Synthesis, Spectral Characterization and Anticonvulsant Studies of the Novel Triazolothiadiazoles Bearing Benzoxazole Moiety

Introduction

Epilepsy is a disorder of neurological ailment portrayed by the occasional, unusual and hypersynchronous release of numbers of neurons that influencepersons of all ages^1-2.It is the acts of abrupt qualitative and quantitative unsettling influences of consciousness, and of sensor, autonomic and motor function and is the second most predominant neurological scatter inthe industrial world³. In worldwide battle, World Health Organization (WHO) targeting epilepsy by the organization with the International Bureau for Epilepsy (IBE) plus International League Against Epilepsy (ILAE) roughly about 0.5-1% to the general populace will be affected, whenever is harrowed with this neurological disorder⁴. Each year nearly 2.5 million new cases are added to these numbers^4-7. Some of the at present accessible dynamic medications,(for example, stiripentol, pregabalin, tiagabine, zonisamide, lamotrigine, topiramate, levetiracetam) have demonstrated to be convincing in diminishing seizure, whilst their therapeutic viability is overwhelmed by some negative side effects like nausea, hepatotoxicity, ataxia, anxiety, anorexia, drowsiness, hirsutism and gastrointestinal ailments lessen their therapeutic efficacy since they have not been directly connected with a particular receptor inside the brain⁸.It is too hard to even think about identifying regular pharmacophore liable for anticipation or capture of seizure action mostly on account of the variety of organic molecules and mode of action in regulating the seizures⁴. In addition, about 30% of patients have uncontrolled seizures^8,9. Hence, the quest for antiepileptic compounds with a progressively particular action and least toxicity keeps on being a region of investigation in medicinal chemistry^10,11. In any investigation three strategies are utilized for this purpose¹², first- screening of recently synthesized chemicals with various structure and obscure system of activity; second- structure varieties of notable antiepileptic drugs; third-discerning medication plan with the advancement of medications that are specifically combined for following up on track epileptogenic component^13,14. From the past investigations it was indicated that anticonvulsant activities have been appeared by various triazoles and thiadiazoles. The prime necessity was to look through the molecule that could have a combination of both the structures. This time initiates the synthesis of the fused triazolo-thiadiazole core. Literature study exposes that no attentive idea for antiepileptic action of the fused triazolo-thiadiazoles.

Thus, that was supposed to prepare andassimilate a fusion of 1,2,4-triazolo-1,3,4-thiadiazoles as the basic nucleus got together with substituted benzoxazole moiety within a solitary casing. This kind of assemblage is lead to better lipophilic nature with favorable anticonvulsant properties.Fused derivatives of triazolo-thiadiazole had been located for miscellaneous biological action take the instance of, anti-inflammatory^15-17, antimicrobial^18,19 and anticancer^20,21.Substituted triazolo-thiadiazoles is an instance of the heterocyclic compound of different biological behavior is seen as one of the novel modules of anticonvulsants as discovered in a review of literatures²². Our point was to check for a potential anticonvulsant action of the recently synthetized fused triazolo-thiadiazole nucleus.

Materials and Methods

Chemistry

All the substances and solvents employed throughout synthesis provided from CDS, SD Fine chemicals (India) and Merck. On a digital melting point apparatus, the melting point was resolved and is uncorrected. All the chemical reactions were checked by TLC performed on aluminiumsheets precoated with silica gel G (Merck, India) by using the appropriate solvent systems. By using, (BIO-RAD FTS), FT-IR spectrophotometer the IR spectra are registeredviaKBr optics. ¹H-NMR spectra proved with DRX-300 NMR spectrometer and BRUKER 400 Ultra Shield^TM and chemical changes (δ) in ppm in DMSO-d₆/CDCl₃ comparative to tetramethylsilane (TMS).The spectra of mass were found through the UPLC-MS / MS spectrometer (WATERS, version 4.1 of Mass Lynx).  Utilizing Perkin-Elmer model 240 analyzer for elemental analysisand all investigation were reliable within ± 0.4%. The spots of TLC visualized under UV light and Iodine chamber.

Synthesis

Synthesis of benzoxazole carboxylate

A combination of α-bromo phenylacetic acid andmethyl-3-amino-4-hydroxybenzoate (0.01mol) refluxed about 15 hrs. Then reaction mixtures poured, cooled over the squashed ice by mixing for acquire the compounds^8,10.

Synthesis of compound (1)

In absolute ethanol, an equimolar quantity of a mixture of hydrazine hydrate and methyl 2-[bromo(phenyl)methyl]-1,3-benzoxazole-5-carboxylate was heated under the reflux (18-20 hrs). The obtained compound was cooled, the solid precipitate was filtered and recrystallized by using ethanol^8,10.

Synthesis of compound (2)

An equimolar number of compound (1) and carbon disulfide were stirred at room temperature for 10-12 h in presence of 25 ml alcoholic potassium hydroxide solution. The resulting mixture were cooled and condensed to ice. Separated potassium dithiocarbazinate washed with ether, and dried²².

Synthesis of compound (3)

The hydrazine hydrate (0.04 mol) and compound (2) (0.02 mol) in water (50 mL) remained refluxed for about 10-15 hrs through random pulsation. The shade to the resulting blend altered into light green per advancement from hydrogen sulfide gas. A consistent combination acquired during the progression of reaction.The resulting mixture cooled to normal temperature then diluted by using cold water (20 mL).Upon acidification with dil. HCl, a whitish precipitate was obtained, which was filtered and rinsed with cooled water and dried²².

General method used to prepare compounds (4a-o)

In a combination of substituted aromatic acids and compound(3) (0.01 mol) phosphorous oxychloride (10 mL) was applied and refluxed for nearly five hours. Once the reaction was completed it was poured drop by dropinto the chilled water, alkalified with aq. ammonia, which was filtered and crystallized with ethanol to achieve compound (4a).

The other compounds (4b-o) have been synthesized by the same methods²².

Compound (4a)

IR (KBr, cm^-1): 3001 (C-H aromatic), 1609 (C=N), 1478 (C-N), 1227 (N-N=C), 711 (C-S-C), 522 (C-Br).¹H-NMR (DMSO-_d6, δ, ppm): 7.51-8.17 (13H, m, Ar-H), 6.33 (1H, s, CHBr). Anal calc. for C₂₃H₁₄BrN₅OS:C, 56.78; H, 3.021; N, 14.18. Found: C, 56.57; H, 2.85; N, 14.34.

Compound (4b)

IR (KBr, cm^-1): 3008 (C-H aromatic), 1611 (C=N), 1471 (C-N), 1234 (N-N=C), 705 (C-S-C), 525 (C-Br). ¹H-NMR (DMSO- _d6, δ, ppm): 7.22-8.09 (12H, m, Ar-H), 6.33 (1H, s, CHBr), 2.86 (3H, s, CH₃). Anal. calc. for C₂₄H₁₆BrN₅OS: C, 56.99; H, 3.12; N, 13.62. Found: C, 57.38; H, 3.21; N, 13.94.

Compound (4c)

IR (KBr, cm^-1): 3034 (C-H aromatic), 1601 (C=N), 1499 (C-N), 1225 (N-N=C), 710 (C-S-C), 529 (C-Br). ¹H-NMR (DMSO- _d6, δ, ppm): 7.19-8.11 (12H, m, Ar-H), 6.27 (1H, s, CHBr), 2.57 (3H, s, CH₃). Anal. Calc. for C₂₄H₁₆BrN₅OS: C, 56.99; H, 3.12; N, 13.62. Found: C, 57.38; H, 3.21; N, 13.94.

Compound (4d)

IR (KBr, cm^-1): 3022 (C-H aromatic), 1613 (C=N), 1482 (C-N), 1221 (N-N=C), 717 (C-S-C), 545 (C-Br). ¹H-NMR (DMSO- _d6, δ, ppm): 7.26-8.14 (12H, m, Ar-H), 6.34 (1H, s, CHBr), 2.46(3H, s, CH₃). Anal. calc. for C₂₄H₁₆BrN₅OS: C, 56.99; H, 3.12; N, 13.62. Found: C, 57.38; H, 3.21; N, 13.94.

Compound (4e)

IR (KBr, cm^-1): 3078 (C-H aromatic), 1622 (C=N), 1512 (C-N), 1201 (N-N=C), 711 (C-S-C). 544 (C-Br). ¹H-NMR (DMSO- _d6, δ, ppm): 7.27-8.21 (12H, m, Ar-H), 6.56 (1H, s, CHBr), 4.56 (2H, s, CH₂Br).Mass m/z: 579.940 (M+1). Anal. calc. for C₂₄H₁₅Br₂N₅OS: C, 49.79; H, 2.44; N, 12.36. Found: C, 49.59; H, 2.60; N, 12.05.

Compound (4f)

IR (KBr, cm^-1): 3033 (C-H aromatic), 1611 (C=N), 1480 (C-N), 1227 (N-N=C), 711 (C-S-C), 522 (C-Br). ¹H-NMR (DMSO- _d6, δ, ppm): 7.03-8.11 (12H, m, Ar-H), 6.32 (1H, s, CHBr), 3.86 (3H, s, OCH₃).Anal. calc.for C₂₄H₁₆BrN₅O₂S: C, 55.83; H, 3.01; N, 13.48. Found: C, 55.61; H, 3.11; N, 13.51.

Compound (4g)

IR (KBr, cm^-1): 3036 (C-H aromatic), 1591 (C=N), 1478 (C-N), 1239 (N-N=C), 717 (C-S-C), 523 (C-Br), ¹H-NMR (DMSO- _d6, δ, ppm): 6.93-8.09 (13H, m, Ar-H), 6.22 (1H, s, CHBr). 5.06 (2H, s, OCH₂). Mass m/z:518.029 (M+1). Anal. calc. for C₂₄H₁₆BrN₅O₂S: C, 55.85; H, 3.43; N, 13.67. Found: C, 55.61; H, 3.11; N, 13.51.

Compound (4h)

IR (KBr, cm^-1): 3065 (C-H aromatic), 1733 (C=O), 1611 (C=N), 1489 (C-N), 1223 (N-N=C), 711 (C-S-C), 520 (C-Br). ¹H-NMR (DMSO- _d6, δ, ppm): 10.11 (1H, s, CHO), 7.12-8.08 (12H, m, Ar-H), 6.32(1H, s, CHBr), 5.24 (2H, s, OCH₂). Mass m/z: 546.022 (M+1). Anal. calc. for C₂₅H₁₆BrN₅O₃S: C, 54.44; H, 3.08; N, 12.99. Found: C, 54.95; H, 2.95; N, 12.82.

Compound (4i)

IR (KBr, cm^-1): 3033 (C-H aromatic), 1738 (C=O), 1623 (C=N), 1490 (C-N), 1223 (N-N=C), 692 (C-S-C), 524 (C-Br). ¹H-NMR (DMSO- _d6, δ, ppm): 10.03 (1H, s, CHO), 7.36-8.08 (12H, m, Ar-H), 6.44 (1H, s, CHBr). Mass m/z:516.012 (M+1). Anal. calc. for C₂₄H₁₄BrN₅O₂S: C, 55.41; H, 2.38; N, 13.25. Found: C, 55.82; H, 2.73; N, 13.56.

Compound (4j)

IR (KBr, cm^-1): 3020 (C-H aromatic), 1611 (C=N), 1498 (C-N), 1256 (N-N=C), 698 (C-S-C), 557 (C-Br). ¹H-NMR (DMSO- _d6, δ, ppm): 9.26 (1H, s, pyridine), 7.48-8.79 (11H, m, Ar-H), 6.55 (1H, s, CHBr).Anal. calc.for C₂₂H₁₃BrN₆OS: C, 54.13; H, 3.01; N, 17.32. Found: C, 54.00; H, 2.68; N, 17.17.

Compound (4k)

IR (KBr, cm^-1): 3037 (C-H aromatic), 1601 (C=N), 1484 (C-N), 1244, (N-N=C), 700 (C-S-C), 514 (C-Br). ¹H-NMR (DMSO- _d6, δ, ppm):7.21-8.14 (13H, m, Ar-H), 6.11 (1H, s, CHBr), 3.77(2H, s, CH₂). Anal. calc. for C₂₄H₁₆BrN₅OS: C, 57.10; H, 3.15; N, 13.80. Found: C, 57.38; H, 3.21; N, 13.94.

Compound (4l)

IR (KBr, cm^-1): 3061 (C-H aromatic), 1636 (C=N), 1491 (C-N), 1241 (N-N=C), 733 (C-Cl), 711 (C-S-C), 533 (C-Br). ¹H-NMR (DMSO- _d6, δ, ppm):7.16-8.11 (12H, m, Ar-H), 6.46 (1H, s, CHBr), 2.81 (2H, s, CH₂). Anal. calc. for C₂₄H₁₅BrClN₅OS: C, 53.65; H, 3.01; N, 13.44. Found: C, 53.70; H, 2.82; N, 13.05.

Compound (4m)

IR (KBr, cm^-1): 3075 (C-H aromatic), 1612 (C=N), 1512 (C-N), 1255 (N-N=C), 710 (C-S-C), 566 (C-Br). ¹H-NMR (DMSO- _d6, δ, ppm): 7.03-8.08 (12H, m, Ar-H), 6.21 (1H, s, CHBr), 3.77 (2H, s, CH₂). Anal. calc. for C₂₄H₁₅Br₂N₅OS: C, 49.11; H, 2.13; N, 12.40. Found: C, 49.59; H, 2.60; N, 12.05.

Compound (4n)

IR (KBr, cm^-1): 3048 (C-H aromatic), 1633 (C=N), 1510 (C-N), 1234 (N-N=C), 711 (C-S-C), 531 (C-Br). ¹H-NMR (DMSO- _d6, δ, ppm):7.21-8.21 (13H, m, Ar-H), 6.36 (2H, s, 2×CHBr). Anal. calc. for C₂₄H₁₅Br₂N₅OS: C, 50.00; H, 2.13; N, 12.32. Found: C, 49.59; H, 2.60; N, 12.05.

Compound (4o)

IR (KBr, cm^-1): 3576 (OH), 2998 (C-H aromatic), 1608 (C=N), 1490 (C-N), 1235 (N-N=C), 701 (C-S-C), 534 (C-Br). ¹H-NMR (DMSO- _d6, δ, ppm): 10.78 (3H, s, 3×OH), 6.86-8.98 (10H,m, Ar-H), 6.33 (1H, s, CHBr).Anal. calc. for C₂₃H₁₄BrN₅O₄S: C, 51.34; H, 2.44; N, 14.83. Found: C, 51.50; H, 2.63; N, 14.90.

Biological Activity

Anticonvulsant Screening

Each of those compounds were tested using scPTZ and MES methods for their antiepileptic behavior, as demonstrated by the National Institute of Anticonvulsant Screening Program^23-24.Compounds were suspended in polyethylene glycol and tested by the Institutional Animal Ethics Committee, R.V.Northland College, Dadri, Greater Noida, Uttar Pradesh, India, under the RVNI/IAEC/2017/05proposal number. Finding rata are listed in Table 2.

Maximum Electroshock (MES)Test

Mice received a 50-mA 60 Hz ac voltage for 0.2s via ear pins, and the responses were analyzed at 0.5 and 4.0 hrs after an i.p. injection of the product(30, 100, and 300 mg/kg).Consequently, protection against seizure was noted²².

Pentylenetetrazole Test

Intra peritoneal at 75 mg/kg scPTZ was injected which produces seizures in the mice. The dose of test analogs was found to the animals for 30 min later. Defense against clonic spasm was described as protection against the spread of seizures of at least 5 s duration^22,23.

Neurotoxicity Test

The neurological intervention was shown on the mice using rotarod method^21,22.The tested micefailure to manage equilibrium during at least one minute for two successive studies on a continuously circulating plastic rod (10 rpm) with a diameter of 2.3 cm proposed motor dysfunction.

Lipophilic/Hydrophobic identification

Lipophilic character regulates the efficacy of synthesized compounds working on the brain, determined by established procedure²⁵. It was found that the highest efficacy of the compounds acting in the central nervous systemis achieved by congeners possessingideal lipophilicity (logP) close to two and was determined using chloroform phosphate with the measured logP value²⁶.

Results and Discussion

Scheme 1 details the synthetic route used to synthesize title compounds. Methyl-2-[bromo(phenyl)methyl]-1,3-benzoxazole-5-carboxylate and its hydrazide was produced by the reaction of methyl-4-hydroxy benzoate and a mixture of aluminum nitrate, acetic anhydride, 2- bromo-2-phenylacetic acid and hydrazine hydrate⁴. In the presence of potassium hydroxide, the acid hydrazide (1) reacted with carbon disulfide to provide potassium 2-[2-(3-chlorophenyl)-1,3- benzoxazol-5-yl] carbonyl hydrazine dithiocarbonate (2). This salt was cyclized to give 4-amino- 5-[2-(3-chlorophenyl)- 1,3-benzoxazol-5-yl}-4H-1,2,4-triazole-3-thiol (3) by an excess of hydrazine hydrate. In the presence of phosphorous oxychloride, the resulting triazole was further converted to titled compounds by condensing with specific aromatic acids by one-pot reaction. In all cases the product’s TLC revealed single spot that verified the chromatogram. The physical constants record in Table 1. Structure (3) was verified through results from ¹H-NMR, displayed a singlet downfield attributed to the -SH group at around 13.85 ppm and amino group seemed as a singlet at about 5.63 ppm, respectively. Lack of peak of amino and -SH indicates, triazole was changed into titled compounds (4a-n) by retorting with the aromatic acid moiety -COOH.The structure of prepared compounds distinguished through elemental analysis and spectral data information were noted to experimental protocols.

Scheme 1: Synthesis of fused triazolo thiadiazoles. Click here to View scheme

Table 1: Physical constants of the synthesized molecules (4a-o).

S.No.	R	Mol. Formula	bM.P (°C)	cLogP	Yield (%)	dRf Value
4a	C6H5	C23H14BrN5OS	130-132	0.84	67	0.80
4b	2-CH3C6H4	C24H16BrN5OS	145-147	0.84	67	0.80
4c	3-CH3C6H4	C24H16BrN5OS	150-152	0.85	56	0.81
4d	4-CH3C6H4	C24H16BrN5OS	145-147	0.99	55	0.61
4e	4-BrCH2C6H4	C24H15Br2N5OS	160-152	2.54	45	0.70
4f	4-OCH3C6H4	C24H16BrN5O2S	150-152	0.56	40	0.70
4g	C6H5OCH2	C24H16BrN5O2S	155-156	1.87	77	0.75
4h	4-CHOC6H4OCH2	C25H16BrN5O3S	160-162	1.11	45	0.80
4i	4-CHOC6H4	C24H14BrN5O2S	150-152	1.03	67	0.63
4j	C5H4N	C22H13BrN6OS	180-181	2.32	66	0.60
4k	C6H5CH2	C24H16BrN5OS	140-142	0.94	70	0.82
4l	4-ClC6H4CH2	C24H15BrClN5OS	175-176	2.02	71	0.81
4m	4-BrC6H4CH2	C24H15Br2N5OS	155-157	2.36	39	0.62
4n	C6H5CHBr	C24H15Br2N5OS	165-167	2.41	45	0.51
4o	3,4,5-tri OHC6H2	C23H14BrN5O4S	160-161	1.14	70	0.66

Solvent of crystallization — ethanol.

Moleculesmelted during the decomposition process.

LogP was calculated at 30 °C via chloroform/phosphate buffer method.

Solvent system — benzene: acetone (8: 2, v/v), benzene: ethanol (2 :0.5, v/v), toluene: ethylacetate: formic acid (5: 4: 1, v/v/v).

Newly synthesized compounds (4a-o) were subjected to anticonvulsant activity, according to the standard protocol established by the division of epilepsy which requires the maximum electroshock seizure⁸ and the subcutaneous pentylenetetrazole⁹. In addition, the rotarod test can almost always detect acute toxicity of antiepileptic drugs in rodents¹¹. Data are provided in Table 2. Standard drugs used for the analysis were phenytoin and carbamazepine.

Table 2: Anticonvulsant and neurotoxicity studies of compounds (4a-o).

Compound (n=4)	i.p.injection in mice				Neurotoxicity screening
	(MES screen)		(scPTZscreen)
	0.5h	4h	0.5h	4h	0.5h	4h
4a	‒	‒	‒	‒	×	×
4b	300	‒	‒	‒	‒	300
4c	300	‒	‒	‒	×	×
4d	300	‒	‒	300	300	‒
4e	30	300	300	300	300	‒
4f	‒	‒	‒	‒	‒	300
4g	100	300	300	‒	300	‒
4h	300	300	‒	‒	‒	‒
4i	300	‒	‒	‒	×	×
4j	30	300	300	300	‒	300
4k	‒	‒	‒	‒	×	×
4l	100	300	300	‒	‒	‒
4m	30	300	300	‒	‒	300
4n	30	300	300	‒	300	‒
4o	300	‒	‒	‒	‒	‒
Phenytoin	30	30	‒	‒	100	100
Carbamazepine	30	100	100	300	300	300

Mice was given doses of 30, 100, and 300 mg/kg via intraperitoneal path. The table describes the average dose at which therapeutic efficacy were detected in half or more of the mice. The animals were detected at 0.5 and 4.0 hours after obtaining the treatment. The dash (‒) depicts the omission of effect at optimal dosage, while the cross (×) denotes not screened. Propylene glycol (0.1 ml, i.p.) was used as control solvent.

Data from reference^22-24.

In the anticonvulsant screening, each compound except 4a, 4f and 4k suggested motivating intervention. Compounds 4e, 4j, 4m and 4n believed to be positively competitive towards MES testing at 30 mg/kg dosage at interval of 0.5 h which is characteristic of its desire to stop seizing progression at a usually reduced dose. At a dose of 100 mg/kg only two molecules (4g and 4l) demonstrated reasonable level of safety. The 4e, 4g, 4h, 4j, 4l, 4m and 4n compounds showed activity at time intervals of both 0.5 and 4.0 hrs.For this way, the most ofthe compounds showed an encouraging anticonvulsant effect at an interval of 0.5 h indicated they had an instant emergence but reduced duration of action.

In chemo shock test, compounds 4e, 4g, 4j, 4l, 4m and 4n display behavior indicative of their ability to inhibit seizure spread at maximum dose during half an hour, signifying that fast onset but reduced duration of action. Only three molecules 4d, 4e and 4j became vigorous after prolonged operation duration of 4.0 hrs. At both time intervals, only two compound 4e and 4j displayed action at maximum dose level.

Rotarod test used for the study of neurotoxicity to assessment undesired effects like sedation and ataxia induced through the compounds. Compounds 4h, 4l and 4o showed no toxicity at the maximum doses. At 0.5 and 4.0 hrs no any molecules were toxic, while 4d, 4e, 4g and 4n showed toxicity at 0.5 hrs and no toxicity at 4.0 hrs. Some 4b, 4f, 4j and 4m compounds demonstrated delayed toxicity, i.e. toxicity after only 4.0 hours which is equivalent to carbamazepine (300mg/kg). Most of the compounds were however not as much of toxic than phenytoin (100mg/kg).

Compounds 4e, 4g, 4j, 4l, 4m and 4n were found to have more lipophilic activity with active anticonvulsants. Other molecules were fewer lipophilic and were less active.

Conclusion

Fifteen new triazolo thiadiazoles have been made and subjected for anticonvulsant movement by MES and scPTZ methods. All molecules exposed anticonvulsant action on MES screen except 4a, 4f and 4k. The primary MES screening compounds 4e, 4g, 4h, 4j, 4l, 4m and 4n displayed activity against seizures at both 0.5 and 4.0 hours, approving their potential value as per prototypic molecules. Anticonvulsant activity records exposed that most compounds exhibited notable reduction in the extender process of the hind limb tonic convulsion and molecules 4e, 4j, 4m and 4n were to be the greatest effective. What’s more, the anticonvulsant activities of different compounds contemplated have been seen as abundant less successful than standard drugs. It appears that the existence of halo substituted aryl at benzoxazole moiety(such as chloro and bromo) and alkyl group attached to the triazolo thiadiazole ring on the aryl ring showed the strongest anticonvulsant activity and favorable high safety.Some compounds such as 4e, 4g, 4j, 4l, 4m and 4nhad high lipid character and were high active. Other candidates were also lipophilic, but were less active in MES screening.A significant lot of the formerly stated compounds have shown an advanced level of safety and could have a potential duty apparently.

Acknowledgement

Authors are extremely indebted to IIT Delhi and Jamia Hamdard University for the spectral study of the synthesized molecules. We are also grateful for finalizing the assessment by adopted the Antiepileptic Drug Development Program.

Conflict of Interest

No conflict of interest occurs between authors.

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