII and cathepsin B is a promising strategy to target cancer. Methodology & Results: 22 novel 1,2,4-triazole derivatives were synthesized and evaluated for their inhibition efficacy against hCA I, II, IX, XII isoforms and cathepsin B. The compounds demonstrated effective inhibition against hCA IX and/or XII isoforms with considerable selectivity over off-target hCA I/II. All compounds presented significant anticathepsin B activities at a low concentration of 10-7 M and in vitro results were also supported by the molecular modeling studies. Conclusion: Insights of present study can be utilized in the rational design of effective and selective hCA IX and XII inhibitors capable of inhibiting cathepsin B.

Correction: Dastghaib et al. Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells. Cells 2020, 9, 2339.

In the original publication [...].

Segawa Syndrome, a Dramatic Response to Dopamine.

Segawa syndrome usually manifests as dystonia, disturbance of gait with fatigue, and may be confused with spasticity. Also known as dopamine-responsive dystonia (DRD), it should be considered in any child who presents with paroxysmal or progressive hypertonia of unknown etiology, which responds dramatically to levodopa. It is a clinical diagnosis, but the level of pterins in cerebrospinal fluid and guanosine triphosphate cyclohydrolase-1 (GTCH 1) gene mutation testing done by molecular genetic testing are confirmatory. Our case is a 45-year female with a family history of similar illness expressed as autosomal recessive inheritance pattern. She had symptoms onset at an early age of 13 years with features of dystonia of predominantly lower limbs, hence the inability to maintain posture and walk. Dramatic improvement with levodopa but sudden deterioration to dystonia due to noncompliance was evident in our patient with troublesome features of concomitant adjustment disorder during presentation.

Insights on Strain-Substrate Interactions and Antioxidant and Anti-Bacterial Properties of the Velvet Foot Medicinal Mushroom Flammulina velutipes (Agaricomycetes).

To study the best substrate for the Indian subcontinent, four different substrates (sawdust + wheat bran, wheat straw + wheat bran + corn cobs, sawdust + corn cobs and wheat straw + wheat bran) were screened for six different Flammulina velutipes strains. The antioxidant and antibacterial properties were studied for these strains. In study it was found that the strain DMRX-767 and DMRX-768 were the most promising for yield and biological efficiency in all substrates and wheat straw + wheat bran being the best with respect to BE. To corroborate the findings, the best strain and best substrate trails were repeated. DMRX-767 and DMRX-768 were the most promising for yield and biological efficiency in all substrates, with wheat straw+wheat bran were again found the best. The methanolic extract of strain DMRX-166 showed highest antibacterial properties as highest inhibition is found for Bacillus subtilis and Pseudomonas syringae. However, DMRO-253 inhibited Ralstonia solanacearum and Xanthomonas campestris. DMRX-768 has the best scavenging ability followed by DMRO-253.

Heated tobacco product IQOS induces unique metabolic signatures in human bronchial epithelial cells.

Metabolic signatures are lacking for heated tobacco products, making it crucial to identify new biosignatures of lung damage. This will enable the establishment of product-specific guidelines and an understanding of associated toxicity. https://bit.ly/3TkhBox.

First report of leaf spot of maize caused by Curvularia verruculosa in India.

Curvularia leaf spot affects maize plants worldwide and is commonly caused by Curvularia lunata, C. geniculata, and C. pallescens (Manzar et al. 2022; Manzar et al. 2021; Choudhary et al. 2011). In February 2017, leaf spot symptoms were observed in a Deogaon, (25.74 N, 82.99 E) in Uttar Pradesh, India, with disease incidence of less than 10% of the plants in maize fields. On the leaves and sheaths, variously shaped yellow spots were developed. The spots were 2.5 mm in diameter and frequently grew larger, reaching a diameter of 1 cm. They were encircled by a chlorotic halo with dark borders. The symptomatic tissue showing leaf spots of 10 plants was taken and cut into pieces (4 mm2) then surface sterilized with 1% sodium hypochlorite for 1 min, and rinsed three times with distilled water. The cut leaf tissue was placed on the Petri plate containing potato dextrose agar medium amended with streptomycin sulfate (125 ppm). Then incubated at 25±2°C with a 12-h light and dark period, after 5 days of incubation, five pure cultures were obtained using the hyphal tip technique. The pure culture was incubated at 26±2°C for 10 days. The upper surface of the colony was dark grayish black with fluffy mycelia, and the reverse colony was dark brown. The conidia have three septa, are light brown to dark brown in color, straight to curved, ellipsoidal to fusiform, and have two bigger, darker central cells than terminal cells. On average, conidia are between 27.22 to 31.21 mm long and 10.61 to 12.62 mm wide (n=30). The morphological description is similar to the Curvularia verruculosa morphological traits described by Tandon & Bilgrami (Ellis 1966). Molecular identification was done in addition to supporting morphological identification. The nucleopore GDNA Fungus Kit (Genetix Brand, India) was used to extract the genomic DNA of the E40 isolate. The ITS rDNA region (White et al. 1990) and the glyceraldehyde-3-phosphate dehydrogenase (gpd) gene (Berbee et al. 1999) were amplified through PCR(Manzar et al., 2022).The amplicons were bidirectional sequenced through the Sanger sequencing method. The similarity percentage of E40 isolate matched 100% with MH859788 (CBS444.70 ) of Curvularia verruculosa strain for ITS, and 100% with LT715824 (CBS150.63) of Curvularia verruculosa strain for gpd after Blastn analysis. The gene sequences were deposited to GenBank and accession no. OR262893 for ITS, and LC773704 for gpd were assigned. As a result, C. verruculosa was determined to be the presumed pathogen by both morphology and molecular characteristics. The pathogenicity of E40 isolate was performed twice by spraying (106 conidia/ml in sterile water) onto the leaves of 25 days old maize plant cv. Kanchan (n = 10). Uninoculated healthy maize plants (n=5) were sprayed only with autoclaved water. All pots are kept in a glass house at 25°C±2°C with 90% relative humidity. After 15 days of pathogen inoculation the foliar spots with chlorotic halo, enlarger upto 1cm, and from these spots the identical fungus was reisolated. The reisolated fungus showed similar morphological characteristics to C. verruculosa. Control plants showed no symptoms. C. verruculosa has been previously reported as a causative agent of leaf spot disease in Common beans (Wei et al., 2022), Cotton (Shirsath et al., 2018). To our knowledge, this is the first report of leaf blight caused by C. verruculosa on maize in India.

1,2,3-Triazole-based esters and carboxylic acids as nonclassical carbonic anhydrase inhibitors capable of cathepsin B inhibition.

Herein, we report the design and synthesis of a library of 28 new 1,2,3-triazole derivatives bearing carboxylic acid and ester moieties as dual inhibitors of carbonic anhydrase (CA) and cathepsin B enzymes. The synthesised compounds were assayed in vitro for their inhibition potential against four human CA (hCA) isoforms, I, II, IX and XII. The carboxylic acid derivatives displayed low micromolar inhibition against hCA II, IX and XII in contrast to the ester derivatives. Most of the target compounds showed poor inhibition against the hCA I isoform. 4-Fluorophenyl appended carboxylic acid derivative 6c was found to be the most potent inhibitor of hCA IX and hCA XII with a KI value of 0.7 µM for both the isoforms. The newly synthesised compounds showed dual inhibition towards CA as well as cathepsin B. The ester derivatives exhibited higher % inhibition at 10-7 M concentration as compared with the corresponding carboxylic acid derivatives against cathepsin B. The results from in silico studies of the target compounds with the active site of cathepsin B were found in good correlation with the in vitro results. Moreover, two compounds, 5i and 6c, showed cytotoxic activity against A549 lung cancer cells, with IC50 values lower than 100 µM.

Prevalence of Suicidal Behavior Among Students in South-East Asia: A Systematic Review and Meta-Analysis.

OBJECTIVES: Estimation of rates of suicidal behaviors (ideation, plan, and attempt) would help to understand the burden and prioritize prevention strategies. However, no attempt to assess suicidal behavior among students was identified in South-East Asia (SEA). We aimed to assess the prevalence of suicidal behavior (ideation, plan, and attempt) among students in SEA. METHODS: We followed PRISMA 2020 guidelines and registered the protocol in PROSPERO (CRD42022353438). We searched in Medline, Embase, and PsycINFO and performed meta-analyses to pool the lifetime, 1-year, and point prevalence rates for suicidal ideation, plans, and attempts. We considered the duration of a month for point prevalence. RESULTS: The search identified 40 separate populations from which 46 were included in the analyses, as some studies included samples from multiple countries. The pooled prevalence of suicidal ideation was 17.4% (confidence interval [95% CI], 12.4%-23.9%) for lifetime, 9.33% (95% CI, 7.2%-12%) for the past year, and 4.8% (95% CI, 3.6%-6.4%) for the present time. The pooled prevalence of suicide plans was 9% (95% CI, 6.2%-12.9%) for lifetime, 7.3% (95% CI, 5.1%-10.3%) for the past year, and 2.3% (95% CI, 0.8%-6.7%) for the present time. The pooled prevalence of suicide attempts was 5.2% (95% CI, 3.5%-7.8%) for lifetime and 4.5% (95% CI, 3.4%-5.8%) for the past year. Higher rates of suicide attempts in the lifetime were noted in Nepal (10%) and Bangladesh (9%), while lower rates were reported in India (4%) and Indonesia (5%). CONCLUSIONS: Suicidal behaviors are a common phenomenon among students in the SEA region. These findings call for integrated, multisectoral efforts to prevent suicidal behaviors in this group.

Electroconvulsive therapy in South Asia: Past, present, and future.

The practice of electroconvulsive therapy (ECT) varies both between and within countries. We aimed to review historical and current trends in ECT practices, perceptions, and legislations in South Asia, a region with a high burden of mental illness and suicide. We searched MEDLINE (PubMed) and Google Scholar databases for relevant literature on ECT from each country. Additionally, a team of country-specific investigators performed supplemental searches and contacted key country contacts for relevant information. Relevant data were abstracted under the following headings: ECT practices, perceptions, and legislations. Knowledge gaps and research priorities were synthesized. Modified bitemporal ECT, delivered using brief pulse devices, was most commonly offered across institutions. Schizophrenia, not affective illness, was the most common indication. Electroencephalographic monitoring of seizures was rarely practiced. Thiopentone or propofol was preferred for anesthetic induction, while the favored muscle relaxant was succinylcholine. In India and Sri Lanka, perceptions about ECT were largely favorable; not so in Pakistan and Nepal. Only India and Pakistan had laws that governed any aspect of ECT practice; ECT practice guidelines were available only in India. There is a lack of research on efficacy, ECT in special populations, continuation ECT practices, and interventions to improve ECT-related perceptions. Most regional institutions offered modified brief-pulse ECT, and schizophrenia was the most common indication. Knowledge of and attitude towards ECT varied between countries. There is a need to develop a regional ECT consortium to facilitate uniform training, advocacy efforts, and the development of regional practice guidelines.

Synthesis and biological evaluation of novel benzenesulfonamide incorporated thiazole-triazole hybrids as antimicrobial and antioxidant agents.

A library of 20 novel benzenesulfonamide incorporating thiazole tethered 1,2,3-triazoles 1-4a-e was synthesized and screened for their antimicrobial, antioxidant, and cytotoxicity studies. Amoxicillin and fluconazole were used as reference antibacterial and antifungal drugs, respectively. Further, energies of frontier molecular orbitals were calculated for all the synthesized target compounds 1-4a-e to correlate electronic parameters with the observed biological results. Global reactivity descriptors, including highest occupied molecular orbitals-lowest unoccupied molecular orbitals energy gap, electronegativity, chemical hardness, chemical softness, and electrophilicity index, were also calculated for the synthesized molecules. All the tested compounds possessed moderate to excellent antibacterial potency; however, 3d and 4d exhibited the overall highest antibacterial effect (minimum inhibitory concentration [MIC] values 5-11 µM) while 2c showed the highest antifungal effect (MIC value 6 µM). Compound 3c exhibited the highest antioxidant activity with a % radical scavenging activity value of 95.12. The cytotoxicity of the compounds 1-4a-e was also checked against an animal cell line and a plant seed germination cell line, and the compounds were found to be safe against both the tested cell lines.

Association of Neutrophil Lymphocyte Ratio and Platelet Lymphocyte Ratio with Persistent Allergic Rhinitis.

Allergic rhinitis is a disease that affects approximately 15-25% of the World population. It is characterized by itching, sneezing, and nasal or postnasal drip. Generally, diagnosis is based on clinical findings and patient history. Laboratory tests that can be used in the diagnosis and clinical course of AR are still limited and should be improved. Neutrophil-lymphocyte ratio (NLR) and Platelet Lymphocyte Ration(PLR) are novel markers for the evaluation of inflammation. This study aims to investigate whether NLR and PLR, would be useful in diagnosis and monitoring the severity of disease in allergic rhinitis. It is a 1 year cross sectional study which assesses 140 patients, 70 belonging each to case and control group. NLR and PLR ratio was measured and compared in case and control groups. Mean NLR was 1.92 in patient group and in control group it was 1.54 (P value < 0.001). Mean PLR was 1.33 in patient group and in control group it was 0.88 (p < 0.001). Mean NLR in mild cases was 1.68 and in moderate to severe cases was 2.15 (p value 0.002). Mean PLR was 1.49 in moderate to severe disease and in mild disease it was 1.18 (p value 0.006). To conclude NLR and PLR were significantly higher in moderate to severe allergic rhinitis and not so in mild cases. Hence in allergic rhinitis NLR and PLR can be used as a marker of severity of disease according to symptoms of the disease.

Phase III randomized clinical studies to evaluate the immunogenicity, lot-to-lot consistency, and safety of ROTAVAC® liquid formulations (ROTAVAC 5C & 5D) and non-inferiority comparisons with licensed ROTAVAC® (frozen formulation) in healthy infants.

The WHO pre-qualified rotavirus vaccine, ROTAVAC®, is derived naturally from the neonatal 116E rotavirus strain, and stored at -20°C. As refrigerator storage is preferable, immunogenicity and safety of liquid formulations kept at 2-8°C, having excipients to stabilize the rotavirus, with or without buffers, were compared with ROTAVAC® in different clinical studies. Study-1, the pivotal trial for this entire product development work, was a randomized, single-blind trial with two operationally seamless phases: (i) an exploratory phase involving 675 infants in which two formulations, ROTAVAC 5C (LnHRV-1.5 mL and LnHRV-2.0 mL) containing buffer and excipients to stabilize the virus against gastric acidity and temperature, were compared with ROTAVAC®. As the immune response of ROTAVAC 5C (LnHRV-2.0 mL) was non-inferior to ROTAVAC®, it was selected for (ii) confirmatory phase, involving 1,302 infants randomized 1:1:1:1 to receive three lots of LnHRV-2.0 mL, or ROTAVAC®. Primary objectives were the evaluation of non-inferiority and lot-to-lot consistency. The secondary objectives were to assess the safety and interference with the concomitant pentavalent vaccine. As it was separately established that buffers are not required for ROTAVAC®, in Study-2, the safety and immunogenicity of ROTAVAC 5D® (with excipients) were compared with ROTAVAC® and lot-to-lot consistency was assessed in another study. All lots elicited consistent immune responses, did not interfere with UIP vaccines, and had reactogenicity similar to ROTAVAC®. ROTAVAC 5C and ROTAVAC 5D® were immunogenic and well tolerated as ROTAVAC®. ROTAVAC 5D® had comparable immunogenicity and safety profiles with ROTAVAC® and can be stored at 2-8°C, leading to WHO pre-qualification.Clinical Trials Registration: Clinical Trials Registry of India (CTRI): CTRI/2015/02/005577CTRI/2016/11/007481 and CTRI/2019/03/017934.

Delirious Mania in an Elderly, Challenges in Diagnosis and Treatment.

Delirious mania is an acute neurobehavioral syndrome which can have the features of mania, delirium, psychosis and catatonia. There are no diagnostic and treatment guidelines of delirious mania which can lead to delayed treatment, increasing morbidity and mortality. The primary goal of this report is to raise awareness among healthcare professionals and improve patient outcomes for this potentially life-threatening condition. In this case report, we present an octogenarian female, a case of bipolar disorder, current episode manic, who had impaired orientation, delusion of persecution, and altered sleep-wake cycle. She was treated with a combination of mood stabilizer and antipsychotic and discharged after 24 days of admission.

Keto-bridged dual triazole-linked benzenesulfonamides as potent carbonic anhydrase and cathepsin B inhibitors.

Background: Inhibition of human carbonic anhydrase (hCA) isoforms IX and XII with concurrent inhibition of cathepsin B is a promising approach for targeting cancers. Methods/results: 28 keto-bridged dual triazole-containing benzenesulfonamides were synthesized and tested, following the multitarget approach, for their efficacy as inhibitors of cathepsin B and hCA isoforms (I, II, IX, XII). The synthesized compounds showed excellent inhibition of CA isoforms (IX and XII) and cathepsin B. Compound 8i exhibited better and more selective inhibition of the cancer-associated isoform hCA IX as compared with acetazolamide (reference drug) and SLC-0111 (potent lead as carbonic anhydrase inhibitor). Molecular docking studies were also carried out. Conclusion: The present work gives important generalizations for the development of isoform-selective hCA inhibitors endowed with anti-cathepsin properties.

Potent inhibitors of tumor associated carbonic anhydrases endowed with cathepsin B inhibition.

Twenty-one novel extended analogs of acetazolamide were synthesized and screened in vitro for their inhibition efficacy against human carbonic anhydrase (hCA) isoforms I, II, IX, XII, and cathepsin B. The majority of the compounds were found to be effective inhibitors of tumor-associated hCA IX and XII, and poor inhibitors of cytosolic hCA I. Despite the strong to moderate inhibition potential possessed by these compounds toward another cytosolic isoform hCA II, some of them demonstrated better potency against hCA IX and/or XII isoforms as compared to hCA II. Four compounds (11f, 11g, 12c, and 12g) effectively inhibited hCA IX and/or XII isoforms with considerable selectivity over the off-targets hCA I and II. Interestingly, five compounds, including 11f, 11g, 12c, 12d, and 12g, inhibited hCA IX even better than the clinically used acetazolamide. Some of the novel synthesized compounds exhibited higher anti-cathepsin B potential than acetazolamide, with % inhibition of around 50%, at a concentration of 10-7 M. Further, two compounds (12g and 12c) that showed effective and selective inhibition activity profiles against hCA IX and XII were additionally found to be effective inhibitors of cathepsin B.