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  1. Synthesis and biological activity of oxadiazole and triazolothiadiazole derivatives as tyrosinase inhibitors
    Lam KW, Syahida A, Ul-Haq Z, Abdul Rahman MB, Lajis NH
    Bioorg Med Chem Lett, 2010 Jun 15;20(12):3755-9.
    PMID: 20493688 DOI: 10.1016/j.bmcl.2010.04.067
    A series of 16 oxadiazole and triazolothiadiazole derivatives were designed, synthesized and evaluated as mushroom tyrosinase inhibitors. Five derivatives were found to display high inhibition on the tyrosinase activity ranging from 0.87 to 1.49 microM. Compound 5 exhibited highest tyrosinase inhibitory activity with an IC(50) value of 0.87+/-0.16 microM. The in silico protein-ligand docking using AUTODOCK 4.1 was successfully performed on compound 5 with significant binding energy value of -5.58 kcal/mol. The docking results also showed that the tyrosinase inhibition might be due to the metal chelating effect by the presence of thione functionality in compounds 1-5. Further studies revealed that the presence of hydrophobic group such as cycloamine derivatives played a major role in the inhibition. Piperazine moiety in compound 5 appeared to be involved in an extensive hydrophobic contact and a 2.9A hydrogen bonding with residue Glu 182 in the active site.
  2. Indole acrylonitriles as potential anti-hyperglycemic agents: Synthesis, α-glucosidase inhibitory activity and molecular docking studies
    Solangi M, Kanwal, Mohammed Khan K, Saleem F, Hameed S, Iqbal J, et al.
    Bioorg Med Chem, 2020 Nov 01;28(21):115605.
    PMID: 33065441 DOI: 10.1016/j.bmc.2020.115605
    One of the most prevailing metabolic disorder diabetes mellitus has become the global health issue that has to be addressed and cured. Different marketed drugs have been made available for the treatment of diabetes but there is still a need of introducing new therapeutic agents that are economical and have lesser or no side effects. The current study deals with the synthesis of indole acrylonitriles (3-23) and the evaluation of these compounds for their potential for α-glucosidase inhibition. The structures of these synthetic molecules were deduced by using different spectroscopic techniques. Acarbose (IC50 = 2.91 ± 0.02 μM) was used as standard in this study and the synthetic molecules (3-23) have shown promising α-glucosidase inhibitory activity. Compounds 4, 8, 10, 11, 14, 18, and 21 displayed superior inhibition of α-glucosidase enzyme in the range of (IC50 = 0.53 ± 0.01-1.36 ± 0.04 μM) as compared to the standard acarbose. Compound 10 (IC50 = 0.53 ± 0.01 μM) was the most effective inhibitor of this library and displayed many folds enhanced activity in contrast to the standard. Molecular docking of synthetic compounds was performed to verify the binding interactions of ligand with the active site of enzyme. This study had identified a number of potential α-glucosidase inhibitors that can be used for further research to identify a potent therapeutic agent against diabetes.
  3. Synthesis of azachalcones, their α-amylase, α-glucosidase inhibitory activities, kinetics, and molecular docking studies
    Saleem F, Kanwal, Khan KM, Chigurupati S, Solangi M, Nemala AR, et al.
    Bioorg Chem, 2021 01;106:104489.
    PMID: 33272713 DOI: 10.1016/j.bioorg.2020.104489
    Diabetes being a chronic metabolic disorder have attracted the attention of medicinal chemists and biologists. The introduction of new and potential drug candidates for the cure and treatment of diabetes has become a major concern due to its increased prevelance worldwide. In the current study, twenty-seven azachalcone derivatives 3-29 were synthesized and evaluated for their antihyperglycemic activities by inhibiting α-amylase and α-glucosidase enzymes. Five compounds 3 (IC50 = 23.08 ± 0.03 µM), (IC50 = 26.08 ± 0.43 µM), 5 (IC50 = 24.57 ± 0.07 µM), (IC50 = 27.57 ± 0.07 µM), 6 (IC50 = 24.94 ± 0.12 µM), (IC50 = 27.13 ± 0.08 µM), 16 (IC50 = 27.57 ± 0.07 µM), (IC50 = 29.13 ± 0.18 µM), and 28 (IC50 = 26.94 ± 0.12 µM) (IC50 = 27.99 ± 0.09 µM) demonstrated good inhibitory activities against α-amylase and α-glucosidase enzymes, respectively. Acarbose was used as the standard in this study. Structure-activity relationship was established by considering the parent skeleton and different substitutions on aryl ring. The compounds were also subjected for kinetic studies to study their mechanism of action and they showed competitive mode of inhibition against both enzymes. The molecular docking studies have supported the results and showed that these compounds have been involved in various binding interactions within the active site of enzyme.
  4. Biology-oriented drug synthesis (BIODS), in vitro urease inhibitory activity, and in silico studies on ibuprofen derivatives
    Seraj F, Kanwal, Khan KM, Khan A, Ali M, Khalil R, et al.
    Mol Divers, 2021 Feb;25(1):143-157.
    PMID: 31965436 DOI: 10.1007/s11030-019-10032-x
    Novel ibuprofen derivatives 1-19 including ibuprofen hydrazide 1, and substituted thiourea derivatives 2-19 were synthesized and characterized by EI-MS, FAB-MS, HREI-MS, HRFAB-MS, 1H-, and 13C-NMR spectroscopic techniques. The synthetic molecules 1-19 were examined for their in vitro urease inhibition and were found to display a diversified degree of inhibitory potential in the range of IC50 = 2.96-178 μM as compared to the standard thiourea (IC50 = 21.32 ± 0.22 μM). Out of nineteen, thirteen derivatives 2-4, 6, 7, 9, 11-15, 17, and 18 demonstrated remarkable inhibitory activity with IC50 values of 2.96 ± 1.11 to 16.1 ± 1.07 μM, compound 5 exhibited moderate inhibition with IC50 value of 37.3 ± 0.41 μM, whereas, compounds 1, 8, and 10 demonstrated weak inhibition against urease enzyme. Almost all structural features are participating in the activity; however, limited structure-activity relationship was discussed on the basis of different structural features, i.e., different functional groups and their positions at aryl part. In addition, molecular docking study was performed in order to understand the ligands binding interactions with the active site of urease enzyme.
  5. Fulltext Phytochemical characterization and anti-arthritic potential of Croton bonplandianus leaves extract: In-vivo and in-silico approach
    Javed E, Khan HM, Shahzad Q, Shahzad Y, Yasin H, Ul-Haq Z, et al.
    Saudi Pharm J, 2023 Dec;31(12):101860.
    PMID: 38192284 DOI: 10.1016/j.jsps.2023.101860
    Croton bonplandianus, a natural source traditionally used for treating various illnesses, including rheumatoid arthritis, was evaluated in this study. The effects of ethanolic extracts (CBEE) and aqueous fractions (CBAF) of C. bonplandianus leaves on arthritis-induced inflammation were studied using an albino rat model of inflammation induced by Freund's complete adjuvant. Eight test groups (n = 5 per group) and one vehicle control were used to evaluate the antiarthritic effects of different doses of CBEE and CBAF (125 mg.kg-1, 250 mg.kg-1, and 500 mg.kg-1) on days 5, 10, 15, and 20 compared to arthritic and vehicle controls. Arthritis severity was assessed using macroscopic arthritis grading, histological analysis, body weights, and paw thickness. CBEE and CBAF were found to reduce the prevalence of arthritis, increase body weight, and decrease paw inflammation compared to the vehicle control group by the 23rd day. In addition, they showed no effect on biochemical parameters, but a significant difference (p 
  6. Fulltext Betamethasone Dipropionate Derivatization, Biotransformation, Molecular Docking, and ADME Analysis as Glucocorticoid Receptor
    Rashid S, Anjum S, Ahmad A, Nadeem R, Ahmed M, Shah SAA, et al.
    Biomed Res Int, 2022;2022:6865472.
    PMID: 35865666 DOI: 10.1155/2022/6865472
    Betamethasone is an important glucocorticoids (GCs), frequently used to cure allergies (such as asthma and angioedema), Crohn's disease, skin diseases (such as dermatitis and psoriasis), systemic lupus erythematosus, rheumatic disorders, and leukemia. Present investigation deals to find potential agonist of glucocorticoid receptors after biotransformation of betamethasone dipropionate (1) and to carry out the molecular docking and ADME analyses. Biotransformation of 1 was carried out with Launaea capitata (dandy) roots and Musa acuminate (banana) leaves. M. acuminate furnished low-cost value-added products such as Sananone dipropionate (2) in 5% yields. Further, biocatalysis of Sananone dipropionate (2) with M. acuminate gave Sananone propionate (3) and Sananone (4) in 12% and 7% yields, respectively. However, Sananone (4) was obtained in 37% yields from Launaea capitata. Compound 5 was obtained in 11% yield after β-elimination of propionic acid at C-17 during oxidation of compound 1. The structure elucidation of new compounds 2-5 was accomplished through combined use of X-ray diffraction and NMR (1D and 2D) studies. In addition to this, molecular docking and ADME analyses of all transformed products of 1 were also done. Compounds 1-5 showed -12.53 to -10.11 kcal/mol potential binding affinity with glucocorticoid receptor (GR) and good ADME profile. Moreover, all the compounds showed good oral bioavailability with the octanol/water partition coefficient in the range of 2.23 to 3.65, which indicated that compounds 1-5 were in significant agreement with the given criteria to be considered as drug-like.
  7. Anti-diarrheal activities of phytol along with its possible mechanism of action through in-vivo and in-silico models
    Islam MT, Rahman MA, Saeed M, Ul-Haq Z, Alam MJ, Mondal M, et al.
    Cell Mol Biol (Noisy-le-grand), 2020 Jun 25;66(4):243-249.
    PMID: 32583783
    Phytol (PHY), a chlorophyll-derived diterpenoid, exhibits numerous pharmacological properties, including antioxidant, antimicrobial, and anticancer activities. This study evaluates the anti-diarrheal effect of phytol (PHY) along with its possible mechanism of action through in-vivo and in-silico models. The effect of PHY was investigated on castor oil-induced diarrhea in Swiss mice by using prazosin, propranolol, loperamide, and nifedipine as standards with or without PHY. PHY at 50 mg/kg (p.o.) and all other standards exhibit significant (p < 0.05) anti-diarrheal effect in mice. The effect was prominent in the loperamide and propranolol groups. PHY co-treated with prazosin and propranolol was found to increase in latent periods along with a significant reduction in diarrheal section during the observation period than other individual or combined groups. Furthermore, molecular docking studies also suggested that PHY showed better interactions with the α- and β-adrenergic receptors, especially with α-ADR1a and β-ADR1. In the former case, PHY showed interaction with hydroxyl group of Ser192 at a distance of 2.91Å, while in the latter it showed hydrogen bond interactions with Thr170 and Lys297 with a distance of 2.65 and 2.72Å, respectively. PHY exerted significant anti-diarrheal effect in Swiss mice, possibly through blocking α- and β-adrenergic receptors.
  8. Fulltext Design, Synthesis and Docking Studies of Flavokawain B Type Chalcones and Their Cytotoxic Effects on MCF-7 and MDA-MB-231 Cell Lines
    Abu Bakar A, Akhtar MN, Mohd Ali N, Yeap SK, Quah CK, Loh WS, et al.
    Molecules, 2018 Mar 08;23(3).
    PMID: 29518053 DOI: 10.3390/molecules23030616
    Flavokawain B (1) is a natural chalcone extracted from the roots of Piper methysticum, and has been proven to be a potential cytotoxic compound. Using the partial structure of flavokawain B (FKB), about 23 analogs have been synthesized. Among them, compounds 8, 13 and 23 were found in new FKB derivatives. All compounds were evaluated for their cytotoxic properties against two breast cancer cell lines, MCF-7 and MDA-MB-231, thus establishing the structure-activity relationship. The FKB derivatives 16 (IC50 = 6.50 ± 0.40 and 4.12 ± 0.20 μg/mL), 15 (IC50 = 5.50 ± 0.35 and 6.50 ± 1.40 μg/mL) and 13 (IC50 = 7.12 ± 0.80 and 4.04 ± 0.30 μg/mL) exhibited potential cytotoxic effects on the MCF-7 and MDA-MB-231 cell lines. However, the methoxy group substituted in position three and four in compound 2 (IC50 = 8.90 ± 0.60 and 6.80 ± 0.35 μg/mL) and 22 (IC50 = 8.80 ± 0.35 and 14.16 ± 1.10 μg/mL) exhibited good cytotoxicity. The lead compound FKB (1) showed potential cytotoxicity (IC50 = 7.70 ± 0.30 and 5.90 ± 0.30 μg/mL) against two proposed breast cancer cell lines. It is evident that the FKB skeleton is unique for anticancer agents, additionally, the presence of halogens (Cl and F) in position 2 and 3 also improved the cytotoxicity in FKB series. These findings could help to improve the future drug discovery process to treat breast cancer. A molecular dynamics study of active compounds revealed stable interactions within the active site of Janus kinase. The structures of all compounds were determined by ¹H-NMR, EI-MS, IR and UV and X-ray crystallographic spectroscopy techniques.
  9. Long-Term Impact of Multiple Micronutrient Supplementation on Micronutrient Status, Hemoglobin Level, and Growth in Children 24 to 59 Months of Age: A Non-Randomized Community-Based Trial from Pakistan
    Khan A, Ul-Haq Z, Fatima S, Ahmed J, Alobaid HM, Fazid S, et al.
    Nutrients, 2023 Mar 30;15(7).
    PMID: 37049531 DOI: 10.3390/nu15071690
    Cost-effective interventions are needed to address undernutrition, particularly micronutrient deficiencies, which are common in children under the age of five in low- and middle-income countries. A community-based, non-randomized clinical trial was undertaken in the Kurram district of Khyber Pakhtunkhwa from January 2018 to June 2019, to evaluate the effect of locally produced micronutrient powder (local name: Vita-Mixe) on plasma micronutrient status, hemoglobin level, and anthropometric outcomes. Children aged 24-48 months old were recruited and allocated to the intervention and control arm of the study. The enrolled children in the intervention arm received one micronutrient powder (MNP) sachet for consumption on alternate days for 12 months. To assess the impact of the intervention on plasma levels of zinc, vitamin D, vitamin A, and hemoglobin level, blood samples were taken at baseline and after one year following the intervention. The analysis was conducted using Enzyme-Linked Immunosorbent Assay (ELISA), atomic absorption spectrometry, and an automated hematology analyzer. For the impact on growth parameters, the anthropometric assessment was performed using WHO standard guidelines. A 24 h dietary recall interview was used to assess the nutrient intake adequacy. Results showed that in the intervention arm, children had on average a 7.52 ng/mL (95% CI 5.11-9.92, p-value < 0.001) increase in the plasma level of vitamin A, 4.80 ng/mL (95% CI 1.63-7.95, p-value < 0.002) increase in vitamin D levels and 33.85 µg/dL (95% CI 24.40-43.30, p-value < 0.001) increase in the plasma zinc level, as well as a 2.0g/dL (95% CI 1.64-2.40, p-value < 0.001) increase in hemoglobin level. Statistically significant improvement was observed in the weight-for-height z-score (WHZ) (from -1.0 ± 0.88 to -0.40 ± 1.01, p < 0.001) and weight-for-age z-score (WAZ) (from -1.40 ± 0.50 to -1.05 ± 0.49, p < 0.001) in the intervention group compared to the control group. No statistically significant change was observed in the height-for-age z-score (HAZ) in the intervention group (p = 0.93). In conclusion, micronutrient powder supplementation is a cost-effective intervention to improve the micronutrient status, hemoglobin level, and growth parameters in under-five children, which can be scaled up in the existing health system to address the alarming rates of undernutrition in Pakistan and other developing countries.
  10. Fulltext Effectiveness of locally produced ready to use supplementary food on hemoglobin, anthropometrics, and plasma micronutrients concentrations of 6 to 23 months age children: a non-randomized community-based trial from Pakistan
    Khan A, Ul-Haq Z, Fazid S, Fatima S, Muhammad N, Ahmed J, et al.
    Front Nutr, 2023;10:1176778.
    PMID: 37575332 DOI: 10.3389/fnut.2023.1176778
    BACKGROUND: Micronutrient deficiencies including vitamin A, vitamin D, and zinc are highly prevalent in children below 5 years of age in low and -middle-income countries. We aimed to evaluate the effectiveness of ready-to-use Lipid-based Nutrient Supplement-Medium Quantity (LNS-MQ) local name "Wawa-mum" on plasma micronutrient status, hemoglobin concentration and anthropometric measurements.

    METHODS: A community-based non-randomized trial was conducted in the Kurram district of Khyber Pakhtunkhwa from January 2018 to June 2019. A total of 110 children aged 6 to 23 months old were recruited and allocated to the intervention and control arm of the study. A total of 57 children in the intervention arm received a daily ration of 50 g of Wawa-mum, for one year. To assess the impact of the intervention on primary outcome measures, i.e., serum vitamin A, D concentration, plasma zinc, and hemoglobin concentration. Blood samples were collected at baseline and after one year following the intervention. The vitamins concentration in serum were assessed using Enzyme-Linked Immunosorbent Assay (ELISA) and plasma zinc by atomic absorption spectrometry. The hemoglobin concentration was measured by an automated hematology analyzer. A 24-h dietary recall interview was used to assess the nutrient intake adequacy. Multivariate Linear regression models were used to analyze the outcomes while controlling for potential confounders.

    RESULTS: In the intervention arm, children had on average 6.2 μg/dL (95% CI 3.0-9.3, value of p<0.001) increase in the serum vitamin A concentration, 8.1 ng/mL (95% CI 1.3-14.9, value of p 0.02) increase in serum vitamin D concentration and 49.0 μg/dL (95% CI 33.5-64.5, value of p<0.001) increase in the plasma zinc concentration, and 2.7 g/dL (95% CI 2.0-3.3, value of p<0.001) increase in hemoglobin concentration while adjusted for covariates. An addition, length-for-age z-score (LAZ), weight-for-length z-score (WLZ), weight-for-age z-score (WAZ), and prevalence of undernutrition including stunting, wasting, and underweight were calculated as a secondary outcome to investigate the impact of micronutrients on growth parameters, that has been improved significantly after receiving the Wawa-mum.

    CONCLUSION: Wawa-mum (LNS-MQ) is an effective intervention to improve the micronutrient status, hemoglobin concentration, and growth parameters in 6 to 23 months children, which can be scaled up in the existing health system to address the alarming rates of under nutrition in Pakistan and other developing countries.

    CLINICAL TRIAL REGISTRATION: https://doi.org/10.1186/ISRCTN94319790, ISRCTN94319790.

  11. The immunomodulation potential of the synthetic derivatives of benzothiazoles: Implications in immune system disorders through in vitro and in silico studies
    Khan KM, Mesaik MA, Abdalla OM, Rahim F, Soomro S, Halim SA, et al.
    Bioorg Chem, 2016 Feb;64:21-8.
    PMID: 26637945 DOI: 10.1016/j.bioorg.2015.11.004
    Benzothiazole and its natural or synthetic derivatives have been used as precursors for several pharmacological agents for neuroprotective, anti-bacterial, and anti-allergic activities. The objective of the present study was to evaluate effects of benzothiazole analogs (compounds 1-26) for their immunomodulatory activities. Eight compounds (2, 4, 5, 8-10, 12, and 18) showed potent inhibitory activity on PHA-activated peripheral blood mononuclear cells (PBMCs) with IC50 ranging from 3.7 to 11.9 μM compared to that of the standard drug, prednisolone <1.5 μM. Some compounds (2, 4, 8, and 18) were also found to have potent inhibitory activities on the production of IL-2 on PHA/PMA-stimulated PBMCs with IC50 values ranging between <4.0 and 12.8 μM. The binding interaction of these compounds was performed through silico molecular docking. Compounds 2, 8, 9, and 10 significantly suppressed oxidative burst ROS production in phagocytes with IC50 values between <4.0 and 15.2 μM. The lipopolysaccharide (LPS)-induced nitrites in murine macrophages cell line J774 were found to be inhibited by compounds 4, 8, 9, and 18 at a concentration of 25 μg/mL by 56%, 91%, 58%, and 78%, respectively. Furthermore, compounds 5, 8, 12, and 18 showed significant (P<0.05) suppressive activity on Th-2 cytokine, interleukin 4 (IL-4) with an IC50 range of <4.0 to 40.3 μM. Interestingly compound 4 has shown a selective inhibitory activity on IL-2 and T cell proliferation (naïve T cell proliferation stage) rather than on IL-4 cytokine, while compound 12 displayed an interference with T-cell proliferation and IL-4 generation. Moreover compound 8 and 18 exert non-selective inhibition on both IL-2 and IL-4 cytokines, indicating a better interference with stage leading to humoral immune response and hence possible application in autoimmune diseases.
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