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Site-directed mutagenesis of β sesquiphellandrene synthase enhances enzyme promiscuity

Ker DS, Chan KG, Othman R, Hassan M, Ng CL

Phytochemistry, 2020 May;173:112286.
PMID: 32059132 DOI: 10.1016/j.phytochem.2020.112286

The chemical formation of terpenes in nature is carried out by terpene synthases as the main biocatalysts to guide the carbocation intermediate to form structurally diverse compounds including acyclic, mono- and multiple cyclic products. Despite intensive study of the enzyme active site, the mechanism of specific terpene biosynthesis remains unclear. Here we demonstrate that a single mutation of the amino acid L454G or L454A in the active site of Persicaria minor β-sesquiphellandrene synthase leads to a more promiscuous enzyme that is capable of producing additional hydroxylated sesquiterpenes such as sesquicineole, sesquisabinene hydrate and α-bisabolol. Furthermore, the same L454 residue mutation (L454G or L454A) in the active site also improves the protein homogeneity compared to the wild type protein. Taken together, our results demonstrate that residue Leucine 454 in the active site of β-sesquiphellandrene synthase is important for sesquiterpene product diversity as well as the protein homogeneity in solution.
Psychometric Properties of a Theory of Planned Behavior Questionnaire for Assessing the Midwives' Intention to Provide Planned Home Birth Services in Nigeria

Muhammed A, Shariff-Ghazali S, Said SM, Hassan M, Lee K

J Community Health Nurs, 2020 4 3;37(2):77-88.
PMID: 32233947 DOI: 10.1080/07370016.2020.1736377

We developed and psychometrically tested a Theory of Planned Behavior (TPB) questionnaire which focused on assessing the midwives' intention to provide planned home birth (PHB) services. This is a quantitative, cross-sectional survey, conducted among 226 midwives working in ten participating health facilities. The reliability and validity of the theoretical constructs were assessed. The Cronbach's alpha values were >0.8 for all scales, suggesting satisfactory internal consistency. Confirmatory factor analysis revealed sufficient convergent validity (the average variance extracted was >0.5 for each construct) and discriminant validity. The study gathered an evidence of the usefulness of TPB in the specific context of PHB.
Biochar enhanced the nitrifying and denitrifying bacterial communities during the composting of poultry manure and rice straw

Zainudin MH, Mustapha NA, Maeda T, Ramli N, Sakai K, Hassan M

Waste Manag, 2020 Apr 01;106:240-249.
PMID: 32240940 DOI: 10.1016/j.wasman.2020.03.029

Biochar has proven to be a feasible additive for mitigating nitrogen loss during the composting process. This study aims to evaluate the influence of biochar addition on bacterial community and physicochemical properties changes, including ammonium (NH4+), nitrite (NO2-) and nitrate (NO3-) contents during the composting of poultry manure. The composting was carried out by adding 20% (w/w) of biochar into the mixture of poultry manure and rice straw with a ratio of 2:1, and the same treatment without biochar was prepared as a control. The finished product of control compost recorded the high contents of NO2- and NO3- (366 mg/kg and 600 mg/kg) with reduced the total NH4+ content to 10 mg/kg. Meanwhile, biochar compost recorded a higher amount of total NH4+ content (110 mg/kg) with low NO2- and NO3- (161 mg/kg and 137 mg/kg) content in the final composting material. The principal component analysis showed that the dynamics of dominant genera related to Halomonas, Pusillimonas, and Pseudofulvimonas, all of which were known as nitrifying and denitrifying bacteria, was significantly correlated with the dynamic of NO2- and NO3- content throughout the composting process. The genera related to Pusillimonas, and Pseudofulvimonas appeared as the dominant communities as the NO2- and NO3- increased. In contrast, as the NO2- and NO3- concentration decreased, the Halomonas genus were notably enriched in biochar compost. This study revealed the bacterial community shifts corresponded with the change of physicochemical properties, which provides essential information for a better understanding of monitoring and improving the composting process.
Synthesis, molecular docking, dynamic simulations, kinetic mechanism, cytotoxicity evaluation of N-(substituted-phenyl)-4-{(4-[(E)-3-phenyl-2-propenyl]-1-piperazinyl} butanamides as tyrosinase and melanin inhibitors: In vitro, in vivo and in silico approaches

Raza H, Abbasi MA, Aziz-Ur-Rehman, Siddiqui SZ, Hassan M, Abbas Q, et al.

Bioorg Chem, 2020 01;94:103445.
PMID: 31826809 DOI: 10.1016/j.bioorg.2019.103445

In the current research work, different N-(substituted-phenyl)-4-{(4-[(E)-3-phenyl-2-propenyl]-1-piperazinyl}butanamides have been synthesized according to the protocol described in scheme 1. The synthesis was initiated by reacting various substituted anilines (1a-e) with 4-chlorobutanoyl chloride (2) in aqueous basic medium to give various electrophiles, 4-chloro-N-(substituted-phenyl)butanamides (3a-e). These electrophiles were then coupled with 1-[(E)-3-phenyl-2-propenyl]piperazine (4) in polar aprotic medium to attain the targeted N-(substituted-phenyl)-4-{(4-[(E)-3-phenyl-2-propenyl]-1-piperazinyl}butanamides (5a-e). The structures of all derivatives were identified and characterized by proton-nuclear magnetic resonance (1H NMR), carbon-nuclear magnetic resonance (13C NMR) and Infra-Red (IR) spectral data along with CHN analysis. The in vitro inhibitory potential of these butanamides was evaluated against Mushroom tyrosinase, whereby all compounds were found to be biologically active. Among them, 5b exhibited highest inhibitory potential with IC50 value of 0.013 ± 0.001 µM. The same compound 5b was also assayed through in vivo approach, and it was explored that it significantly reduced the pigments in zebrafish. The in silico studies were also in agreement with aforesaid results. Moreover, these molecules were profiled for their cytotoxicity through hemolytic activity, and it was found that except 5e, all other compounds showed minimal toxicity. The compound 5a also exhibited comparable results. Hence, some of these compounds might be worthy candidates for the formulation and development of depigmentation drugs with minimum side effects.
Fulltext Towards health monitoring using remote heart rate measurement using digital camera: A feasibility study

Hassan MA, Malik AS, Fofi D, Karasfi B, Meriaudeau F

Measurement : journal of the International Measurement Confederation, 2020 Jan;149:106804.
PMID: 32287815 DOI: 10.1016/j.measurement.2019.07.032

The paper presents a feasibility study for heart rate measurement using a digital camera to perform health monitoring. The feasibility study investigates the reliability of the state of the art heart rate measuring methods in realistic situations. Therefore, an experiment was designed and carried out on 45 subjects to investigate the effects caused by illumination, motion, skin tone, and distance variance. The experiment was conducted for two main scenarios; human-computer interaction scenario and health monitoring scenario. The human-computer scenario investigated the effects caused by illumination variance, motion variance, and skin tone variance. The health monitoring scenario investigates the feasibility of health monitoring at public spaces (i.e. airports, subways, malls). Five state of the art heart rate measuring methods were re-implemented and tested with the feasibility study database. The results were compared with ground truth to estimate the heart rate measurement error. The heart rate measurement error was analyzed using mean error, standard deviation; root means square error and Pearson correlation coefficient. The findings of this experiment inferred promising results for health monitoring of subjects standing at a distance of 500 cm.
Fulltext Novel Bi-heterocycles as Potent Inhibitors of Urease and Less Cytotoxic Agents: 3-({5-((2-Amino-1,3-thiazol-4-yl)methyl)-1,3,4-oxadiazol-2-yl}sulfanyl)-N-(un/substituted-phenyl)propanamides

Abbasi MA, Ramzan MS, Ur-Rehman A, Siddiqui SZ, Hassan M, Ali Shah SA, et al.

Iran J Pharm Res, 2020;19(1):487-506.
PMID: 32922502 DOI: 10.22037/ijpr.2019.13084.11362

The synthesis of a novel series of bi-heterocyclic propanamides, 7a-l, was accomplished by S-substitution of 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-thiol (3). The synthesis was initiated from ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate (1) which was converted to corresponding hydrazide, 2, by hydrazine hydrate in methanol. The refluxing of hydrazide, 2, with carbon disulfide in basic medium, resulted in 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-thiol (3). A series of electrophiles, 6a-l, was synthesized by stirring un/substituted anilines (4a-l) with 3-bromopropanoyl chloride (5) in a basic aqueous medium. Finally, the targeted compounds, 7a-l, were acquired by stirring 3 with newly synthesized electrophiles, 6a-l, in DMF using LiH as a base and an activator. The structures of these bi-heterocyclic propanamides were confirmed through spectroscopic techniques, such as IR, 1H-NMR, 13C-NMR, and EI-MS. These molecules were tested for their urease inhibitory potential, whereby, the whole series exhibited very promising activity against this enzyme. Their cytotoxic behavior was ascertained through hemolysis and it was observed that all these were less cytotoxic agents. The in-silico molecular docking analysis of these molecules was also in full agreement with their in-vitro enzyme inhibition data.
Ultrasound mediated efficient synthesis of new 4-oxoquinazolin-3(4H)-yl)furan-2-carboxamides as potent tyrosinase inhibitors: Mechanistic approach through chemoinformatics and molecular docking studies

Dige NC, Mahajan PG, Raza H, Hassan M, Vanjare BD, Hong H, et al.

Bioorg Chem, 2019 11;92:103201.
PMID: 31445195 DOI: 10.1016/j.bioorg.2019.103201

We have carried out the synthesis of new 4-oxoquinazolin-3(4H)-yl)furan-2-carboxamide derivatives by the reaction between isatoic anhydride, 2-furoic hydrazide and substituted salicylaldehydes in ethanol: water (5:5 v/v) solvent system using p-TSA as a catalyst under ultrasound irradiation at room temperature. The structures of newly synthesized compounds were confirmed through spectral techniques such as IR, 1H NMR, 13C NMR, and LCMS. The important features of this protocol include simple and easy workup procedure, reaction carried out at ambient temperature, use of ultrasound and high yield of oxoquinazolin-3(4H)-yl)furan-2-carboxamides in short reaction time. The synthesized compounds 4a-4j were screened against tyrosinase enzyme and all these compounds found to be potent inhibitors with much lower IC50 value of 0.028 ± 0.016 to 1.775 ± 0.947 µM than the standard kojic acid (16.832 ± 1.162 µM). The kinetics mechanism for compound 4e was analyzed by Lineweaver-Burk plots which revealed that compound inhibited tyrosinase non-competitively by forming an enzyme-inhibitor complex. Along with this all the synthesized compounds (4a-4j) were scanned for their DPPH free radical scavenging ability. The outputs received through in vitro and in silico analysis are coherent to the each other with good binding energy values (kcal/mol) posed by synthesized ligands.
Designing of promising medicinal scaffolds for Alzheimer's disease through enzyme inhibition, lead optimization, molecular docking and dynamic simulation approaches

Hassan M, Abbasi MA, Aziz-Ur-Rehman, Siddiqui SZ, Shahzadi S, Raza H, et al.

Bioorg Chem, 2019 10;91:103138.
PMID: 31446329 DOI: 10.1016/j.bioorg.2019.103138

In the designed research work, a series of 2-furoyl piperazine based sulfonamide derivatives were synthesized as therapeutic agents to target the Alzheimer's disease. The structures of the newly synthesized compounds were characterized through spectral analysis and their inhibitory potential was evaluated against butyrylcholinesterase (BChE). The cytotoxicity of these sulfonamides was also ascertained through hemolysis of bovine red blood cells. Furthermore, compounds were inspected by Lipinki Rule and their binding profiles against BChE were discerned by molecular docking. The protein fluctuations in docking complexes were recognized by dynamic simulation. From our in vitro and in silico results 5c, 5j and 5k were identified as promising lead compounds for the treatment of targeted disease.
Epidemiology, spectrum of clinical manifestations and diagnostic issue of acquired haemophilia: A case series

Wan Ab Rahman WS, Abdullah WZ, Husin A, Nik Mohd Hassan NFF, Hassan MN, Zulkafli Z

Malays J Pathol, 2019 Aug;41(2):185-189.
PMID: 31427554

INTRODUCTION: Acquired haemophilia A (AHA) is a rare acquired bleeding disorder caused by polyclonal immunoglobulin G autoantibodies against clotting factor VIII (FVIII). The incidence was reported to be rare occurring in 0.2- 4 cases/million/year. Patients may present with different clinical manifestations to various specialties. Early recognition of the disease contributes to favourable clinical outcome.
CASE SERIES: Here, we reported five cases of this disorder with different clinical presentations from two tertiary hospitals in Kelantan state, Malaysia within a two year-period. Most of them were elderly, except for one who presented at the age of 36 years old. No direct or secondary cause was identified except for one patient who had developed from pregnancy-related at 3 weeks postpartum. These patients presented with spontaneous bleeding typically into skin, muscles, and mucous membranes but also at rare site in the epidural space. All patients denied previous history of bleeding or family history of bleeding disorder. FVIII activities were recorded between <1% to 19%, while the inhibitor titre levels were between 3.9 BU to 340 BU. The treatment approaches especially at presentation were complicated by unfamiliarity of managing this rare condition but all these patients received appropriate medical attention.
DISCUSSION: Prompt diagnosis and management in the right hand are critical. Awareness of this disorder by medical personnel at all levels in the community and in various specialties is important.
Predictors of midwives' intention to provide planned home birth services to low-risk women: A theory of planned behaviour approach

Muhammed A, Khuan L, Shariff-Ghazali S, Said SM, Hassan M

Midwifery, 2019 Jun;73:62-68.
PMID: 30884373 DOI: 10.1016/j.midw.2019.03.004

OBJECTIVE: Planned home birth may increase women's access to skilled midwives in all settings. Using theory to understand and predict midwives' intention regarding planned home birth services is rare. Therefore, using the theory of planned behaviour, we determined the factors associated with midwives' intention to provide planned home birth services to low-risk women.
DESIGN: This cross-sectional study adopted a quantitative approach and a survey. Stratified random sampling was used to recruit 226 midwives in Sokoto, Nigeria. Data-including descriptive statistic and multiple linear regression analyses-were analysed using SPSS 23 and significant was set at 0.05.
SETTING: Ten public health facilities in Sokoto, northwestern Nigeria.
PARTICIPANTS: Among all 460 midwives (women aged 20-60 years), working in the maternity wards of health facilities in Sokoto, a sample of 226 midwives was calculated using a power of 0.80 and a 95% confidence interval.
FINDINGS: The multiple linear regression analyses confirmed that the major factors associated with midwives' intention to provide planned home birth services were midwives' attitude towards planned home birth (p < .001) and midwives' previous experience with planned home birth practice (p = .008).
CONCLUSIONS AND IMPLICATIONS: The theory of planned behaviour is a useful framework for identifying factors that affect midwives' intention to provide planned home birth services. While future research may employ a qualitative approach to explore other factors, planned home birth education campaigns should target information that enhances positive attitude and encourages midwives to provide planned home birth services.
Synthesis and structure-activity relationship of tyrosinase inhibiting novel bi-heterocyclic acetamides: Mechanistic insights through enzyme inhibition, kinetics and computational studies

Butt ARS, Abbasi MA, Aziz-Ur-Rehman, Siddiqui SZ, Raza H, Hassan M, et al.

Bioorg Chem, 2019 05;86:459-472.
PMID: 30772647 DOI: 10.1016/j.bioorg.2019.01.036

The present research was designed for the selective synthesis of novel bi-heterocyclic acetamides, 9a-n, and their tyrosinase inhibition to overwhelm the problem of melanogenesis. The structures of newly synthesized compounds were confirmed by spectral techniques such as 1H NMR, 13C NMR, and EI-MS along with elemental analysis. The inhibitory effects of these bi-heterocyclic acetamides (9a-n) were evaluated against tyrosinase and all these molecules were recognized as potent inhibitors relative to the standard used. The Kinetics mechanism was analyzed by Lineweaver-Burk plots which explored that compound, 9h, inhibited tyrosinase competitively by forming an enzyme-inhibitor complex. The inhibition constants Ki calculated from Dixon plots for this compound was 0.0027 µM. The computational study was coherent with the experimental records and these ligands exhibited good binding energy values (kcal/mol). The hemolytic analysis revealed their mild cytotoxicity towards red blood cell membranes and hence, these molecules can be pondered as nontoxic medicinal scaffolds for skin pigmentation and related disorders.
Co-crystallization of a neutral mol-ecule and its zwitterionic tautomer: structure and Hirshfeld surface analysis of 5-methyl-4-(5-methyl-1H-pyrazol-3-yl)-2-phenyl-2,3-di-hydro-1H-pyrazol-3-one 5-methyl-4-(5-methyl-1H-pyrazol-2-ium-3-yl)-3-oxo-2-phenyl-2,3-di-hydro-1H-pyrazol-1-ide monohydrate

Asiri AM, Alzahrani KAH, Faidallah HM, Alamry KA, Jotani MM, Tiekink ERT

Acta Crystallogr E Crystallogr Commun, 2019 May 01;75(Pt 5):565-570.
PMID: 31110787 DOI: 10.1107/S2056989019004389

The title compound, 2C14H14N4O·H2O, comprises a neutral mol-ecule containing a central pyrazol-3-one ring flanked by an N-bound phenyl group and a C-bound 5-methyl-1H-pyrazol-3-yl group (at positions adjacent to the carbonyl substituent), its zwitterionic tautomer, whereby the N-bound proton of the central ring is now resident on the pendant ring, and a water mol-ecule of crystallization. Besides systematic variations in geometric parameters, the two independent organic mol-ecules have broadly similar conformations, as seen in the dihedral angle between the five-membered rings [9.72 (9)° for the neutral mol-ecule and 3.32 (9)° for the zwitterionic tautomer] and in the dihedral angles between the central and pendant five-membered rings [28.19 (8) and 20.96 (8)° (neutral mol-ecule); 11.33 (9) and 11.81 (9)°]. In the crystal, pyrazolyl-N-H⋯O(carbon-yl) and pyrazolium-N-H⋯N(pyrazol-yl) hydrogen bonds between the independent organic mol-ecules give rise to non-symmetric nine-membered {⋯HNNH⋯NC3O} and {⋯HNN⋯HNC3O} synthons, which differ in the positions of the N-bound H atoms. These aggregates are connected into a supra-molecular layer in the bc plane by water-O-H⋯N(pyrazolide), water-O-H⋯O(carbon-yl) and pyrazolyl-N-H⋯O(water) hydrogen bonding. The layers are linked into a three-dimensional architecture by methyl-C-H⋯π(phen-yl) inter-actions. The different inter-actions, in particular the weaker contacts, formed by the organic mol-ecules are clearly evident in the calculated Hirshfeld surfaces, and the calculated electrostatic potentials differentiate the tautomers.
Synthesis and structure-activity relationship of elastase inhibiting novel ethylated thiazole-triazole acetamide hybrids: Mechanistic insights through kinetics and computational contemplations

Butt ARS, Abbasi MA, Aziz-Ur-Rehman, Siddiqui SZ, Hassan M, Raza H, et al.

Bioorg Chem, 2019 05;86:197-209.
PMID: 30711702 DOI: 10.1016/j.bioorg.2019.01.040

Keeping in mind the pharmacological importance of 2-aminothiazole and 1,2,4-triazole heterocyclic moieties, a series of novel ethylated bi-heterocyclic acetamide hybrids, 9a-p, was synthesized in a multi-step protocol. The structures of newly synthesized compounds were characterized by 1H NMR, 13C NMR, IR and EI-MS spectral studies. The inhibitory effects of these bi-heterocyclic acetamides (9a-n) were evaluated against elastase and all these molecules were identified as potent inhibitors relative to the standard used. The Kinetics mechanism was analyzed by Lineweaver-Burk plots which revealed that, 9h, inhibited elastase competitively by forming an enzyme-inhibitor complex. The inhibition constants Ki calculated from Dixon plots for this compound was 0.9 µM. The computational study was articulate with the experimental results and these ligands unveiled good binding energy values (kcal/mol). So, these molecules can be considered as promising medicinal scaffolds for the treatment of skin melanoma, wrinkle formation, uneven pigmentation, and solar elastosis.
Severe anti-D haemolytic disease of fetal and newborn in rhesus D negative primigravida

Hassan MZ, Iberahim S, Abdul Rahman WSW, Zulkafli Z, Bahar R, Ramli M, et al.

Malays J Pathol, 2019 Apr;41(1):55-58.
PMID: 31025639

INTRODUCTION: Anti-D alloimmunisation may occur from the blood transfusion or fetomaternal haemorrhage which can lead to haemolytic disease of fetal and newborn (HDFN). The morbidity and mortality of HDFN related to anti-D is significantly reduced after introduction of anti-D prophylaxis and furthermore, anti-D HDFN in RhD negative primigravida is uncommonly seen.
CASE REPORT: A case of unusual severe HDFN due to anti-D alloimmunisation in undiagnosed RhD negative primigravida Malay woman is reported here. This case illustrates the possibility of an anamnestic response from previous unknown sensitisation event or the development of anti-D in mid trimester. The newborn expired due to hydrops fetalis and severe anaemia. Antenatally, the mother was identified as RhD positive and thus there was no antenatal antibody screening, antepartum anti-D prophylaxis or close fetal monitoring for HDFN.
DISCUSSION: The thorough antenatal ABO and RhD blood grouping with antibody screening is mandatory as part of prevention and early detection of HDFN especially due to anti-D alloimmunisation. Improper management of RhD negative women might lead to severe HDFN including in primigravida.
Bi-heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches

Abbasi MA, Nazir M, Ur-Rehman A, Siddiqui SZ, Hassan M, Raza H, et al.

Arch Pharm (Weinheim), 2019 Mar;352(3):e1800278.
PMID: 30624805 DOI: 10.1002/ardp.201800278

Novel bi-heterocyclic benzamides were synthesized by sequentially converting 4-(1H-indol-3-yl)butanoic acid (1) into ethyl 4-(1H-indol-3-yl)butanoate (2), 4-(1H-indol-3-yl)butanohydrazide (3), and a nucleophilic 5-[3-(1H-indol-3-yl)propyl]-1,3,4-oxadiazole-2-thiol (4). In a parallel series of reactions, various electrophiles were synthesized by reacting substituted anilines (5a-k) with 4-(chloromethyl)benzoylchloride (6) to afford 4-(chloromethyl)-N-(substituted-phenyl)benzamides (7a-k). Finally, the nucleophilic substitution reaction of 4 was carried out with newly synthesized electrophiles, 7a-k, to acquire the targeted bi-heterocyclic benzamides, 8a-k. The structural confirmation of all the synthesized compounds was done by IR, 1 H NMR, 13 C NMR, EI-MS, and CHN analysis data. The inhibitory effects of these bi-heterocyclic benzamides (8a-k) were evaluated against alkaline phosphatase, and all these molecules were identified as potent inhibitors relative to the standard used. The kinetics mechanism was ascribed by evaluating the Lineweaver-Burk plots, which revealed that compound 8b inhibited alkaline phosphatase non-competitively to form an enzyme-inhibitor complex. The inhibition constant Ki calculated from Dixon plots for this compound was 1.15 μM. The computational study was in full agreement with the experimental records and these ligands exhibited good binding energy values. These molecules also exhibited mild cytotoxicity toward red blood cell membranes when analyzed through hemolysis. So, these molecules might be deliberated as nontoxic medicinal scaffolds to render normal calcification of bones and teeth.
Synthesis of novel N-(1,3-thiazol-2-yl)benzamide clubbed oxadiazole scaffolds: Urease inhibition, Lipinski rule and molecular docking analyses

Athar Abbasi M, Raza H, Aziz-Ur-Rehman, Zahra Siddiqui S, Adnan Ali Shah S, Hassan M, et al.

Bioorg Chem, 2019 03;83:63-75.
PMID: 30342387 DOI: 10.1016/j.bioorg.2018.10.018

Present work aimed to synthesize some unique bi-heterocyclic benzamides as lead compounds for the in vitro inhibition of urease enzyme, followed by in silico studies. These targeted benzamides were synthesized in good yields through a multi-step protocol and their structures were confirmed by IR, 1H NMR, 13C NMR, EI-MS and elemental analysis. The in vitro screening results showed that most of the ligands exhibited good inhibitory potentials against the urease. Chemo-informatics analysis envisaged that all these compounds obeyed the Lipinski's rule. Molecular docking results showed that 7h exhibited good binding energy value (-8.40 kcal/mol) and was bound within the active region of urease enzyme. From the present investigation, it was inferred that some of these potent urease inhibitors might serve as novel templates in drug designing.
Synthesis, Antioxidant and In-Silico Studies of Potent Urease Inhibitors: N-(4-{[(4-Methoxyphenethyl)-(substituted)amino]sulfonyl}phenyl)acetamides

Abbasi MA, Raza H, Rehman AU, Siddiqui SZ, Nazir M, Mumtaz A, et al.

Drug Res (Stuttg), 2019 Feb;69(2):111-120.
PMID: 30086567 DOI: 10.1055/a-0654-5074

In this study, a new series of sulfonamides derivatives was synthesized and their inhibitory effects on DPPH and jack bean urease were evaluated. The in silico studies were also applied to ascertain the interactions of these molecules with active site of the enzyme. Synthesis was initiated by the nucleophilic substitution reaction of 2-(4-methoxyphenyl)-1-ethanamine (1: ) with 4-(acetylamino)benzenesulfonyl chloride (2): in aqueous sodium carbonate at pH 9. Precipitates collected were washed and dried to obtain the parent molecule, N-(4-{[(4-methoxyphenethyl)amino]sulfonyl}phenyl)acetamide (3): . Then, this parent was reacted with different alkyl/aralkyl halides, (4A-M: ), using dimethylformamide (DMF) as solvent and LiH as an activator to produce a series of new N-(4-{[(4-methoxyphenethyl)-(substituted)amino]sulfonyl}phenyl)acetamides (5A-M: ). All the synthesized compounds were characterized by IR, EI-MS, 1H-NMR, 13C-NMR and CHN analysis data. All of the synthesized compounds showed higher urease inhibitory activity than the standard thiourea. The compound 5 F: exhibited very excellent enzyme inhibitory activity with IC50 value of 0.0171±0.0070 µM relative to standard thiourea having IC50 value of 4.7455±0.0546 µM. Molecular docking studies suggested that ligands have good binding energy values and bind within the active region of taget protein. Chemo-informatics properties were evaluated by computational approaches and it was found that synthesized compounds mostly obeyed the Lipinski' rule.
Proteomics as a tool for tapping potential of entomopathogens as microbial insecticides

Harith Fadzilah N, Abdul-Ghani I, Hassan M

Arch Insect Biochem Physiol, 2019 Jan;100(1):e21520.
PMID: 30426561 DOI: 10.1002/arch.21520

Biopesticides are collective pest control harnessing the knowledge of the target pest and its natural enemies that minimize the risks of synthetic pesticides. A subset of biopesticides; bioinsecticides, are specifically used in controlling insect pests. Entomopathogens (EPMs) are micro-organisms sought after as subject for bioinsecticide development. However, lack of understanding of EPM mechanism of toxicity and pathogenicity slowed the progress of bioinsecticide development. Proteomics is a useful tool in elucidating the interaction of entomopathogenic fungi, entomopathogenic bacteria, and entomopathogenic virus with their target host. Collectively, proteomics shed light onto insect host response to EPM infection, mechanism of action of EPM's toxic proteins and secondary metabolites besides characterizing secreted and membrane-bound proteins of EPM that more precisely describe relevant proteins for host recognition and mediating pathogenesis. However, proteomics requires optimized protein extraction methods to maximize the number of proteins for analysis and availability of organism's genome for a more precise protein identification.
Fulltext Synthesis and exploration of a novel chlorobenzylated 2-aminothiazole-phenyltriazole hybrid as migratory inhibitor of B16F10 in melanoma cells

Athar Abbasi M, Yu SM, Aziz-Ur-Rehman, Siddiqui SZ, Kim SJ, Raza H, et al.

Toxicol Rep, 2019;6:897-903.
PMID: 31516842 DOI: 10.1016/j.toxrep.2019.08.016

In the study presented here, a novel chlorobenzylated bi-heterocyclic hybrid molecule (7) was synthesized and its structural confirmation was carried out by IR, 1H-NMR, 13C-NMR and CHN analysis data. This compound 7 was subjected to biological study with B16F10 mouse melanoma cells. The anti-proliferative results showed that 7 showed no significant toxicity at concentrations ranging of 0-44 μM. The treatment of B16F10 cells with 7 at aforementioned concentration range indicated that migration of cells was significantly lower than that of the control cells in a dose dependent manner. The possible migration inhibitory effect of these melanoma cells was further evaluated through gelatinolytic activity of MMP-2 and MMP-9 secreted from B16F10 cells. It was inferred from our results that 7 was not affecting the expression and activity of these enzymes. Some other zinc-dependent matrix metalloproteinases (MMPs) were involved in the inhibitory progression. Taken together, compound 7 inhibited migrations of B16F10 mouse melanoma cells. Therefore, it may deserve consideration as a potential agent for the treatment of cancer.
Fulltext Dexibuprofen amide derivatives as potential anticancer agents: synthesis, in silico docking, bioevaluation, and molecular dynamic simulation

Ashraf Z, Mahmood T, Hassan M, Afzal S, Rafique H, Afzal K, et al.

Drug Des Devel Ther, 2019;13:1643-1657.
PMID: 31190743 DOI: 10.2147/DDDT.S178595

BACKGROUND: The amide derivatives of nonsteroidal anti-inflammatory drugs have been reported to possess antitumor activity. The present work describes the synthesis of dexibuprofen amide analogues (4a-j) as potential anticancer agents.
METHODS: The title amides (4a-j) were obtained by simple nucleophilic substitution reaction of dexibuprofen acid chloride with substituted amines in good yield and chemical structures were confirmed by FTIR, 1H NMR, 13C NMR and mass spectral data.
RESULTS: The brine shrimp lethality assay results showed that all of the synthesized compounds are non-toxic to shrimp larvae. The inhibitory effects on tumor growth were evaluated and it was observed that N-(2,5-dichlorophenyl)-2-(4-isobutylphenyl) propionamide (4e) and N-(2-chlorophenyl)-2-(4-isobutylphenyl) propionamide (4g) exhibited excellent antitumor activity compared to all other derivatives. The compound 4e bearing 2,5-dichloro substituted phenyl ring and 4g possesses 2-chloro substituted phenyl ring exhibited 100% inhibition of the tumor growth. The anticancer activity was evaluated against breast carcinoma cell line (MCF-7) and it was observed that derivative 4e exhibited excellent growth inhibition of cancer cells with IC50 value of 0.01±0.002 µm, which is better than the standard drugs. The docking studies against breast cancer type 1 susceptibility protein BRCA1 (PDBID 3K0H) exhibited good binding affinities, which are in good agreement with the wet lab results. The compounds 4e and 4g showed the binding energy values of -6.39 and -6.34 Kcal/mol, respectively. The molecular dynamic (MD) simulation was also carried out to evaluate the residual flexibility of the best docking complexes of compounds 4e and 4g. The MD simulation analysis assured that the 4e formed a more stable complex with the target protein than the 4g. The synthesized amide derivatives exhibited were devoid of gastrointestinal side effects and no cytotoxic effects against human normal epithelial breast cell line (MCF-12A) were found.
CONCLUSION: Based upon our wet lab and dry lab findings we propose that dexibuprofen analogue 4e may serve as a lead structure for the design of more potent anticancer drugs.

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